ALBERT

Beschreibung:    Exome sequencing identifies thousands of DNA variants and a proportion of these are involved in disease. Genotypes derived from exome sequences provide particularly high-resolution coverage enabling study of the linkage disequilibrium structure of individual genes. The extent and strength of linkage disequilibrium reflects the combined influences of mutation, recombination, selection and population history. By constructing linkage disequilibrium maps of individual genes, we show that genes containing OMIM-listed disease variants are significantly under - represented amongst genes with complete or very strong linkage disequilibrium ( P  = 0.0004). In contrast, genes with disease variants are significantly over - represented amongst genes with levels of linkage disequilibrium close to the average for genes not known to contain disease variants ( P  = 0.0038). Functional clustering reveals, amongst genes with particularly strong linkage disequilibrium, significant enrichment of essential biological functions (e.g. phosphorylation, cell division, cellular transport and metabolic processes). Strong linkage disequilibrium, corresponding to reduced haplotype diversity, may reflect selection in utero against deleterious mutations which have profound impact on the function of essential genes. Genes with very weak linkage disequilibrium show enrichment of functions requiring greater allelic diversity (e.g. sensory perception and immune response). This category is not enriched for genes containing disease variation. In contrast, there is significant enrichment of genes containing disease variants amongst genes with more average levels of linkage disequilibrium. Mutations in these genes may less likely lead to in utero lethality and be subject to less intense selection. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1243-6 Authors Jane Gibson, Genetic Epidemiology and Genomic informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Duthie Building (808), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD UK William Tapper, Genetic Epidemiology and Genomic informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Duthie Building (808), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD UK Sarah Ennis, Genetic Epidemiology and Genomic informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Duthie Building (808), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD UK Andrew Collins, Genetic Epidemiology and Genomic informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Duthie Building (808), Southampton General Hospital, Tremona Road, Southampton, SO16 6YD UK Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Colorectal cancer (CRC), one of the most frequent neoplasias worldwide, has both genetic and environmental causes. As yet, however, gene–environment (G × E) interactions in CRC have been studied mostly for a small number of candidate genes only. Therefore, we investigated the possible interaction, in CRC etiology, between single-nucleotide polymorphisms (SNPs) on the one hand, and overweight, smoking and alcohol consumption on the other, at a genome-wide level. To this end, we adopted a two-tiered approach comprising a case-only screening stage I (314 cases) and a case–control validation stage II (259 cases, 1,002 controls). Interactions with the smallest p value in stage I were verified in stage II using multiple logistic regression analysis adjusted for sex and age. In addition, we specifically studied known CRC-associated SNPs for possible G × E interactions. Upon adjustment for sex and age, and after allowing for multiple testing, however, only a single SNP (rs1944511) was found to be involved in a statistically significant interaction, namely with overweight (multiplicity-corrected p  = 0.042 in stage II). Several other G × E interactions were nominally significant but failed correction for multiple testing, including a previously reported interaction between rs9929218 and alcohol consumption that also emerged in our candidate SNP study (nominal p  = 0.008). Notably, none of the interactions identified in our genome-wide analysis was with a previously reported CRC-associated SNP. Our study therefore highlights the potential of an “agnostic” genome-wide approach to G × E analysis. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-012-1239-2 Authors Sabine Siegert, Section of Epidemiology, Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany Jochen Hampe, Department of General Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany Clemens Schafmayer, Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany Witigo von Schönfels, Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany Jan-Hendrik Egberts, Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany Asta Försti, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Bowang Chen, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Jesús Lascorz, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Kari Hemminki, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany Andre Franke, Institute of Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany Michael Nothnagel, Institute of Medical Informatics and Statistics, Christian-Albrechts University Kiel, Brunswiker Straße 10, 24105 Kiel, Germany Ute Nöthlings, Section of Epidemiology, Institute of Experimental Medicine, Christian-Albrechts University Kiel, Kiel, Germany Michael Krawczak, Institute of Medical Informatics and Statistics, Christian-Albrechts University Kiel, Brunswiker Straße 10, 24105 Kiel, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Leon E. Rosenberg and Diane Drobnis Rosenberg: Human Genes and Genomes: Science, Health, Society Content Type Journal Article Category Book Review Pages 1-1 DOI 10.1007/s00439-012-1242-7 Authors Arveen Kamath, Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Bone and muscle, two major tissue types of musculoskeletal system, have strong genetic determination. Abnormality in bone and/or muscle may cause musculoskeletal diseases such as osteoporosis and sarcopenia. Bone size phenotypes (BSPs), such as hip bone size (HBS), appendicular bone size (ABS), are genetically correlated with body lean mass (mainly muscle mass). However, the specific genes shared by these phenotypes are largely unknown. In this study, we aimed to identify the specific genes with pleiotropic effects on BSPs and appendicular lean mass (ALM). We performed a bivariate genome-wide association study (GWAS) by analyzing ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) followed by a replication study in 2,286 unrelated US Caucasians (558 males and 1,728 females). We identified 14 interesting single nucleotide polymorphisms (SNPs) that may contribute to variation of both BSPs and ALM, with p values 〈10 −6 in discovery stage. Among them, the association of three SNPs ( rs2507838 , rs7116722 , and rs11826261 ) in/near GLYAT (glycine- N -acyltransferase) gene was replicated in US Caucasians, with p values ranging from 1.89 × 10 −3 to 3.71 × 10 −4 for ALM–ABS, from 5.14 × 10 −3 to 1.11 × 10 −2 for ALM–HBS, respectively. Meta-analyses yielded stronger association signals for rs2507838 , rs7116722 , and rs11826261 , with pooled p values of 1.68 × 10 −8 , 7.94 × 10 −8 , 6.80 × 10 −8 for ALB–ABS and 1.22 × 10 −4 , 9.85 × 10 −5 , 3.96 × 10 −4 for ALM–HBS, respectively. Haplotype allele ATA based on these three SNPs was also associated with ALM–HBS and ALM–ABS in both discovery and replication samples. Interestingly, GLYAT was previously found to be essential to glucose metabolism and energy metabolism, suggesting the gene’s dual role in both bone development and muscle growth. Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1236-5 Authors Yan-Fang Guo, School of Basic Medical Science, Institute of Bioinformatics, Southern Medical University, Guangzhou, 510515 People’s Republic of China Li-Shu Zhang, School of Science, College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China Yong-Jun Liu, Department of Biostatistics, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA 70112, USA Hong-Gang Hu, School of Science, College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China Jian Li, Department of Biostatistics, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA 70112, USA Qing Tian, Department of Biostatistics, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA 70112, USA Ping Yu, Department of Biostatistics, School of Public Health and Tropical Medicine, Center for Bioinformatics and Genomics, Tulane University, New Orleans, LA 70112, USA Feng Zhang, The Key Laboratory of Biomedical Information Engineering, Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049 People’s Republic of China Tie-Lin Yang, The Key Laboratory of Biomedical Information Engineering, Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049 People’s Republic of China Yan Guo, The Key Laboratory of Biomedical Information Engineering, Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049 People’s Republic of China Xiang-Lei Peng, School of Science, College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China Meng Dai, School of Science, College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China Wei Chen, Department of Epidemiology, School of Public Health and Tropical Medicine, Center for Cardiovascular Health, Tulane University, New Orleans, LA 70112, USA Hong-Wen Deng, School of Science, College of Life Sciences and Bioengineering, Beijing Jiaotong University, Beijing, 100044 People’s Republic of China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Familial prostate cancer and HOXB13 founder mutations: geographic and racial/ethnic variations Content Type Journal Article Category Editorial Pages 1-4 DOI 10.1007/s00439-012-1226-7 Authors Henry T. Lynch, Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA Trudy G. Shaw, Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Bardet–Biedl syndrome (BBS) is a genetically heterogeneous disorder that is generally inherited in an autosomal recessive fashion. However, in some families, trans mutant alleles interact with the primary causal locus to modulate the penetrance and/or the expressivity of the phenotype. CCDC28B ( MGC1203 ) was identified as a second site modifier of BBS encoding a protein of unknown function. Here we report the first functional characterization of this protein and show it affects ciliogenesis both in cultured cells and in vivo in zebrafish. Consistent with this biological role, our in silico analysis shows that the presence of CCDC28B homologous sequences is restricted to ciliated metazoa. Depletion of Ccdc28b in zebrafish results in defective ciliogenesis and consequently causes a number of phenotypes that are characteristic of BBS and other ciliopathy mutants including hydrocephalus, left–right axis determination defects and renal function impairment. Thus, this work reports CCDC28B as a novel protein involved in the process of ciliogenesis whilst providing functional insight into the cellular basis of its modifier effect in BBS patients. Content Type Journal Article Category Original Investigation Pages 1-15 DOI 10.1007/s00439-012-1228-5 Authors Magdalena Cardenas-Rodriguez, Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay Daniel P. S. Osborn, Molecular Medicine Unit, Institute of Child Health, University College London, 30 Guilford St, London, WC1N 1EH UK Florencia Irigoín, Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay Martín Graña, Bioinformatics Unit, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay Héctor Romero, Laboratorio de Organización y Evolución del Genoma, Facultad de Ciencias/C.U.R.E., Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay Philip L. Beales, Molecular Medicine Unit, Institute of Child Health, University College London, 30 Guilford St, London, WC1N 1EH UK Jose L. Badano, Human Molecular Genetics Laboratory, Institut Pasteur de Montevideo, Mataojo 2020, 11400 Montevideo, Uruguay Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2 / PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2 / PACRG . For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence ( P  = 1.1 × 10 −5 ) for association among Vietnamese patients. Next, we enrolled a case–control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture 〉80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy ( P  〈 10 −8 ). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1227-6 Authors Andrea Alter, McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Vinicius Medeiros Fava, McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Nguyen Thu Huong, Hospital for Dermato-Venereology, Nguyen Thong Street, District 3, Ho Chi Minh City, Vietnam Meenakshi Singh, Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, Ansari Nagar, 110029 New Delhi, India Marianna Orlova, McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Nguyen Van Thuc, Hospital for Dermato-Venereology, Nguyen Thong Street, District 3, Ho Chi Minh City, Vietnam Kiran Katoch, Central JALMA Institute of Leprosy and Other Infectious Diseases, Taj Ganj, 282001 Agra, India Vu Hong Thai, Hospital for Dermato-Venereology, Nguyen Thong Street, District 3, Ho Chi Minh City, Vietnam Nguyen Ngoc Ba, Hospital for Dermato-Venereology, Nguyen Thong Street, District 3, Ho Chi Minh City, Vietnam Laurent Abel, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Unit 980, Paris, France Narinder Mehra, Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, Ansari Nagar, 110029 New Delhi, India Alexandre Alcaïs, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Unit 980, Paris, France Erwin Schurr, McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P  = 9.9 × 10 −8 [odds ratio 4.42 (95 % confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring ( P  = 6.5 × 10 −6 ). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1229-4 Authors Jianfeng Xu, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Ethan M. Lange, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA Lingyi Lu, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Siqun L. Zheng, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Zhong Wang, Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA Stephen N. Thibodeau, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Lisa A. Cannon-Albright, University of Utah ICPCG Group, University of Utah School of Medicine, Salt Lake City, UT, USA Craig C. Teerlink, University of Utah ICPCG Group, University of Utah School of Medicine, Salt Lake City, UT, USA Nicola J. Camp, University of Utah ICPCG Group, University of Utah School of Medicine, Salt Lake City, UT, USA Anna M. Johnson, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA Kimberly A. Zuhlke, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA Janet L. Stanford, Fred Hutchinson Cancer Research Center (FHCRC) ICPCG Group, Seattle, WA, USA Elaine A. Ostrander, Fred Hutchinson Cancer Research Center (FHCRC) ICPCG Group, Seattle, WA, USA Kathleen E. Wiley, Johns Hopkins University ICPCG Group, Baltimore, MD, USA Sarah D. Isaacs, Johns Hopkins University ICPCG Group, Baltimore, MD, USA Patrick C. Walsh, Johns Hopkins University ICPCG Group, Baltimore, MD, USA Christiane Maier, University of Ulm ICPCG Group, University of Ulm, Ulm, Germany Manuel Luedeke, University of Ulm ICPCG Group, University of Ulm, Ulm, Germany Walther Vogel, University of Ulm ICPCG Group, University of Ulm, Ulm, Germany Johanna Schleutker, University of Tampere ICPCG Group, University of Tampere and Fimlab Laboratories, Tampere, Finland Tiina Wahlfors, University of Tampere ICPCG Group, University of Tampere and Fimlab Laboratories, Tampere, Finland Teuvo Tammela, University of Tampere ICPCG Group, University of Tampere and Fimlab Laboratories, Tampere, Finland Daniel Schaid, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Shannon K. McDonnell, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Melissa S. DeRycke, Mayo Clinic ICPGC Group, Mayo Clinic, Rochester, MN, USA Geraldine Cancel-Tassin, CeRePP ICPCG Group, Paris, France Olivier Cussenot, CeRePP ICPCG Group, Paris, France Fredrik Wiklund, Karolinska ICPCG Group, Karolinska Institutet, Stockholm, Sweden Henrik Grönberg, Karolinska ICPCG Group, Karolinska Institutet, Stockholm, Sweden Ros Eeles, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Doug Easton, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Zsofia Kote-Jarai, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Alice S. Whittemore, BC/CA/HI ICPCG Group, Stanford School of Medicine, Stanford, CA, USA Chih-Lin Hsieh, BC/CA/HI ICPCG Group, Stanford School of Medicine, Stanford, CA, USA Graham G. Giles, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK John L. Hopper, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Gianluca Severi, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK William J. Catalona, Northwestern University ICPCG Group, Chicago, IL, USA Diptasri Mandal, Louisiana State University ICPCG Group, New Orleans, LA, USA Elisa Ledet, Louisiana State University ICPCG Group, New Orleans, LA, USA William D. Foulkes, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Nancy Hamel, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Lovise Mahle, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Pal Moller, ACTANE (Anglo/Canadian/Texan/Australian/Norwegian/EU Biomed) Consortium ICPCG Group, Surrey, UK Isaac Powell, African American Hereditary Prostate Cancer ICPCG Group, Detroit, MI, USA Joan E. Bailey-Wilson, African American Hereditary Prostate Cancer ICPCG Group, Detroit, MI, USA John D. Carpten, African American Hereditary Prostate Cancer ICPCG Group, Detroit, MI, USA Daniela Seminara, National Cancer Institute, NIH, Bethesda, MD, USA Kathleen A. Cooney, University of Michigan ICPCG Group, University of Michigan Medical School, Ann Arbor, MI, USA William B. Isaacs, Johns Hopkins University ICPCG Group, Baltimore, MD, USA International Consortium for Prostate Cancer Genetics Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Adherents to the Jewish faith have resided in numerous geographic locations over the course of three millennia. Progressively more detailed population genetic analysis carried out independently by multiple research groups over the past two decades has revealed a pattern for the population genetic architecture of contemporary Jews descendant from globally dispersed Diaspora communities. This pattern is consistent with a major, but variable component of shared Near East ancestry, together with variable degrees of admixture and introgression from the corresponding host Diaspora populations. By combining analysis of monoallelic markers with recent genome-wide variation analysis of simple tandem repeats, copy number variations, and single-nucleotide polymorphisms at high density, it has been possible to determine the relative contribution of sex-specific migration and introgression to map founder events and to suggest demographic histories corresponding to western and eastern Diaspora migrations, as well as subsequent microevolutionary events. These patterns have been congruous with the inferences of many, but not of all historians using more traditional tools such as archeology, archival records, linguistics, comparative analysis of religious narrative, liturgy and practices. Importantly, the population genetic architecture of Jews helps to explain the observed patterns of health and disease-relevant mutations and phenotypes which continue to be carefully studied and catalogued, and represent an important resource for human medical genetics research. The current review attempts to provide a succinct update of the more recent developments in a historical and human health context. Content Type Journal Article Category Review Article Pages 1-9 DOI 10.1007/s00439-012-1235-6 Authors Harry Ostrer, Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA Karl Skorecki, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Rambam Health Care Campus, 8 Ha’Aliyah Street, 31096 Haifa, Israel Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Natural variation in human skin pigmentation is primarily due to genetic causes rooted in recent evolutionary history. Genetic variants associated with human skin pigmentation confer risk of skin cancer and may provide useful information in forensic investigations. Almost all previous gene-mapping studies of human skin pigmentation were based on categorical skin color information known to oversimplify the continuous nature of human skin coloration. We digitally quantified skin color into hue and saturation dimensions for 5,860 Dutch Europeans based on high-resolution skin photographs. We then tested an extensive list of 14,185 single nucleotide polymorphisms in 281 candidate genes potentially involved in human skin pigmentation for association with quantitative skin color phenotypes. Confirmatory association was revealed for several known skin color genes including HERC2 , MC1R , IRF4, TYR, OCA2, and ASIP . We identified two new skin color genes: genetic variants in UGT1A were significantly associated with hue and variants in BNC2 were significantly associated with saturation. Overall, digital quantification of human skin color allowed detecting new skin color genes. The variants identified in this study may also contribute to the risk of skin cancer. Our findings are also important for predicting skin color in forensic investigations. Content Type Journal Article Category Original Investigation Pages 1-12 DOI 10.1007/s00439-012-1232-9 Authors Leonie C. Jacobs, Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands Andreas Wollstein, Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Oscar Lao, Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Albert Hofman, Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands Caroline C. Klaver, Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands André G. Uitterlinden, Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands Tamar Nijsten, Department of Dermatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands Manfred Kayser, Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Fan Liu, Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Recent publications have found an association between variants of exostosin 2 ( EXT2 ) gene and the risk of type 2 diabetes in some population but not in others. In an attempt to address these inconsistencies, we investigated EXT2 variants in two independent cohorts, and conducted a literature-based meta-analysis. Through regression model, we assessed the relationship between the EXT2 single nucleotide polymorphisms (SNPs) (rs3740878, rs11037909 and rs1113132) and the risk of type 2 diabetes in Han Chinese population, including a total of 2,533 cases and 2,643 controls. We combined our data with that from previously published studies and performed a meta-analysis to evaluate the effect size of the gene. Consistent with some studies, we found marginal association for the rs3740878 (OR = 1.07, 95 % CI = 0.99, 1.16, p  = 0.09), rs11037909 (OR = 1.07, 95 % CI = 0.99, 1.16, p  = 0.08), and rs1113132 (OR = 1.08, 95 % CI = 1.00, 1.17, p  = 0.06) in our 2 cohorts. Meta-analysis, comprising 9,224 type 2 diabetes and 10,484 controls, revealed that three SNPs (rs3740878, rs11037909 and rs1113132) in EXT2 were significantly associated with type 2 diabetes (ORs range from 1.06 to 1.07, p  = 0.038, p  = 0.008 and p  = 0.005, respectively). Variation in the EXT2 locus appears to be associated with a small increase in the risk of type 2 diabetes. However, well-designed prospective studies with larger sample size and more ethnic groups are needed to further validate the results. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1231-x Authors Lei Liu, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Xu Yang, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Haoran Wang, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Guanglin Cui, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Yujun Xu, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Peihua Wang, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Gang Yuan, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Xiaojing Wang, School of Dental Medicine, Center for Craniofacial and Dental Genetics, University of Pittsburgh, Pittsburgh, PA 15219, USA Hu Ding, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Dao Wen Wang, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., 430030 Wuhan, People’s Republic of China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: McKinlay Gardner RJ, Sutherland GR, Shaffer LG: Chromosome abnormalities and genetic counselling Content Type Journal Article Category Book Review Pages 1-2 DOI 10.1007/s00439-012-1162-6 Authors John C. K. Barber, Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Common fragile sites (cFSs) are non-random chromosomal regions that are prone to breakage under conditions of replication stress. DNA damage and chromosomal alterations at cFSs appear to be critical events in the development of various human diseases, especially carcinogenesis. Despite the growing interest in understanding the nature of cFS instability, only a few cFSs have been molecularly characterised. In this study, we fine-mapped the location of FRA2H using six-colour fluorescence in situ hybridisation and showed that it is one of the most active cFSs in the human genome. FRA2H encompasses approximately 530 kb of a gene-poor region containing a novel large intergenic non-coding RNA gene (AC097500.2). Using custom-designed array comparative genomic hybridisation, we detected gross and submicroscopic chromosomal rearrangements involving FRA2H in a panel of 54 neuroblastoma, colon and breast cancer cell lines. The genomic alterations frequently involved different classes of long terminal repeats and long interspersed nuclear elements. An analysis of breakpoint junction sequence motifs predominantly revealed signatures of microhomology-mediated non-homologous recombination events. Our data provide insight into the molecular structure of cFSs and sequence motifs affected by their activation in cancer. Identifying cFS sequences will accelerate the search for DNA biomarkers and targets for individualised therapies. Content Type Journal Article Category Original Investigation Pages 1-15 DOI 10.1007/s00439-012-1165-3 Authors Lena M. Brueckner, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Evgeny Sagulenko, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Elisa M. Hess, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Diana Zheglo, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Anne Blumrich, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Manfred Schwab, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Larissa Savelyeva, Division of Tumor Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Combined oral contraceptives (COC) use is a unique risk factor for stroke in women, and may modify the associations between genetic polymorphisms and stroke. To investigate whether the genetic variants identified in a recent genome-wide association study (GWAS) could be replicated in Chinese women, as well as, whether related risk was different in COC users, 451 stroke cases and 831 age- and region-matched controls were recruited from our cohort. Genotyping of 3 SNPs (rs700651, rs10958409, and rs1333040) was performed by the polymerase chain reaction assay with TaqMan probes. The history of contraceptive use and relevant information were obtained from a face-to-face interview. Odds ratios (OR) with 95 % confidence interval (CI) were estimated under conditional logistic regression model after adjustment for cardiovascular covariates. Our study replicated the associations of rs10958409 and rs1333040, with the risk of stroke, especially hemorrhagic subtype, but failed to confirm association of rs700651. COC use was associated with a 1.56-fold (OR 1.56, 95 % CI 1.21–2.01) increased risk of stroke. COC users with rs10958409 GA/AA or rs1333040 CT/TT genotypes had an increased risk of overall stroke by 1.59-fold (OR 2.59, 95 % CI 1.59–4.19) and 3.24-fold (OR 4.24, 95 % CI 1.71–10.49), respectively, compared with the non-users with wild-type genotypes. Moreover, the risk of hemorrhagic stroke increased by 4.81- and 15.06-fold when risk allele carriers of rs10958409 or rs1333040 who took COC. Our results confirmed the associations of two GWAS SNPs, also suggested combination effects of these genetic variants and COC use on stroke risk. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-012-1161-7 Authors Chun Wang, NPFPC Contraceptives Adverse Reaction Monitoring Center, Jiangsu Institute of Planned Parenthood Research, 277 Feng Huang Xi Jie, Nanjing, 210036 China Ying Li, NPFPC Contraceptives Adverse Reaction Monitoring Center, Jiangsu Institute of Planned Parenthood Research, 277 Feng Huang Xi Jie, Nanjing, 210036 China Huiqiao Li, Department of Epidemiology and Biostatistics, Nanjing Medical University, 140 Han Zhong Road, Nanjing, 210029 China Tao Sun, Xuzhou Entry-exit Inspection and Quarantine Bureau, 130 Xi An Nan Road, Xuzhou, 221006 China Guangfu Jin, Department of Epidemiology and Biostatistics, Nanjing Medical University, 140 Han Zhong Road, Nanjing, 210029 China Zhiming Sun, NPFPC Contraceptives Adverse Reaction Monitoring Center, Jiangsu Institute of Planned Parenthood Research, 277 Feng Huang Xi Jie, Nanjing, 210036 China Jian Zhou, NPFPC Contraceptives Adverse Reaction Monitoring Center, Jiangsu Institute of Planned Parenthood Research, 277 Feng Huang Xi Jie, Nanjing, 210036 China Lei Ba, NPFPC Contraceptives Adverse Reaction Monitoring Center, Jiangsu Institute of Planned Parenthood Research, 277 Feng Huang Xi Jie, Nanjing, 210036 China Zhizheng Huang, Department of Epidemiology and Biostatistics, Nanjing Medical University, 140 Han Zhong Road, Nanjing, 210029 China Jianling Bai, Department of Epidemiology and Biostatistics, Nanjing Medical University, 140 Han Zhong Road, Nanjing, 210029 China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    African Pygmies are hunter-gatherer populations from the equatorial rainforest that present the lowest height averages among humans. The biological basis and the putative adaptive role of the short stature of Pygmy populations has been one of the most intriguing topics for human biologists in the last century, which still remains elusive. Worldwide convergent evolution of the Pygmy size suggests the presence of strong selective pressures on the phenotype. We developed a novel approach to survey the genetic architecture of phenotypes and applied it to study the genomic covariation between allele frequencies and height measurements among Pygmy and non-Pygmy populations. Among the regions that were most associated with the phenotype, we identified a significant excess of genes with pivotal roles in bone homeostasis, such as PPPT3B and the height associated SUPT3H - RUNX2 . We hypothesize that skeletal remodeling could be a key biological process underlying the Pygmy phenotype. In addition, we showed that these regions have most likely evolved under positive selection. These results constitute the first genetic hint of adaptive evolution in the African Pygmy phenotype, which is consistent with the independent emergence of the Pygmy height in other continents with similar environments. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-012-1157-3 Authors Isabel Mendizabal, Departament de Ciències de la Salut i de la Vida, Institut de Biologia Evolutiva (CSIC-UPF), Universitat Pompeu Fabra, 08003 Barcelona, Spain Urko M. Marigorta, Departament de Ciències de la Salut i de la Vida, Institut de Biologia Evolutiva (CSIC-UPF), Universitat Pompeu Fabra, 08003 Barcelona, Spain Oscar Lao, Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, 3015 GE Rotterdam, The Netherlands David Comas, Departament de Ciències de la Salut i de la Vida, Institut de Biologia Evolutiva (CSIC-UPF), Universitat Pompeu Fabra, 08003 Barcelona, Spain Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Several genome-wide association studies (GWASs) have reported associations between single nucleotide polymorphisms (SNPs) and uric acid concentrations or gout in a number of different ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of the qualitative trait gout, in the present study, the associations between two SNPs in the glucokinase (hexokinase 4) regulator ( GCKR ) gene and gout were assessed in a male Chinese Han population. The study population comprised 476 male gout patients and 465 male controls. Multiple PCR was performed using time-of-flight mass spectrometry (MALDI-TOF MS) to identify genotypes. Two SNPs, rs780093 and rs780094, located in intronic regions of the GCKR gene were found to be significantly associated with the development of gout. Thus, the association between the two GCKR SNPs and gout was replicated in the male Han Chinese population investigated in the present study. Furthermore, GCKR was identified as a novel candidate gene associated with gout. Content Type Journal Article Category Original Investigation Pages 1-5 DOI 10.1007/s00439-012-1151-9 Authors Jing Wang, Graduate School, Peking Union Medical College, Beijing, China Shiguo Liu, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Binbin Wang, Graduate School, Peking Union Medical College, Beijing, China Zhimin Miao, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Lin Han, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Nan Chu, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Kun Zhang, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Dongmei Meng, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Changgui Li, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Xu Ma, Graduate School, Peking Union Medical College, Beijing, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Approximately 40 single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk have been identified through genome-wide association studies (GWAS). However, these GWAS-identified PCa risk-associated SNPs can explain only a small proportion of heritability (~13%) of PCa risk. Gene–gene interaction is speculated to be one of the major factors contributing to the so-called missing heritability. To evaluate the gene–gene interaction and PCa risk, we performed a two-stage genome-wide gene–gene interaction scan using a novel statistical approach named “Boolean Operation-based Screening and Testing”. In the first stage, we exhaustively evaluated all pairs of SNP–SNP interactions for ~500,000 SNPs in 1,176 PCa cases and 1,101 control subjects from the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) study. No SNP–SNP interaction reached a genome-wide significant level of 4.4E−13. The second stage of the study involved evaluation of the top 1,325 pairs of SNP–SNP interactions ( P interaction 〈1.0E−08) implicated in CGEMS in another GWAS population of 1,964 PCa cases from the Johns Hopkins Hospital (JHH) and 3,172 control subjects from the Illumina iControl database. Sixteen pairs of SNP–SNP interactions were significant in the JHH population at a P interaction cutoff of 0.01. However, none of the 16 pairs of SNP–SNP interactions were significant after adjusting for multiple tests. The current study represents one of the first attempts to explore the high-dimensional etiology of PCa on a genome-wide scale. Our results suggested a list of SNP–SNP interactions that can be followed in other replication studies. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1148-4 Authors Sha Tao, Center for Genetic Epidemiology and Prevention, Van Andel Research Institute, Grand Rapids, MI, USA Junjie Feng, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Timothy Webster, Center for Genetic Epidemiology and Prevention, Van Andel Research Institute, Grand Rapids, MI, USA Guangfu Jin, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Fang-Chi Hsu, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Shyh-Huei Chen, Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA Seong-Tae Kim, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Zhong Wang, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Zheng Zhang, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Siqun L. Zheng, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA William B. Isaacs, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD, USA Jianfeng Xu, Center for Genetic Epidemiology and Prevention, Van Andel Research Institute, Grand Rapids, MI, USA Jielin Sun, Center for Cancer Genomics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I ( P  = 0.012, OR = 0.51; 95% confidence interval 0.30–0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry ( P meta  = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk ( P meta  = 0.010, OR = 0.77; 95% confidence interval 0.62–0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-012-1139-5 Authors Zhaoming Wang, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Hemang Parikh, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Jinping Jia, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Timothy Myers, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Meredith Yeager, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Kevin B. Jacobs, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Amy Hutchinson, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Laurie Burdett, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Arpita Ghosh, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Michael J. Thun, Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA Susan M. Gapstur, Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA W. Ryan Diver, Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA Jarmo Virtamo, Department of Chronic Disease Prevention, National Institute for Health and Welfare, 00300 Helsinki, Finland Demetrius Albanes, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Geraldine Cancel-Tassin, Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020 Paris, France Antoine Valeri, Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020 Paris, France Olivier Cussenot, Centre de Recherche pour les Pathologies Prostatiques (CeRePP), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, 75020 Paris, France Kenneth Offit, Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Box 192, 1275 York Avenue, New York, NY 10065, USA Ed Giovannucci, Channing Laboratory, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA Jing Ma, Channing Laboratory, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA Meir J. Stampfer, Channing Laboratory, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA J. Michael Gaziano, Channing Laboratory, Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA David J. Hunter, Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA Ana Dutra-Clarke, Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Box 192, 1275 York Avenue, New York, NY 10065, USA Tomas Kirchhoff, Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Box 192, 1275 York Avenue, New York, NY 10065, USA Michael Alavanja, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Laura B. Freeman, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Stella Koutros, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Robert Hoover, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Sonja I. Berndt, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Richard B. Hayes, Division of Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York, NY 10016, USA Ilir Agalliu, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NewYork, NY 10461, USA Robert D. Burk, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NewYork, NY 10461, USA Sholom Wacholder, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Gilles Thomas, Synergie-Lyon-Cancer, Universite Lyon 1, Centre Leon Berard, 69373 Lyon Cedex 08, France Laufey Amundadottir, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Lactase is the intestinal enzyme responsible for digestion of the milk sugar lactose. Lactase gene expression declines dramatically upon weaning in mammals and during early childhood in humans (lactase nonpersistence). In various ethnic groups, however, lactase persists in high levels throughout adulthood (lactase persistence). Genetic association studies have identified that lactase persistence in northern Europeans is strongly associated with a single nucleotide polymorphism (SNP) located 14 kb upstream of the lactase gene: −13910*C/T. To determine whether the −13910*T SNP can function in vivo to mediate lactase persistence, we generated transgenic mice harboring human DNA fragments with the −13910*T SNP or the ancestral −13910*C SNP cloned upstream of a 2-kb rat lactase gene promoter in a luciferase reporter construct. We previously reported that the 2-kb rat lactase promoter directs a post-weaning decline of luciferase transgene expression similar to that of the endogenous lactase gene. In the present study, the post-weaning decline directed by the rat lactase promoter is impeded by addition of the −13910*T SNP human DNA fragment, but not by addition of the −13910*C ancestral SNP fragment. Persistence of transgene expression associated with the −13910*T SNP represents the first in vivo data in support of a functional role for the −13910*T SNP in mediating the human lactase persistence phenotype. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1140-z Authors Lin Fang, Department of Pediatrics (Gastroenterology), Stanford University School of Medicine, 300 Pasteur Drive, Grant Building G-310, Stanford, CA 94305-5208, USA Jong Kun Ahn, Department of Pediatrics (Gastroenterology), Stanford University School of Medicine, 300 Pasteur Drive, Grant Building G-310, Stanford, CA 94305-5208, USA Dariusz Wodziak, Department of Pediatrics (Gastroenterology), Stanford University School of Medicine, 300 Pasteur Drive, Grant Building G-310, Stanford, CA 94305-5208, USA Eric Sibley, Department of Pediatrics (Gastroenterology), Stanford University School of Medicine, 300 Pasteur Drive, Grant Building G-310, Stanford, CA 94305-5208, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30–34 = 1.7 [0.7–4], ≥35 = 1.3 [0.5–3.3]; de novo vs. familial ORs 30–34 = 2.8 [1.0–8.4], ≥35 = 1.6 [0.6–4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-011-1126-2 Authors Melissa B. Mills, Department of Genetics, Stanford University School of Medicine/Lucile Packard Children’s Hospital, 300 Pasteur Drive, Boswell Building A097, Stanford, CA 94304, USA Louanne Hudgins, Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Drive, Boswell Building A097, Stanford, CA 94304, USA Raymond R. Balise, Health Research and Policy, Stanford University School of Medicine, Redwood Bldg. T213D, MC 5092, Stanford, CA 94305, USA David H. Abramson, Ophthalmic Oncology Service, Memorial Sloan-Kettering Cancer Center, 70 East 66th St., New York, NY 10065, USA Ruth A. Kleinerman, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, EPS 7044, 6120 Executive Blvd, Rockville, MD 20852, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Both taking folic acid-containing vitamins around conception and consuming food fortified with folic acid have been reported to reduce omphalocele rates. Genetic factors are etiologically important in omphalocele as well; our pilot study showed a relationship with the folate metabolic enzyme gene methylenetetrahydrofolate reductase ( MTHFR ). We studied 169 non-aneuploid omphalocele cases and 761 unaffected, matched controls from all New York State births occurring between 1998 and 2005 to look for associations with single nucleotide polymorphisms (SNPs) known to be important in folate, vitamin B12, or choline metabolism. In the total study population, variants in the transcobalamin receptor gene ( TCblR ), rs2232775 (p.Q8R), and the MTHFR gene, rs1801131 (c.1298A〉C), were significantly associated with omphalocele. In African-Americans, significant associations were found with SNPs in genes for the vitamin B12 transporter ( TCN2 ) and the vitamin B12 receptor ( TCblR ). A SNP in the homocysteine-related gene, betaine-homocysteine S -methyltransferase ( BHMT ), rs3733890 (p.R239Q), was significantly associated with omphalocele in both African-Americans and Asians. Only the TCblR association in the total population remained statistically significant if Bonferroni correction was applied. The finding that transcobalamin receptor ( TCblR ) and transporter ( TCN2 ) SNPs and a BHMT SNP were associated with omphalocele suggests that disruption of methylation reactions, in which folate, vitamin B12, and homocysteine play critical parts, may be a risk factor for omphalocele. Our data, if confirmed, suggest that supplements containing both folic acid and vitamin B12 may be beneficial in preventing omphaloceles. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-011-1117-3 Authors James L. Mills, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, 6100 Building, Room 7B03, Bethesda, MD 20892, USA Tonia C. Carter, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, 6100 Building, Room 7B03, Bethesda, MD 20892, USA Denise M. Kay, Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA Marilyn L. Browne, Congenital Malformations Registry, New York State Department of Health, Troy, NY 12180, USA Lawrence C. Brody, Genome Technology Branch, National Human Genome Research Institute, NIH, DHHS, Bethesda, MD 20892, USA Aiyi Liu, Division of Epidemiology, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, 6100 Building, Room 7B03, Bethesda, MD 20892, USA Paul A. Romitti, Department of Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA 52242, USA Michele Caggana, Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA Charlotte M. Druschel, Congenital Malformations Registry, New York State Department of Health, Troy, NY 12180, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    It is not well known whether genetic markers identified through genome-wide association studies (GWAS) confer similar or different risks across people of different ancestry. We screened a regularly updated catalog of all published GWAS curated at the NHGRI website for GWAS-identified associations that had reached genome-wide significance ( p  ≤ 5 × 10 −8 ) in at least one major ancestry group (European, Asian, African) and for which replication data were available for comparison in at least two different major ancestry groups. These groups were compared for the correlation between and differences in risk allele frequencies and genetic effects’ estimates. Data on 108 eligible GWAS-identified associations with a total of 900 datasets (European, n  = 624; Asian, n  = 217; African, n  = 60) were analyzed. Risk-allele frequencies were modestly correlated between ancestry groups, with 〉10% absolute differences in 75–89% of the three pairwise comparisons of ancestry groups. Genetic effect (odds ratio) point estimates between ancestry groups correlated modestly (pairwise comparisons’ correlation coefficients: 0.20–0.33) and point estimates of risks were opposite in direction or differed more than twofold in 57%, 79%, and 89% of the European versus Asian, European versus African, and Asian versus African comparisons, respectively. The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups. Content Type Journal Article Category Original Investigation Pages 1-15 DOI 10.1007/s00439-011-1124-4 Authors Evangelia E. Ntzani, Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece George Liberopoulos, Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece Teri A. Manolio, Office of Population Genomics, National Human Genome Research Institute, Bethesda, MD 20892-2152, USA John P. A. Ioannidis, Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Current genome-wide association studies (GWAS) use commercial genotyping microarrays that can assay over a million single nucleotide polymorphisms (SNPs). The number of SNPs is further boosted by advanced statistical genotype-imputation algorithms and large SNP databases for reference human populations. The testing of a huge number of SNPs needs to be taken into account in the interpretation of statistical significance in such genome-wide studies, but this is complicated by the non-independence of SNPs because of linkage disequilibrium (LD). Several previous groups have proposed the use of the effective number of independent markers ( M e ) for the adjustment of multiple testing, but current methods of calculation for M e are limited in accuracy or computational speed. Here, we report a more robust and fast method to calculate M e . Applying this efficient method [implemented in a free software tool named Genetic type 1 error calculator (GEC)], we systematically examined the M e , and the corresponding p -value thresholds required to control the genome-wide type 1 error rate at 0.05, for 13 Illumina or Affymetrix genotyping arrays, as well as for HapMap Project and 1000 Genomes Project datasets which are widely used in genotype imputation as reference panels. Our results suggested the use of a p -value threshold of ~10 −7 as the criterion for genome-wide significance for early commercial genotyping arrays, but slightly more stringent p -value thresholds ~5 × 10 −8 for current or merged commercial genotyping arrays, ~10 −8 for all common SNPs in the 1000 Genomes Project dataset and ~5 × 10 −8 for the common SNPs only within genes. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-011-1118-2 Authors Miao-Xin Li, Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong Juilian M. Y. Yeung, Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong Stacey S. Cherny, Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong Pak C. Sham, Department of Psychiatry, The University of Hong Kong, Pokfulam, Hong Kong Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Host immune response against Mycobacterium leprae plays an important role in providing resistance to infection and disease progression. Genome-wide linkage and association studies suggest the possibility of multiple risk loci within HLA (6p21.3) region. Any systematic study of relevance within the histocompatibility complex of importance in host immune response would be pertinent because of non-replication of the known loci and unavailable information on some of the unexplored genes and regions. A systematic scan was performed of the selected region involving LTA-TNF-LTB genes within 6p21.3 with a resolution of 1SNP/127 bp; and the SNPs in flanking BAT1, NFKBIL and BTNL2-DRA genes on the basis of their tag status or their presence in promoter/exonic regions with MAF of 〉5%. Nine SNPs located in BAT1 , LTA , TNF genes and BTNL2 - DRA interval showed strong association with leprosy susceptibility in two independent sets of North Indian population which was replicated in a geographically distinct East Indian population. Conditional logistic regression showed at least one functional SNP remaining significant in each gene, suggesting an independent role of each of the disease associated SNPs. In vitro reporter assay revealed that two SNPs located at BAT1 promoter and 13 kb upstream to LTA gene affected the transcription factor binding site, hence the gene expression. We unravel the role of unexplored immunologically important genes, BAT1 and BTNL2 , in addition to known LTA and TNF genes, and the haplotypes of the significantly associated SNPs therein, to understand susceptibility to the disease, leprosy and its differential severity. Content Type Journal Article Category Original Investigation Pages 1-14 DOI 10.1007/s00439-011-1114-6 Authors Shafat Ali, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Rupali Chopra, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Shweta Aggarwal, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Amit Kumar Srivastava, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Ponnusamy Kalaiarasan, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Dheeraj Malhotra, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Sailesh Gochhait, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Vijay K. Garg, Department of Dermatology and Sexually Transmitted Diseases, Maulana Azad Medical College, Lok Nayak Jai Prakash Hospital, New Delhi, 110002 India S. N. Bhattacharya, Department of Dermatology and Venereology, University College of Medical Sciences and GTB Hospital, Delhi, 110095 India Rameshwar N. K. Bamezai, National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067 India Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Advances in our ability to modify the mouse genome have enhanced our understanding of the genetic and neurobiological mechanisms contributing to addiction-related behaviors underlying substance use and abuse. These experimentally induced manipulations permit greater spatial and temporal specificity for modification of gene expression within specific cellular populations and during select developmental time periods. In this review, we consider the current mouse genetic model systems that have been employed to understand aspects of addiction and highlight significant conceptual advances achieved related to substance use and abuse. The mouse models reviewed herein include conventional knockout and knockin, conditional knockout, transgenic, inducible transgenic, mice suitable for optogenetic control of discrete neuronal populations, and phenotype-selected mice. By establishing a reciprocal investigatory relationship between genetic findings in humans and genomic manipulations in mice, a far better understanding of the discrete neuromechanisms underlying addiction can be achieved, which is likely to provide a strong foundation for developing and validating novel therapeutics for the treatment of substance abuse disorders. Content Type Journal Article Category Review Paper Pages 1-17 DOI 10.1007/s00439-011-1129-z Authors Christie D. Fowler, Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps, Florida, Jupiter, FL 33458, USA Paul J. Kenny, Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps, Florida, Jupiter, FL 33458, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Randall H. Morse (ed.): Chromatin remodelling: methods and protocols Content Type Journal Article Category Book Review Pages 1-1 DOI 10.1007/s00439-012-1166-2 Authors Raymond Waters, Institute of Cancer and Genetics, Medical School, Cardiff University, Heath Park, Cardiff, CF14 4XN UK Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    CD33 and MS4A6A genes play potential key roles in the pathogenesis of Alzheimer’s disease (AD). One recent genome-wide association study has revealed that the rs3865444 polymorphism in the CD33 gene and rs610932 polymorphism in the MS4A6A gene are associated with susceptibility to AD in Caucasians. To evaluate the relationship between the polymorphism of the CD33, MS4A6A gene and AD in the ethnic Chinese Han, we conducted a case–control study ( n  = 383, age 〉 54) to determine the prevalence of single-nucleotide polymorphism of two genes in patients with AD in Chinese population of Mainland, and clarified whether these polymorphisms are risk factors for AD. The prevalence of the allele (T) in the rs3865444 polymorphism of the CD33 gene and allele (C) in rs610932 polymorphism of the MS4A6A gene was significantly different in AD patients and control subjects ( P  〈 0.001, respectively), and the results were not influenced by age, gender, or APOE status. Our data revealed the allele (T) of the rs3865444 polymorphism of the CD33 gene and the allele (C) of the rs610932 polymorphism of the MS4A6A gene may contribute to AD risk in the Chinese Han population. Content Type Journal Article Category Original Investigation Pages 1-5 DOI 10.1007/s00439-012-1154-6 Authors Yu-Lei Deng, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Li-Hua Liu, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Ying Wang, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Hui-Dong Tang, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Ru-Jing Ren, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Wei Xu, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Jian-Fang Ma, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Li-Ling Wang, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Jun-Peng Zhuang, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Gang Wang, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Sheng-Di Chen, Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype × diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level × genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism. Content Type Journal Article Category Original Investigation Pages 1-9 DOI 10.1007/s00439-012-1150-x Authors Xiang Yang Zhang, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA Da Chun Chen, Center for Psychiatric Research, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China Mei Hong Xiu, Center for Psychiatric Research, Beijing HuiLongGuan Hospital, Beijing, People’s Republic of China Colin N. Haile, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA Xingguang Luo, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Ke Xu, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Hui Ping Zhang, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Lingjun Zuo, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Zhijun Zhang, Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, People’s Republic of China Xiangrong Zhang, Department of Neurology, Affiliated ZhongDa Hospital of Southeast University, Nanjing, People’s Republic of China Therese A. Kosten, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA Thomas R. Kosten, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Clopidogrel has been used to prevent recurrent ischemic events after acute coronary syndrome and/or coronary stent implantation. An impaired platelet response to this drug (residual high platelet reactivity) has been identified as a risk factor for recurrent ischemic events. The platelet response to clopidogrel is highly heritable (73%) suggesting a substantial genetic component. Two sequential cytochrome P450-dependent oxidative steps are required to convert clopidogrel to its active metabolite. The first step leads to the formation of 2-oxo-clopidogrel, which is then metabolized to the active metabolite. Cytochrome P450s are large highly polymorphic family of mono-oxygenases. Many alleles have been reported, and some of these are able to modify the activity of proteins, reducing or increasing the concentration of active metabolites and the drug effect. Loss-of-function variants in the hepatic cytochrome 2C19 (mainly *2 allele) system have been found to be the predominant genetic mediators of clopidogrel response. Variant carriers have higher treatment platelet reactivity and higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death. Although value of CYP2C19 genotyping has been demonstrated in ACS population treated with PCI, there is still a wide interindividual variability within each genotype to systematically advocate this genetic testing in clinical practice. The CYP2C19*2 variant only explained 12% of the platelet response to clopidogrel. In the near future, it is highly probable that additional gene variants or epigenetic phenomenon will emerge as significant contributors to clopidogrel response that will allow recommending genetic testing for routine use. The purpose of this review is to discuss the contribution of individual genetic differences responsible for variations of action and clopidogrel efficacy. Content Type Journal Article Category Review Paper Pages 1-12 DOI 10.1007/s00439-011-1130-6 Authors Thomas Cuisset, Department of Cardiology, CHU Timone, Marseille, France Pierre-Emmanuel Morange, Laboratory of Hematology, CHU Timone, Marseille, France Marie-Christine Alessi, Laboratory of Hematology, CHU Timone, Marseille, France Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Many smokers attempt to quit smoking but few are successful in the long term. The heritability of nicotine addiction and smoking relapse have been documented, and research is focused on identifying specific genetic influences on the ability to quit smoking and response to specific medications. Research in genetically modified cell lines and mice has identified nicotine acetylcholine receptor subtypes that mediate the pharmacological and behavioral effects of nicotine sensitivity and withdrawal. Human genetic association studies have identified single nucleotide polymorphisms (SNPs) in genes encoding nicotine acetylcholine receptor subunits and nicotine metabolizing enzymes that influence smoking cessation phenotypes. There is initial promising evidence for a role in smoking cessation for SNPs in the β2 and α5/α3/β4 nAChR subunit genes; however, effects are small and not consistently replicated. There are reproducible and clinically significant associations of genotypic and phenotypic measures of CYP2A6 enzyme activity and nicotine metabolic rate with smoking cessation as well as response to nicotine replacement therapies and bupropion. Prospective clinical trials to identify associations of genetic variants and gene–gene interactions on smoking cessation are needed to generate the evidence base for both medication development and targeted therapy approaches based on genotype. Content Type Journal Article Category Review Paper Pages 1-20 DOI 10.1007/s00439-012-1143-9 Authors Allison B. Gold, Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, PA 19104, USA Caryn Lerman, Center for Interdisciplinary Research on Nicotine Addiction, University of Pennsylvania, 3535 Market Street, Suite 4100, Philadelphia, PA 19104, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Drug abuse and dependence are multifaceted disorders with complex genetic underpinnings. Identifying specific genetic correlates is challenging and may be more readily accomplished by defining endophenotypes specific for addictive disorders. Symptoms and syndromes, including acute drug response, consumption, preference, and withdrawal, are potential endophenotypes characterizing addiction that have been investigated using model organisms. We present a review of major genes involved in serotonergic, dopaminergic, GABAergic, and adrenoreceptor signaling that are considered to be directly involved in nicotine, opioid, cannabinoid, and ethanol use and dependence. The zebrafish genome encodes likely homologs of the vast majority of these loci. We also review the known expression patterns of these genes in zebrafish. The information presented in this review provides support for the use of zebrafish as a viable model for studying genetic factors related to drug addiction. Expansion of investigations into drug response using model organisms holds the potential to advance our understanding of drug response and addiction in humans. Content Type Journal Article Category Review Paper Pages 1-32 DOI 10.1007/s00439-011-1128-0 Authors Eric W. Klee, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA Henning Schneider, Department of Biology, DePauw University, 1 E. Hanna St, Greencastle, IN 46135, USA Karl J. Clark, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA Margot A. Cousin, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA Jon O. Ebbert, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA W. Michael Hooten, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA Victor M. Karpyak, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA David O. Warner, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA Stephen C. Ekker, Mayo Clinic, Mayo Addiction Research Center, 200 First St SW, Rochester, MN 55905, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Abnormalities in type III collagen in the arterial walls cause certain familial intracranial aneurysms (IAs); however, it remains unknown whether COL3A1 variants contribute to the risk of sporadic IAs. To study whether COL3A1 variants are associated with sporadic IAs, the association of COL3A1 variants with sporadic IAs was tested in 298 cases and 488 controls, replicated in an independent population of 192 cases and 1,690 controls, and further verified in 633 patients with intra-cerebral hemorrhage, 1,074 hypertensives, and 1,883 controls. We found that allele A of SNP rs1800255 conferred a 1.71-fold increased risk for IAs (adjusted odds ratio: OR = 1.71, 95% confidence interval: CI 1.19–2.45, P  = 0.004) and results in an amino acid change of Ala698Thr, which led to a lower thermal stability of the peptide. These results were confirmed in the independent study. The associations were independent of the presence of hemorrhagic stroke and hypertension. These results support the view that the functional variant of COL3A1 is genetic risk factors for IAs in the Chinese population. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1138-6 Authors Jingzhou Chen, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, 100037 People’s Republic of China Yufang Zhu, Department of Surgery, Shandong Tumor Hospital, Jinan, 250117 People’s Republic of China Yuhua Jiang, Department of Interventional Neurosurgery, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, 6, Tiantan, Xili, Beijing, 100050 People’s Republic of China Hui Yu, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, 100037 People’s Republic of China Kai Sun, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, 100037 People’s Republic of China Weihua Song, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, 100037 People’s Republic of China Liming Luan, Department of Neurosurgery, Shandong Provincial Hospital, Shandong University, 324 Jingwuweiqi Road, Jinan, 250021 Shandong, People’s Republic of China Kejia Lou, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, 100037 People’s Republic of China Youxiang Li, Department of Interventional Neurosurgery, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, 6, Tiantan, Xili, Beijing, 100050 People’s Republic of China Peng Jiang, Department of Interventional Neurosurgery, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, 6, Tiantan, Xili, Beijing, 100050 People’s Republic of China Qi Pang, Department of Neurosurgery, Shandong Provincial Hospital, Shandong University, 324 Jingwuweiqi Road, Jinan, 250021 Shandong, People’s Republic of China Rutai Hui, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing, 100037 People’s Republic of China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Genome-wide association studies of Parkinson’s disease (PD) have recently identified a new susceptibility locus GAK (PARK17) (rs1564282 variant) in subjects of European ancestry. Its role in other races is still unclear. The potential differences of the clinical characteristics between carriers and non-carriers have not been examined in detail. Using a case–control methodology, we analyzed the GAK rs1564282 variant in an ethnic Han Chinese population and conducted a meta-analysis combining our result and available published data. A total of 1,574 ethnic Han Chinese study subjects comprising 812 sporadic PD patients and 762 control individuals were included. The minor allele frequency was significantly different at SNP rs1564282 between the cases and the controls (OR = 1.59, 95% CI = 1.09, 1.69, P  = 0.007) in the overall PD population. Subjects with CT + TT genotypes have an increased risk (OR = 1.34, 95% CI = 1.05, 1.72, P  = 0.017) compared to those with CC genotype. A meta-analysis revealed that the frequency of carrier's genotypes was significantly higher in PD than in control subjects (OR = 1.31, 95% CI = 1.19, 1.44, P  〈 0.00001). The gender, age of onset, Hoehn–Yahr stage and UPDRS scores and clinical features were similar between carriers and non-carriers. In conclusion, we demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of PD in Han Chinese patients from mainland China and the meta-analysis with European populations revealed a similar finding. However, carriers cannot be distinguished from non-carriers based on their clinical features or motor severity. Functional studies of GAK to unravel its role in the pathophysiologic pathway of PD will be useful. Content Type Journal Article Category Original Investigation Pages 1-5 DOI 10.1007/s00439-011-1133-3 Authors Nan-Nan Li, Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China Xue-Li Chang, Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China Xue-Ye Mao, Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China Jin-Hong Zhang, Department of Internal Medicine, Wangjiang Hospital, Sichuan University, Chengdu, 610041 Sichuan, China Dong-Mei Zhao, Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China Eng-King Tan, Department of Neurology, Singapore General Hospital, Outram Road, Singapore, 169608 Singapore Rong Peng, Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments. Previous studies have identified several genes involved in skin pigmentation differences among African, Asian, and European populations. However, none have examined skin pigmentation variation among Indigenous American populations, creating a critical gap in our understanding of skin pigmentation variation. This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans. Analysis was performed on two samples of Indigenous Americans genotyped on genome-wide SNP arrays. Using four tests for natural selection—locus-specific branch length (LSBL), ratio of heterozygosities (ln RH ), Tajima’s D difference, and extended haplotype homozygosity (EHH)—we identified 14 selection-nominated candidate genes (SNCGs). SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground-level ultraviolet radiation. In addition to SLC24A5 and SLC45A2 , genes previously associated with European/non-European differences in skin pigmentation, OPRM1 and EGFR were associated with variation in skin pigmentation in New World populations for the first time. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-011-1135-1 Authors Ellen E. Quillen, Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA Marc Bauchet, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany Abigail W. Bigham, Department of Anthropology, University of Michigan, Ann Arbor, MI 48109, USA Miguel E. Delgado-Burbano, División Antropología, Facultad de Ciencias Naturales y Museo, Universidad Nacional de La Plata, Paseo del Bosque s/n., La Plata, B1900FWA Argentina Franz X. Faust, Department of Anthropology, Universidad del Cauca, Popayán, 949020 Colombia Yann C. Klimentidis, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA Xianyun Mao, Department of Statistics, Pennsylvania State University, University Park, PA 16802, USA Mark Stoneking, Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany Mark D. Shriver, Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The association between schizophrenia and tobacco smoking has been described in more than 1,000 articles, many with inadequate methodology. The studies on this association can focus on: (1) current smoking, ever smoking or smoking cessation; (2) non-psychiatric controls or controls with severe mental illness (e.g., bipolar disorder); and (3) higher smoking frequency or greater usage in smokers. The association with the most potential for genetic studies is that between ever daily smoking and schizophrenia; it may reflect a shared genetic vulnerability. To reduce the number of false-positive genes, we propose a three-stage approach derived from epidemiological knowledge. In the first stage, only genetic variations associated with ever daily smoking that are simultaneously significant within the non-psychiatric controls, the bipolar disorder controls and the schizophrenia cases will be selected. Only those genetic variations that are simultaneously significant in the three hypothesis tests will be tested in the second stage, where the prevalence of the genes must be significantly higher in schizophrenia than in bipolar disorder, and significantly higher in bipolar disorder than in controls. The genes simultaneously significant in the second stage will be included in a third stage where the gene variations must be significantly more frequent in schizophrenia patients who did not start smoking daily until their 20s (late start) versus those who had an early start. Any genetic approach to psychiatric disorders may fail if attention is not given to comorbidity and epidemiological studies that suggest which comorbidities are likely to be explained by genetics and which are not. Our approach, which examines the results of epidemiological studies on comorbidities and then looks for genes that simultaneously satisfy epidemiologically suggested sets of hypotheses, may also apply to the study of other major illnesses. Content Type Journal Article Category Review Paper Pages 1-25 DOI 10.1007/s00439-011-1122-6 Authors Jose de Leon, University of Kentucky Mental Health Research Center at Eastern State Hospital, 627 West Fourth St., Lexington, KY 40508, USA Francisco J. Diaz, Department of Biostatistics, The University of Kansas Medical Center, Kansas City, KS, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    While substance abuse disorders only occur in humans, mice and other model organisms can make valuable contributions to genetic studies of these disorders. In this review, we consider a few specific examples of how model organisms have been used in conjunction with studies in humans to study the role of genetic factors in substance use disorders. In some examples genes that were first discovered in mice were subsequently studied in humans. In other examples genes or specific polymorphisms in genes were first studied in humans and then modeled in mice. Using anatomically and temporally specific genetic, pharmacological and other environmental manipulations in conjunction with histological analyses, mechanistic insights that would be difficult to obtain in humans have been obtained in mice. We hope these examples illustrate how novel biological insights about the effect of genes on substance use disorders can be obtained when mouse and human genetic studies are successfully integrated. Content Type Journal Article Category Review Paper Pages 1-9 DOI 10.1007/s00439-011-1123-5 Authors Abraham A. Palmer, Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA Harriet de Wit, Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL 60637, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The alcohol dehydrogenase 1C (ADH1C) subunit is an important member of the alcohol dehydrogenase family, a set of genes that plays a major role in the catabolism of ethanol. Numerous association studies have provided compelling evidence that ADH1C gene variation (formerly ADH3 ) is associated with altered genetic susceptibility to alcoholism and alcohol-related liver disease, cirrhosis, or pancreatitis. However, the results have been inconsistent, partially, because each study involved a limited number of subjects, and some were underpowered. Using cumulative data over the past two decades, this meta-analysis (6,796 cases and 6,938 controls) considered samples of Asian, European, African, and Native American origins to examine whether the aggregate genotype provide statistically significant evidence of association. The results showed strong evidence of association between ADH1C Ile350Val (rs698, formerly ADH1C *1/*2) and alcohol dependence (AD) and abuse in the combined studies. The overall allelic (Val vs. Ile or *2 vs. *1) P value was 1 × 10 −8 and odds ratio (OR) was 1.51 (1.31, 1.73). The Asian populations produced stronger evidence of association with an allelic P value of 4 × 10 −33 [OR 2.14 (1.89, 2.43)] with no evidence of heterogeneity, and the dominant and recessive models revealed even stronger effect sizes. The strong evidence remained when stricter criteria and sub-group analyses were applied, while Asians always showed stronger associations than other populations. Our findings support that ADH1C Ile may lower the risk of AD and alcohol abuse as well as alcohol-related cirrhosis in pooled populations, with the strongest and most consistent effects in Asians. Content Type Journal Article Category Original Investigation Pages 1-14 DOI 10.1007/s00439-012-1163-5 Authors Dawei Li, Department of Psychiatry, School of Medicine, Yale University, 300 George Street, Suite 503, New Haven, CT 06511, USA Hongyu Zhao, Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, CT 06511, USA Joel Gelernter, Department of Psychiatry, School of Medicine, Yale University, 300 George Street, Suite 503, New Haven, CT 06511, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Erratum to: Association between gout and polymorphisms in GCKR in male Han Chinese Content Type Journal Article Category Publisher's Erratum Pages 1-1 DOI 10.1007/s00439-012-1159-1 Authors Jing Wang, Graduate School, Peking Union Medical College, Beijing, China Shiguo Liu, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Binbin Wang, Graduate School, Peking Union Medical College, Beijing, China Zhimin Miao, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Lin Han, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Nan Chu, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Kun Zhang, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Dongmei Meng, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Changgui Li, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao Key Laboratory of Common Diseases Gout Laboratory, The Affiliated Hospital of the Medical College, Qingdao University, Qingdao, Shandong, China Xu Ma, Graduate School, Peking Union Medical College, Beijing, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Disease risk-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) have the potential to be used for disease risk prediction. An important feature of these risk-associated SNPs is their weak individual effect but stronger cumulative effect on disease risk. To date, a stable summary estimate of the joint effect of genetic variants on disease risk prediction is not available. In this study, we propose to use the graded response model (GRM), which is based on the item response theory, for estimating the individual risk that is associated with a set of SNPs. We compare the GRM with a recently proposed risk prediction model called cumulative relative risk (CRR). Thirty-three prostate cancer risk-associated SNPs were originally discovered in GWAS by December 2009. These SNPs were used to evaluate the performance of GRM and CRR for predicting prostate cancer risk in three GWAS populations, including populations from Sweden, Johns Hopkins Hospital, and the National Cancer Institute Cancer Genetic Markers of Susceptibility study. Computational results show that the risk prediction estimates of GRM, compared to CRR, are less biased and more stable. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1160-8 Authors Shyh-Huei Chen, Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Wells Fargo Center 23rd floor, Medical Center Blvd, Winston-Salem, NC 27157, USA Edward H. Ip, Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Wells Fargo Center 23rd floor, Medical Center Blvd, Winston-Salem, NC 27157, USA Jianfeng Xu, Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA Jielin Sun, Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA Fang-Chi Hsu, Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Wells Fargo Center 23rd floor, Medical Center Blvd, Winston-Salem, NC 27157, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Familial dilated cardiomyopathy is a primary myocardial disease that can result in the development of congestive heart failure and sudden cardiac death. Spontaneous animal models of familial dilated cardiomyopathy exist and the Doberman pinscher dog is one of the most commonly reported canine breeds. The objective of this study was to evaluate familial dilated cardiomyopathy in the Doberman pinscher dog using a genome-wide association study for a genetic alteration(s) associated with the development of this disease in this canine model. Genome-wide association analysis identified an area of statistical significance on canine chromosome 14 ( p raw  = 9.999e−05 corrected for genome-wide significance), fine-mapping of additional SNPs flanking this region localized a signal to 23,774,190–23,781,919 ( p  = 0.001) and DNA sequencing identified a 16-base pair deletion in the 5′ donor splice site of intron 10 of the pyruvate dehydrogenase kinase 4 gene in affected dogs ( p  〈 0.0001). Electron microscopy of myocardium from affected dogs demonstrated disorganization of the Z line, mild to moderate T tubule and sarcoplasmic reticulum dilation, marked pleomorphic mitochondrial alterations with megamitochondria, scattered mitochondria with whorling and vacuolization and mild aggregates of lipofuscin granules. In conclusion, we report the identification of a splice site deletion in the PDK4 gene that is associated with the development of familial dilated cardiomyopathy in the Doberman pinscher dog. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1158-2 Authors Kathryn M. Meurs, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA Sunshine Lahmers, Washington State University College of Veterinary Medicine, Pullman, WA, USA Bruce W. Keene, North Carolina State University College of Veterinary Medicine, Raleigh, NC, USA Stephen N. White, Washington State University College of Veterinary Medicine, Pullman, WA, USA Mark A. Oyama, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA Evan Mauceli, Broad Institute of MIT and Harvard, Cambridge, MA, USA Kerstin Lindblad-Toh, Broad Institute of MIT and Harvard, Cambridge, MA, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Leprosy is an ancient infectious disease, with over 200,000 affected people (mainly in Asia and Africa) being registered annually. Genetic factors may confer susceptibility to this disease. In the present study, we genotyped 12 genetic variants of the MRC1 gene and the IFNG gene in 527 Han Chinese with leprosy and 583 healthy individuals from Yunnan, China, to discern potential association of these two genes with leprosy. In particular, we aimed to validate the recently reported association of MRC1 variant rs1926736 (p.G396S) and IFNG variant rs2430561 (+874 T〉A) with leprosy, which were initially observed in Vietnamese and Brazilian populations, respectively. Our results failed to confirm the reported association between variants rs1926736 and rs2430561 and leprosy in Han Chinese. However, we found that variants rs692527 ( P  = 0.022) and rs34856358 ( P  = 0.022) of the MRC1 gene were associated with paucibacillary leprosy, and rs3138557 of the IFNG gene was significantly associated with multibacillary leprosy. The exact role of the MRC1 gene and the IFNG gene in leprosy awaits future study. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1153-7 Authors Dong Wang, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, 650223 Yunnan, China Jia-Qi Feng, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, 650223 Yunnan, China Yu-Ye Li, Department of Dermatology, The First Affiliated Hospital of Kunming Medical College, Kunming, 650032 Yunnan, China Deng-Feng Zhang, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, 650223 Yunnan, China Xiao-An Li, Yuxi City Center for Disease Control and Prevention, Yuxi, 653100 Yunnan, China Qing-Wei Li, School of Life Science, Liaoning Normal University, Dalian, 116081 Liaoning, China Yong-Gang Yao, Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, 650223 Yunnan, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The adiponutrin ( PNPLA3 ) rs738409 polymorphism has been found to be associated with susceptibility to non-alcoholic fatty liver disease (NAFLD) in various cohorts. We further investigated the association of this polymorphism with non-alcoholic steatohepatitis (NASH) severity and with histological features of NAFLD. A total of 144 biopsy-proven NAFLD patients and 198 controls were genotyped for PNPLA3 gene polymorphism (rs738409 C〉G). The biopsy specimens were histologically graded by a qualified pathologist. We observed an association of G allele with susceptibility to NAFLD in the pooled subjects (OR 2.34, 95% CI 1.69–3.24, p  〈 0.0001), and following stratification, in each of the three ethnic subgroups, namely Chinese, Indian and Malay (OR 1.94, 95% CI 1.12–3.37, p  = 0.018; OR 3.51, 95% CI 1.69–7.26, p  = 0.001 and OR 2.05, 95% CI 1.25–3.35, p  = 0.005, respectively). The G allele is associated with susceptibility to NASH (OR 2.64, 95% CI 1.85–3.75, p  〈 0.0001), with NASH severity (OR 1.85, 95% CI 1.05–3.26, p  = 0.035) and with presence of fibrosis (OR 1.95, 95% CI 1.17–3.26, p  = 0.013) but not with simple steatosis nor with other histological parameters. Although the serum triglyceride level is significantly higher in NAFLD patients compared to controls, the G allele is associated with decreased level of triglycerides ( p  = 0.029) in the NAFLD patients. Overall, the rs738409 G allele is associated with severity of NASH and occurence of fibrosis in patients with NAFLD. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-012-1141-y Authors Shamsul Mohd Zain, The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia Rosmawati Mohamed, Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia Sanjiv Mahadeva, Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia Phaik Leng Cheah, Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia Sanjay Rampal, Department of Social and Preventive Medicine, Faculty of Medicine, Julius Centre University of Malaya, University of Malaya, 50603 Kuala Lumpur, Malaysia Roma Choudhury Basu, Clinical Investigation Centre, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia Zahurin Mohamed, The Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Coexisting long QT gene mutations/polymorphisms in Tetralogy of Fallot (TOF) patients may aggravate the repolarization abnormality from cardiac repair. We investigated the impact of these genes on the risk of life-threatening events. Genetic variants of the three common long QT genes were identified from patients with repaired TOF. Life-threatening events were defined as sudden cardiac death and hemodynamic unstable ventricular arrhythmia. Biophysical characterization of the alleles of the genetic variants was performed using a whole-cell voltage clamp with expression in Xenopus oocytes. A total of 84 patients (56.0 % male with 1,215 patients-year follow-up) were enrolled. Six rare variants and six non-synonymous single nucleotide polymorphisms (SNPs) were found in 40 (47.6 %) patients. Life-threatening events occurred in five patients; four received implantable cardioverter defibrillator and one died of sudden cardiac death. Life-threatening events occurred more often in those with genetic variants than those without (5/40 vs. 0/44, P  = 0.021); particularly, the hERG or SCN5A gene mutations/polymorphisms (2/5 vs. 3/79, P  = 0.027 and 5/27 vs. 0/57, P  = 0.003, respectively). Among the five patients with life-threatening events, three had compound variants (hERG p.M645R/SCN5A p.R1193Q, hERG p.K897T/SCN5A p.H558R, and KVLQT1 p.G645S/SCN5A p.P1090L), that also increased the risk of events. Their QTc and JTc were all prolonged. Functional study of the novel variant (hERG gene p.M645R) from patients with life-threatening events revealed a dominant negative effect. In conclusion, in repaired TOF patients, coexisting long QT mutations/polymorphisms might have additive effects on the repolarization abnormality from surgery and thereby increase the risks of life-threatening events. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1156-4 Authors Shuenn-Nan Chiu, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan Mei-Hwan Wu, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan Ming-Jai Su, Department of Pharmacology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan Jou-Kou Wang, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan Ming-Tai Lin, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan Chien-Chih Chang, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan Hui-Wen Hsu, Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan Ching-Tsuen Shen, Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan Olivier Thériault, Centre de Recherche Université Laval Robert-Giffard, Quebec City, QC, Canada Mohamed Chahine, Centre de Recherche Université Laval Robert-Giffard, Quebec City, QC, Canada Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma ( p  = 7.3 × 10 −12 ); however, this association did not achieve genome-wide significance ( p  ≤ 10 −7 ) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [ n  = 2,529 cases; p  = 7.1 × 10 −8 ; allelic risk = 0.80, 95% confidence interval (CI) = 0.74–0.87]. There was also evidence of association with squamous cell carcinoma of the lung ( n  = 302 cases; p  = 0.037; allelic risk = 0.82, 95% CI = 0.67–0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1144-8 Authors H. Dean Hosgood, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Wen-Chang Wang, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Yun-Chul Hong, Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Jiu-Cun Wang, Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China Kexin Chen, Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, 300060 People’s Republic of China I-Shou Chang, National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan Chien-Jen Chen, Genomics Research Center, Academia Sinica, Taipei, Taiwan Daru Lu, Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China Zhihua Yin, Department of Epidemiology, School of Public Health, China Medical University, No 92 North Second Road, Heping District, Shenyang, 110001 People’s Republic of China Chen Wu, Departments of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Wei Zheng, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Institute for Medicine and Public Health, Vanderbilt University School of Medicine, Nashville, TN, USA Biyun Qian, Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, 300060 People’s Republic of China Jae Yong Park, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea Yeul Hong Kim, Genomic Research Center for Lung and Breast/Ovarian Cancers, Korea University Anam Hospital, Seoul, Republic of Korea Nilanjan Chatterjee, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Ying Chen, Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore Gee-Chen Chang, Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Chin-Fu Hsiao, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Meredith Yeager, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Ying-Huang Tsai, Department of Pulmonary and Critical Care, Chang Gung Memorial Hospital, Chia Yi, Taiwan Hu Wei, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Young Tae Kim, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea Wei Wu, Department of Epidemiology, School of Public Health, China Medical University, No 92 North Second Road, Heping District, Shenyang, 110001 People’s Republic of China Zhenhong Zhao, Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China Wong-Ho Chow, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Xiaoling Zhu, Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, 300060 People’s Republic of China Yen-Li Lo, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Sook Whan Sung, Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea Kuan-Yu Chen, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Jeff Yuenger, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Joo Hyun Kim, Department of Thoracic and Cardiovascular Surgery, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea Liming Huang, Departments of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Ying-Hsiang Chen, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Yu-Tang Gao, Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China Jin Hee Kim, Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Ming-Shyan Huang, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Tae Hoon Jung, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea Neil Caporaso, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Xueying Zhao, Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China Zhang Huan, Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, 300060 People’s Republic of China Dianke Yu, Departments of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Chang Ho Kim, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea Wu-Chou Su, Department of Internal Medicine, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan Xiao-Ou Shu, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Institute for Medicine and Public Health, Vanderbilt University School of Medicine, Nashville, TN, USA In-San Kim, Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea Bryan Bassig, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Yuh-Min Chen, Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan Sung Ick Cha, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea Wen Tan, Departments of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Hongyan Chen, Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China Tsung-Ying Yang, Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Jae Sook Sung, Genomic Research Center for Lung and Breast/Ovarian Cancers, Korea University Anam Hospital, Seoul, Republic of Korea Chih-Liang Wang, Department of Pulmonary and Critical Care, Chang Gung Memorial Hospital, Chia Yi, Taiwan Xuelian Li, Department of Epidemiology, School of Public Health, China Medical University, No 92 North Second Road, Heping District, Shenyang, 110001 People’s Republic of China Kyong Hwa Park, Genomic Research Center for Lung and Breast/Ovarian Cancers, Korea University Anam Hospital, Seoul, Republic of Korea Chong-Jen Yu, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Jeong-Seon Ryu, Department of Internal Medicine, Inha University College of Medicine, Incheon, Republic of Korea Yongbing Xiang, Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China Amy Hutchinson, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Jun Suk Kim, Genomic Research Center for Lung and Breast/Ovarian Cancers, Korea University Anam Hospital, Seoul, Republic of Korea Qiuyin Cai, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Institute for Medicine and Public Health, Vanderbilt University School of Medicine, Nashville, TN, USA Maria Teresa Landi, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Kyoung-Mu Lee, Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea Jen-Yu Hung, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Ju-Yeon Park, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea Margaret Tucker, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Chien-Chung Lin, Department of Internal Medicine, National Cheng Kung University Hospital and College of Medicine, Tainan, Taiwan Yangwu Ren, Department of Epidemiology, School of Public Health, China Medical University, No 92 North Second Road, Heping District, Shenyang, 110001 People’s Republic of China Reury-Perng Perng, Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan Chih-Yi Chen, Cancer Center, China Medical University Hospital, Taipei, Taiwan Li Jin, Ministry of Education Key Laboratory of Contemporary Anthropology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China Kun-Chieh Chen, Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan Yao-Jen Li, Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan Yu-Fang Chiu, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Fang-Yu Tsai, National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan Pan-Chyr Yang, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Joseph F. Fraumeni, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Adeline Seow, Department of Epidemiology and Public Health, National University of Singapore, Singapore, Singapore Dongxin Lin, Departments of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China Baosen Zhou, Department of Epidemiology, School of Public Health, China Medical University, No 92 North Second Road, Heping District, Shenyang, 110001 People’s Republic of China Stephen Chanock, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Chao Agnes Hsiung, Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Nathaniel Rothman, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Qing Lan, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., EPS 8118, MCS 7240, Bethesda, MD 20892-7240, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Dopamine plays a key role in reward behavior, yet the association of drug dependence as a chronic, relapsing disorder with the genes encoding the various dopaminergic receptor subtypes remains difficult to delineate. In the context of subsequent genome-wide association (GWAS) research and post-GWAS investigations, we summarize the novel data that link genes encoding molecules involved in the dopaminergic system (dopamine receptors, transporter and enzymes in charge of its metabolism) to drug addiction. Recent reports indicate that the heritability of drug addiction should be high enough to allow a significant role for a specific set of genes, and the available genetic studies, which might not be already conclusive because of the heterogeneity of designs, methods and recruited samples, should support the idea of a significant role of at least one gene related to dopaminergic system. Evolutionary changes in primates and non-primate animals of genes coding for molecules involved in dopaminergic system highlight why addictive disorders are mainly limited to humans. Restricting the analyses to more specific intermediate phenotypes (or endophenotypes) such as attention allocation, stress reactivity, novelty seeking, behavioral disinhibition and impulsivity, instead of the broad addictive disorder concept can be instrumental to identify novel genes associated with these traits in the context of genome-wide studies. Content Type Journal Article Category Review Paper Pages 1-20 DOI 10.1007/s00439-012-1145-7 Authors Philip Gorwood, Groupe Hospitalier Sainte-Anne, CMME, 100 rue de la Santé, 75014 Paris, France Yann Le Strat, INSERM U894 (Centre de Psychiatrie et Neurosciences), Paris, France Nicolas Ramoz, INSERM U894 (Centre de Psychiatrie et Neurosciences), Paris, France Caroline Dubertret, INSERM U894 (Centre de Psychiatrie et Neurosciences), Paris, France Jean-Marie Moalic, INSERM U894 (Centre de Psychiatrie et Neurosciences), Paris, France Michel Simonneau, INSERM U894 (Centre de Psychiatrie et Neurosciences), Paris, France Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Two primary chitinases have been identified in humans—acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host’s immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case–control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV 1 ) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV 1 and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV 1 . Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-011-1127-1 Authors F. Aminuddin, James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul’s Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada L. Akhabir, James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul’s Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada D. Stefanowicz, James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul’s Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada P. D. Paré, James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul’s Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada J. E. Connett, Division of Biostatistics, University of Minnesota, Minneapolis, USA N. R. Anthonisen, Faculty of Medicine, University of Manitoba, Winnipeg, Canada J. V. Fahy, Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA M. A. Seibold, Department of Medicine, National Jewish Health, Denver, CO, USA E. G. Burchard, Department of Bioengineering and Therapeutic Sciences, Lung Biology Center, Institute for Human Genetics, University of California, San Francisco, CA, USA C. Eng, Department of Bioengineering and Therapeutic Sciences, Lung Biology Center, Institute for Human Genetics, University of California, San Francisco, CA, USA A. Gulsvik, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway P. Bakke, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway M. H. Cho, Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA A. Litonjua, Channing Laboratory and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA D. A. Lomas, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK W. H. Anderson, GlaxoSmithKline Research and Development, Research Triangle Park, Durham, NC, USA T. H. Beaty, Johns Hopkins School of Public Health, Baltimore, MD, USA J. D. Crapo, Department of Medicine, National Jewish Health, Denver, CO, USA E. K. Silverman, Channing Laboratory and Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA A. J. Sandford, James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul’s Hospital, The University of British Columbia, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group ( P  = 0.42) or in the male group ( P  = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 ( df  = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E−35 ( df  = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-011-1131-5 Authors Yanbo Chen, National Lab of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing, 100005 P. R. China Jiexu Zhang, National Lab of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing, 100005 P. R. China Li Zhang, Health Human Resources Development Center, MOH, Beijing, China Yan Shen, National Lab of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing, 100005 P. R. China Qi Xu, National Lab of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, No.5 Dong Dan San Tiao, Beijing, 100005 P. R. China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders resulting in severe visual loss and blindness that have remained incurable till date. We report the mapping of the disease locus in a 3-generation family of Indian origin with autosomal dominant RP (ADRP). Diagnosis of RP and recruitment was made after a complete clinical evaluation of all members. Manifestations of the disease included night blindness with blurred central vision in some cases, loss of peripheral vision, and diffuse degeneration of the retinal pigment epithelium. Linkage analysis using microsatellite markers was carried out on 34 members (14 affected). After testing for linkage to known retinal dystrophy loci as well as a subsequent genome-wide analysis, we detected linkage to markers on chromosome 6q23: D6S262 at 130 cM, D6S457 (130 cM) and D6S1656 (131 cM) gave significant 2-point LOD scores of 3.0–3.8. Multipoint LOD scores of ≥3.0 were obtained for markers between 121 and 130 cM. Haplotype analysis with several markers in the same region on chromosome 6 shows a disease-cosegregating region of about 25 Mb between 109 and 135 Mb. There are no known RP genes in this interval, which contains 〉100 genes. This study provides evidence for a novel ADRP locus on chromosome 6q23. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-011-1115-5 Authors Chitra Kannabiran, Kallam Anji Reddy Molecular Genetics Laboratory, Hyderabad Eye Research Foundation, L.V. Prasad Eye Institute, L.V. Prasad Marg, Banjara Hills, Hyderabad, 500034 Andhra Pradesh, India Hardeep Pal Singh, Kallam Anji Reddy Molecular Genetics Laboratory, Hyderabad Eye Research Foundation, L.V. Prasad Eye Institute, L.V. Prasad Marg, Banjara Hills, Hyderabad, 500034 Andhra Pradesh, India Subhadra Jalali, Smt Kannuri Santhamma Retina-Vitreous Centre, L.V. Prasad Eye Institute, L.V. Prasad Marg, Banjara Hills, Hyderabad, 500034 Andhra Pradesh, India Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene ( ALDH2 ) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case–control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3 × 10 −56 and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys–lys + lys–glu vs. glu–glu) also showed strong association with P value of 1 × 10 −44 and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P  = 2 × 10 −28 for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-011-1116-4 Authors Dawei Li, Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06511, USA Hongyu Zhao, Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, CT 06511, USA Joel Gelernter, Department of Psychiatry, School of Medicine, Yale University, New Haven, CT 06511, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-011-1121-7 Authors Tiffany Renee Oliver, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Stuart W. Tinker, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Emily Graves Allen, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Natasha Hollis, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Adam E. Locke, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Lora J. H. Bean, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Reshmi Chowdhury, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA Ferdouse Begum, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA Mary Marazita, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA Vivian Cheung, Departments of Pediatrics and Genetics, University of Pennsylvania, Philadelphia, PA, USA Eleanor Feingold, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA Stephanie L. Sherman, Department of Human Genetics, Emory University School of Medicine, 615 Michael St, Suite 301, Whitehead Bldg, Atlanta, GA 30322, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F , are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by 〉100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by ~tenfold. Surprisingly, the V1727F mutant also displayed increased binding to α-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to α-dystroglycan, mimics non-neural (z−) agrin and are important determinants of the pathogenesis of the disease. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-011-1132-4 Authors Ricardo A. Maselli, Department of Neurology, University of California Davis, Davis, CA 95616, USA Jose M. Fernandez, Service of Clinical Neurophysiology, University Hospital of Vigo, Vigo (Pontevedra), Spain Juan Arredondo, Department of Neurology, University of California Davis, Davis, CA 95616, USA Carmen Navarro, Department of Pathology, University Hospital of Vigo and CIBERER (Centro de Investigacion Biomedica en Red en Enfermedades Raras), Vigo (Pontevedra), Spain Maian Ngo, Department of Neurology, University of California Davis, Davis, CA 95616, USA David Beeson, Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS UK Órla Cagney, Department of Neurology, University of California Davis, Davis, CA 95616, USA D. Colette Williams, Veterinary Medical Teaching Hospital, University of California Davis, Davis, CA 95616, USA Robert L. Wollmann, Department of Pathology, University of Chicago, Chicago, IL 60637, USA Vladimir Yarov-Yarovoy, Department of Physiology and Membrane Biology, University of California Davis, One Shields Ave., Davis, CA 95616, USA Michael J. Ferns, Department of Physiology and Membrane Biology, University of California Davis, One Shields Ave., Davis, CA 95616, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case–control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case–control GWAS are also associated with disease risk in HPC families. Content Type Journal Article Category Original Investigation Pages 1-9 DOI 10.1007/s00439-011-1136-0 Authors Guangfu Jin, Data Coordinating Center for the ICPCG and Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA Lingyi Lu, Data Coordinating Center for the ICPCG and Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA Kathleen A. Cooney, University of Michigan ICPCG Group, Ann Arbor, USA Anna M. Ray, University of Michigan ICPCG Group, Ann Arbor, USA Kimberly A. Zuhlke, University of Michigan ICPCG Group, Ann Arbor, USA Ethan M. Lange, University of Michigan ICPCG Group, Ann Arbor, USA Lisa A. Cannon-Albright, University of Utah ICPCG Group, Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA Nicola J. Camp, University of Utah ICPCG Group, Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA Craig C. Teerlink, University of Utah ICPCG Group, Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84108, USA Liesel M. FitzGerald, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA 98195, USA Janet L. Stanford, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, WA 98195, USA Kathleen E. Wiley, Johns Hopkins University ICPCG Group, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA Sarah D. Isaacs, Johns Hopkins University ICPCG Group, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA Patrick C. Walsh, Johns Hopkins University ICPCG Group, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA William D. Foulkes, Program in Cancer Genetics, McGill University, Montreal, QC H3T 1E2, Canada Graham G. Giles, Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, VIC 3053, Australia John L. Hopper, Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, VIC 3010, Australia Gianluca Severi, Cancer Epidemiology Centre, Cancer Council Victoria, Carlton, VIC 3053, Australia Ros Eeles, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK Doug Easton, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Cambridge, CB1 8RN UK Zsofia Kote-Jarai, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK Michelle Guy, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK Antje Rinckleb, Department of Urology, University of Ulm, Ulm, Germany Christiane Maier, Department of Urology, University of Ulm, Ulm, Germany Walther Vogel, Institute for Human Genetics, University of Ulm, Ulm, Germany Geraldine Cancel-Tassin, CeRePP ICPCG Group, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020 Paris, France Christophe Egrot, CeRePP ICPCG Group, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020 Paris, France Olivier Cussenot, CeRePP ICPCG Group, Hopital Tenon, Assistance Publique-Hopitaux de Paris, 75020 Paris, France Stephen N. Thibodeau, Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA Shannon K. McDonnell, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Daniel J. Schaid, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA Fredrik Wiklund, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Henrik Grönberg, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Monica Emanuelsson, Oncologic Centre, Umeå University, 90187 Umeå, Sweden Alice S. Whittemore, Department of Health Research and Policy, Stanford School of Medicine, Stanford, CA 94305, USA Ingrid Oakley-Girvan, Cancer Prevention Institute of California, 2201 Walnut Ave Suite 300, Fremont, CA 94538, USA Chih-Lin Hsieh, Department of Urology, University of Southern California, Los Angeles, CA 90089, USA Tiina Wahlfors, Institute of Biomedical Technology, University of Tampere, BioMediTech, Tampere, Finland Teuvo Tammela, Department of Urology, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland Johanna Schleutker, Department of Medical Biochemistry and Genetics, University of Turku, 20014 Turku, Finland William J. Catalona, Northwestern University ICPCG Group, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA S. Lilly Zheng, Data Coordinating Center for the ICPCG and Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA Elaine A. Ostrander, Cancer Genetics Branch, National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD 20892, USA William B. Isaacs, Johns Hopkins University ICPCG Group, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA Jianfeng Xu, Data Coordinating Center for the ICPCG and Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, NC 27157 USA International Consortium for Prostate Cancer Genetics Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The human genome is constantly subjected to evolutionary forces which shape its architecture. Insertions of mitochondrial DNA sequences into nuclear genome (NumtS) have been described in several eukaryotic species, including Homo sapiens and other primates. The ongoing process of the generation of NumtS has made them valuable markers in primate phylogenetic studies, as well as potentially informative loci for reconstructing the genetic history of modern humans. Here, we report the identification of 53 human-specific NumtS by inspection of the UCSC genome browser, showing that they may be direct insertions of mitochondrial DNA into the human nuclear DNA after the human-chimpanzee split. In silico analyses allowed us to identify 14 NumtS which are polymorphic in terms of their presence/absence within the human genome in individuals of different ancestry. The allele frequencies of these polymorphic NumtS were calculated for 1000 Genomes Project sequence data from 13 populations worldwide, and principal components analysis and hierarchical clustering methods allowed the detection of strong signals of geographical structure related to the genetic diversity of these loci. All identified polymorphic human-specific NumtS together with a tandemly duplicated NumtS have also been validated by PCR amplification on a panel of 60 samples belonging to five native populations worldwide, confirming the expected NumtS variability. On the basis of these findings, we have succeeded in depicting the landscape of variation of a series of NumtS in several ethnic groups, making an advance in their identification as useful markers in the study on human population genetics. Content Type Journal Article Category Original Investigation Pages 1-15 DOI 10.1007/s00439-011-1125-3 Authors Martin Lang, Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, U.O. Genetica Medica, Pad.11, Pol.S.Orsola-Malpighi, Università di Bologna, Via Massarenti 9, 40138 Bologna, Italy Marco Sazzini, Dipartimento di Biologia Evoluzionistica Sperimentale, Laboratorio di Antropologia Molecolare, Università di Bologna, 40138 Bologna, Italy Francesco Maria Calabrese, Dipartimento di Biochimica e Biologia Molecolare “E. Quagliariello”, Università di Bari, 70126 Bari, Italy Domenico Simone, Dipartimento di Biochimica e Biologia Molecolare “E. Quagliariello”, Università di Bari, 70126 Bari, Italy Alessio Boattini, Dipartimento di Biologia Evoluzionistica Sperimentale, Laboratorio di Antropologia Molecolare, Università di Bologna, 40138 Bologna, Italy Giovanni Romeo, Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, U.O. Genetica Medica, Pad.11, Pol.S.Orsola-Malpighi, Università di Bologna, Via Massarenti 9, 40138 Bologna, Italy Donata Luiselli, Dipartimento di Biologia Evoluzionistica Sperimentale, Laboratorio di Antropologia Molecolare, Università di Bologna, 40138 Bologna, Italy Marcella Attimonelli, Dipartimento di Biochimica e Biologia Molecolare “E. Quagliariello”, Università di Bari, 70126 Bari, Italy Giuseppe Gasparre, Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, U.O. Genetica Medica, Pad.11, Pol.S.Orsola-Malpighi, Università di Bologna, Via Massarenti 9, 40138 Bologna, Italy Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Animal studies have been instrumental in providing knowledge about the molecular and neural mechanisms underlying drug addiction. Recently, the fruit fly Drosophila melanogaster has become a valuable system to model not only the acute stimulating and sedating effects of drugs but also their more complex rewarding properties. In this review, we describe the advantages of using the fly to study drug-related behavior, provide a brief overview of the behavioral assays used, and review the molecular mechanisms and neural circuits underlying drug-induced behavior in flies. Many of these mechanisms have been validated in mammals, suggesting that the fly is a useful model to understand the mechanisms underlying addiction. Content Type Journal Article Category Review Paper Pages 1-17 DOI 10.1007/s00439-012-1146-6 Authors Karla R. Kaun, Department of Anatomy, University of California San Francisco, 1550 4th St, MC2822, San Francisco, CA 94158, USA Anita V. Devineni, Department of Anatomy, University of California San Francisco, 1550 4th St, MC2822, San Francisco, CA 94158, USA Ulrike Heberlein, Department of Anatomy, University of California San Francisco, 1550 4th St, MC2822, San Francisco, CA 94158, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    DNA repair genes play an important role in maintaining stability and integrity of genomic DNA. Polymorphisms in nucleotide excision repair genes may cause variations in DNA repair capacity phenotype and thus contribute to cancer risk. In this case–control study of 1,125 gastric cancer cases and 1,196 cancer-free controls, we investigated the association between three functional single nucleotide polymorphisms (SNPs, rs2296147T 〉 C, rs2094258C 〉 T and rs873601G 〉 A) in the xeroderma pigmentosum group G ( XPG ) gene and gastric cancer risk. We used the Taqman assays to genotype these three SNPs and logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). We found that only the rs873601A variant genotypes were associated with a significant higher risk for gastric adenocarcinoma (adjusted OR = 1.30, 95% CI = 1.03–1.64 for AA vs. GG and adjusted OR = 1.23, 95% CI = 1.01–1.49 for AA vs. GG/AG). Stratification analysis indicated that this risk was more pronounced in subgroups of older age (〉59 years), males, ever-smokers, and patients with NGCA. All these were not found for the other two SNPs (rs2296147T 〉 C and rs2094258C 〉 T). We then performed expression analysis using gastric cancer adjacent normal tissues from 141 patients and found that the A variant allele was associated with non-significantly reduced expression of XPG mRNA ( P trend  = 0.107). Further analysis using mRNA expression data from the HapMap suggested that the A allele was associated with significantly reduced expression of XPG mRNA in normal cell lines for 45 Chinese ( P trend  = 0.003) as well as for 261 subjects with different ethnicities ( P trend  = 0.001). These support the hypothesis that functional XPG variants may contribute to the risk of gastric cancer. Larger studies with different ethnic populations are warranted to validate our findings. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1152-8 Authors Jing He, Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032 China Li-Xin Qiu, Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032 China Meng-Yun Wang, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Rui-Xi Hua, Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032 China Ruo-Xin Zhang, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Hong-Ping Yu, Department of Epidemiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA Ya-Nong Wang, Department of Abdominal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China Meng-Hong Sun, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China Xiao-Yan Zhou, Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China Ya-Jun Yang, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China Jiu-Cun Wang, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China Li Jin, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China Qing-Yi Wei, Cancer Research Laboratory, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032 China Jin Li, Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032 China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    While pathogenic copy number variations (CNVs) in 15q11.2 were recently identified in Caucasian patients with idiopathic generalized epilepsies (IGEs), the epilepsy-associated gene(s) in this region is/are still unknown. Our study investigated whether the CNVs in 15q11.2 are associated with childhood absence epilepsy (CAE) in Chinese patients and whether the selective magnesium transporter NIPA2 gene affected by 15q11.2 microdeletions is a susceptive gene for CAE. We assessed IGE-related CNVs by Affymetrix SNP 5.0 microarrays in 198 patients with CAE and 198 controls from northern China, and verified the identified CNVs by high-density oligonucleotide-based CGH microarrays. The coding region and exon–intron boundaries of NIPA2 were sequenced in all 380 patients with CAE and 400 controls. 15q11.2 microdeletions were detected in 3 of 198 (1.5%) patients and in no controls. Furthermore, we identified point mutations or indel in a heterozygous state of the NIPA2 gene in 3 out of 380 patients, whereas they were absent in 700 controls ( P  = 0.043). These mutations included two novel missense mutations (c.532A〉T, p.I178F; c.731A〉G, p.N244S) and one small novel insertion (c.1002_1003insGAT, p.N334_335EinsD). No NIPA2 mutation was found in 400 normal controls. We first identified that NIPA2 , encoding a selective magnesium transporter, is a susceptible gene of CAE, and 15q11.2 microdeletions are important pathogenic CNVs for CAE with higher frequency in Chinese populations than that previously reported in Caucasians. The haploinsufficiency of NIPA2 may be a mechanism underlying the neurological phenotypes of 15q11.2 microdeletions. Content Type Journal Article Category Original Investigation Pages 1-8 DOI 10.1007/s00439-012-1149-3 Authors Yuwu Jiang, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Yuehua Zhang, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Pingping Zhang, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Tian Sang, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Feng Zhang, School of Life Sciences, Fudan University, Shanghai, China Taoyun Ji, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Qionghui Huang, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Han Xie, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Renqian Du, School of Life Sciences, Fudan University, Shanghai, China Bin Cai, CapitalBio Corporation-National Engineering Research Center for Beijing Biochip Technology, Beijing, China Haijuan Zhao, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Jingmin Wang, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Ye Wu, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Husheng Wu, Beijing Children’s Hospital, Beijing, China Keming Xu, Capital Institute of Pediatrics, Beijing, China Xiaoyan Liu, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Piu Chan, Department of Neurobiology and Neurology, Xuanwu Hospital of Capital Medical University, #45 Changchun Street, Beijing, 100053 China Xiru Wu, Department of Pediatrics, Peking University First Hospital, Beijing, 100034 China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Phenotypic variation results from variation in gene expression, which is modulated by genetic and/or epigenetic factors. To understand the molecular basis of human disease, interaction between genetic and epigenetic factors needs to be taken into account. The asthma-associated region 17q12-q21 harbors three genes, the zona pellucida binding protein 2 ( ZPBP2 ), gasdermin B ( GSDMB) and ORM1-like 3 ( ORMDL3 ), that show allele-specific differences in expression levels in lymphoblastoid cell lines (LCLs) and CD4+ T cells. Here, we report a molecular dissection of allele-specific transcriptional regulation of the genes within the chromosomal region 17q12-q21 combining in vitro transfection, formaldehyde-assisted isolation of regulatory elements, chromatin immunoprecipitation and DNA methylation assays in LCLs. We found that a single nucleotide polymorphism rs4795397 influences the activity of ZPBP2 promoter in vitro in an allele-dependent fashion, and also leads to nucleosome repositioning on the asthma-associated allele . However, variable methylation of exon 1 of ZPBP2 masks the strong genetic effect on ZPBP2 promoter activity in LCLs. In contrast, the ORMDL3 promoter is fully unmethylated, which allows detection of genetic effects on its transcription. We conclude that the cis -regulatory effects on 17q12-q21 gene expression result from interaction between several regulatory polymorphisms and epigenetic factors within the cis -regulatory haplotype region. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1142-x Authors Soizik Berlivet, Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada Sanny Moussette, Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada Manon Ouimet, Research Center, CHU Sainte-Justine, Montreal, QC, Canada Dominique J. Verlaan, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada Vonda Koka, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada Abeer Al Tuwaijri, Department of Human Genetics, McGill University, Montreal, QC, Canada Tony Kwan, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada Daniel Sinnett, Research Center, CHU Sainte-Justine, Montreal, QC, Canada Tomi Pastinen, McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada Anna K. Naumova, Department of Obstetrics and Gynecology, McGill University, Montreal, QC, Canada Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The evolutionary history of variation in the human Rh blood group system, determined by variants in the RHD and RHCE genes, has long been an unresolved puzzle in human genetics. Prior to medical treatments and interventions developed in the last century, the D-positive (RhD positive) children of D-negative (RhD negative) women were at risk for hemolytic disease of the newborn, if the mother produced anti-D antibodies following sensitization to the blood of a previous D-positive child. Given the deleterious fitness consequences of this disease, the appreciable frequencies in European populations of the responsible RHD gene deletion variant (for example, 0.43 in our study) seem surprising. In this study, we used new molecular and genomic data generated from four HapMap population samples to test the idea that positive selection for an as-of-yet unknown fitness benefit of the RHD deletion may have offset the otherwise negative fitness effects of hemolytic disease of the newborn. We found no evidence that positive natural selection affected the frequency of the RHD deletion. Thus, the initial rise to intermediate frequency of the RHD deletion in European populations may simply be explained by genetic drift/founder effect, or by an older or more complex sweep that we are insufficiently powered to detect. However, our simulations recapitulate previous findings that selection on the RHD deletion is frequency dependent and weak or absent near 0.5. Therefore, once such a frequency was achieved, it could have been maintained by a relatively small amount of genetic drift. We unexpectedly observed evidence for positive selection on the C allele of RHCE in non-African populations (on chromosomes with intact copies of the RHD gene) in the form of an unusually high F ST value and the high frequency of a single haplotype carrying the C allele. RhCE function is not well understood, but the C/c antigenic variant is clinically relevant and can result in hemolytic disease of the newborn, albeit much less commonly and severely than that related to the D-negative blood type. Therefore, the potential fitness benefits of the RHCE C allele are currently unknown but merit further exploration. Content Type Journal Article Category Original Investigation Pages 1-12 DOI 10.1007/s00439-012-1147-5 Authors George H. Perry, Department of Anthropology, Pennsylvania State University, University Park, PA 16801, USA Yali Xue, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA UK Richard S. Smith, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave., EBRC 422A, Boston, MA 02115, USA Wynn K. Meyer, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA Minal Çalışkan, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA Omar Yanez-Cuna, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave., EBRC 422A, Boston, MA 02115, USA Arthur S. Lee, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave., EBRC 422A, Boston, MA 02115, USA María Gutiérrez-Arcelus, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave., EBRC 422A, Boston, MA 02115, USA Carole Ober, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA Edward J. Hollox, Department of Genetics, University of Leicester, Leicester, LE1 7RH UK Chris Tyler-Smith, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA UK Charles Lee, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave., EBRC 422A, Boston, MA 02115, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Loss-of-function mutations in filaggrin gene ( FLG ; OMIM #135940) have been reported to cause the semi-dominant keratinizing disorders such as ichthyosis vulgaris (IV; OMIM #146700) and atopic dermatitis (AD; OMIM #605803). Recent linkage analysis and immunohistochemical studies suggest the possible contribution of FLG to psoriatic susceptibility. However, no susceptibility variant in FLG gene associated with psoriasis (OMIM #177900) has been identified. In this study, we identified a non-sense mutation of FLG (p.K4022X) in a Chinese psoriasis/IV coexisting family. The homozygous p.K4022X mutation was detected in a psoriasis patient, whereas the heterozygous p.K4022X mutation was identified in two IV patients and four apparently normal family members. We also genotyped p.K4022X variant in 441 sporadic Chinese psoriasis patients and found homozygous mutation in two patients, while no homozygous variant was found in 500 control individuals. After sequencing the entire coding region of FLG gene in 441 psoriasis patients, we identified another five mutations (p.R826X, p.W2583X, c.7945delA, c.3321delA and p.Q2417X). Although all six FLG mutations as a whole was not significantly associated with psoriasis ( P  = 0.105), mutation p.K4022X was significantly associated with psoriasis ( P  〈 0.05). Our data thus indicates an association of FLG with psoriasis in Chinese population. Content Type Journal Article Category Original Investigation Pages 1-6 DOI 10.1007/s00439-012-1155-5 Authors Zhengmao Hu, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Zhimin Xiong, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Xiaojuan Xu, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Fangfang Li, Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China Lina Lu, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Wei Li, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Juan Su, Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China Yalan Liu, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Deyuan Liu, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Zhiguo Xie, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Yu Peng, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Yehong Kuang, Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China Lisha Wu, Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China Jianglin Zhang, Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, China Qian Pan, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Beisha Tang, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Xiang Chen, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Kun Xia, State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Systemic sclerosis (SSc) is a severe connective tissue disorder characterized by extensive fibrosis, vascular damage, and autoimmune events. During the last years, the number of genetic markers convincingly associated with SSc has exponentially increased. In this report, we aim to offer an updated review of the classical and novel genetic associations with SSc, analyzing the firmest and replicated signals within HLA and non-HLA genes, identified by both candidate gene and genome-wide association (GWA) studies. We will also provide an insight into the future perspectives and approaches that might shed more light into the complex genetic background underlying SSc. In spite of the remarkable advance in the field of SSc genetics during the last decade, the use of the new genetic technologies such as next generation sequencing (NGS), as well as the deep phenotyping of the study cohorts, to fully characterize the genetic component of this disease is imperative. Content Type Journal Article Category Review Paper Pages 1-15 DOI 10.1007/s00439-011-1137-z Authors José Ezequiel Martín, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain Lara Bossini-Castillo, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain Javier Martín, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada, Spain Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The phosphodiesterase 4B ( PDE4B ) is a candidate susceptibility gene for schizophrenia (SCZ), interacting with DISC1 , a known genetic risk factor for SCZ. To examine if variants within PDE4B gene are associated with SCZ in Northwestern Han Chinese, and if these effects vary in gender-specific subgroup, we analyzed 20 SNPs, selected from previous studies and preliminary HapMap data analyses with minor allele frequency (MAF) ≥20%, in a cohort of 428 cases and 572 controls from genetically independent Northwestern Han Chinese. Single SNP association, haplotype association and sex-specific association analysis were performed. We found that rs472952 is significantly associated with SCZ and rs7537440 is associated with SCZ in females. Further analysis indicated that a haplotype block spanning PDE4B2 splice site is highly associated with SCZ and several haplotypes in this block have about twofold to threefold increase in cases. Our results provide further evidence that PDE4B may play important roles in the etiology of SCZ. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-011-1120-8 Authors Fanglin Guan, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China Chen Zhang, The First Department of Orthopedics, The Second Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China Shuguang Wei, Key Laboratory of National Ministry of Health for Forensic Sciences, College of Medicine, Xi’an Jiaotong University, Xi’an, China Hongbo Zhang, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China Xiaomin Gong, Key Laboratory of National Ministry of Health for Forensic Sciences, College of Medicine, Xi’an Jiaotong University, Xi’an, China Jiali Feng, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China Chengge Gao, Department of Psychiatry, The First Affiliated Hospital, College of Medicine, Xi’an Jiaotong University, Xi’an, China Rong Su, Key Laboratory of National Ministry of Health for Forensic Sciences, College of Medicine, Xi’an Jiaotong University, Xi’an, China Huanming Yang, Beijing Genomics Institute, Shenzhen, China Shengbin Li, Institute of Human Genomics and Forensic Sciences, 76 Yanta West Road, Xi’an, 710061 China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    VKORC1 genetic polymorphisms affect warfarin dose response, aortic calcification, and the susceptibility of coronary artery disease as shown in our previous study. Little is known regarding the association of VKORC1 polymorphisms with coronary artery calcification (CAC) and the role of CAC in the association with coronary artery disease (CAD). Due to a natural haplotype block in the VKORC1 gene in Chinese, polymorphism rs2359612 was analyzed in a case–control study and a prospective study. The case–control study included 464 CAD patients with non-calcified plaque (NCP), 562 CAD patients with mixed calcified plaque (MCP), 492 subjects with calcified plaque (CP), and 521 controls. The rs2359612C was only associated with increased risk of MCP, the CAD in the presence of CAC; the odds ratio was 1.397 (95 % CI 1.008–1.937, P  〈 0.05), which was replicated in the second independent population. On the contrary, a negative correlation was observed between rs2359612 and log-transformed Agatston score, and rs2359612 was negatively associated with the number of calcified vessels. Moreover, in a prospective study including 849 CAD patients undergoing revascularization, rs2359612C predicted a higher incidence of cardiovascular events in MCP subgroup; the relative risk was 1.435 (95 % CI 1.008–2.041, P  = 0.045), which was not observed in the NCP subgroup. We conclude that the rs2359612C was associated with a higher risk of CAD in the presence of CAC and a higher incidence of cardiovascular events in CAD patients with CAC, but a lower coronary calcification. VKORC1 polymorphisms may be associated with the endophenotype of CAD, calcification-related atherosclerosis. Content Type Journal Article Category Original Investigation Pages 1-9 DOI 10.1007/s00439-012-1222-y Authors Yibo Wang, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Jinxing Chen, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Yu Zhang, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Lv Bin, Department of Radiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Kai Sun, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Weifeng Yu, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Jibin Liu, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Channa Zhang, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Haiqing Shen, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA Zhihui Hou, Department of Radiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Fangfang Yu, Department of Radiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Rutai Hui, Sino-German Laboratory for Molecular Medicine, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Pharmacogenomics is emerging as a popular type of study for human genetics in recent years. This is primarily due to the many success stories and high potential for translation to clinical practice. In this review, the strengths and limitations of pharmacogenomics are discussed as well as the primary epidemiologic, clinical trial, and in vitro study designs implemented. A brief discussion of molecular and analytic approaches will be reviewed. Finally, several examples of bench-to-bedside clinical implementations of pharmacogenetic traits will be described. Pharmacogenomics continues to grow in popularity because of the important genetic associations identified that drive the possibility of precision medicine. Content Type Journal Article Category Review Paper Pages 1615-1626 DOI 10.1007/s00439-012-1221-z Authors Marylyn D. Ritchie, Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Center for Systems Genomics, Eberly College of Science, The Pennsylvania State University, 512 Wartik Laboratory, University Park, PA 16802, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717 Journal Volume Volume 131 Journal Issue Volume 131, Number 10

Beschreibung:    Large-scale sequencing of cancer genomes has revealed many novel mutations and inter-tumoral heterogeneity. Therefore, prioritizing variants according to their potential deleterious effects has become essential. We constructed a disease gene network and proposed a Bayesian ensemble approach that integrates diverse sources to predict the functional effects of missense variants. We analyzed 23,336 missense disease mutations and 36,232 neutral polymorphisms of 12,039 human proteins. The results showed successful improvement of prediction accuracy in both sensitivity and specificity, and we demonstrated the utility of the method by applying it to somatic mutations obtained from colorectal and breast cancer cell lines. The candidate genes with predicted deleterious mutations as well as known cancer genes were significantly enriched in many KEGG pathways related to carcinogenesis, supporting genetic homogeneity of cancer at the pathway level. The breast cancer-specific network increased the prediction accuracy for breast cancer mutations. This study provides a ranked list of deleterious mutations and candidate cancer genes and suggests that mutations affecting cancer may occur in important pathways and should be interpreted on the phenotype-related network or pathway. A disease gene network may be of value in predicting functional effects of novel disease-specific mutations. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-012-1218-7 Authors Hong-Hee Won, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon, 305-710 South Korea Jong-Won Kim, Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul, 135-710 South Korea Doheon Lee, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, 373-1 Guseong-dong, Yuseong-gu, Daejeon, 305-710 South Korea Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of 〉1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated ( p  〈 0.05) in stage 2, which reached statistical significance levels of 10 −6 and 10 −5 in the stage 1 and 2 combined analysis (rs4322600 at chromosome 14q31: OR = 1.18, p  = 4.3 × 10 −6 ; rs10510333 at chromosome 3p26: OR = 1.15, p  = 1.5 × 10 −5 ). These suggestive risk loci have not been identified in previous GWAS in other populations and will need to be examined in additional samples. Identification of novel risk variants for breast cancer in women of African ancestry will demand testing of a substantially larger set of markers from stage 1 in a larger replication sample. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1214-y Authors Fang Chen, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Gary K. Chen, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Daniel O. Stram, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Robert C. Millikan, Department of Epidemiology, Gillings School of Global Public Health, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA Christine B. Ambrosone, Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA Esther M. John, Cancer Prevention Institute of California, Fremont, CA, USA Leslie Bernstein, Division of Cancer Etiology, Department of Population Science, Beckman Research Institute, City of Hope, Duarte, CA, USA Wei Zheng, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Julie R. Palmer, Slone Epidemiology Center at Boston University, Boston, MA, USA Jennifer J. Hu, Department of Epidemiology and Public Health, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA Tim R. Rebbeck, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Regina G. Ziegler, Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, DC, USA Sarah Nyante, Department of Epidemiology, Gillings School of Global Public Health, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA Elisa V. Bandera, The Cancer Institute of New Jersey, New Brunswick, NJ, USA Sue A. Ingles, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Michael F. Press, Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Edward A. Ruiz-Narvaez, Slone Epidemiology Center at Boston University, Boston, MA, USA Sandra L. Deming, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Jorge L. Rodriguez-Gil, Department of Epidemiology and Public Health, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA Angela DeMichele, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Stephen J. Chanock, Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, DC, USA William Blot, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Lisa Signorello, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Qiuyin Cai, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Guoliang Li, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Jirong Long, Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA Dezheng Huo, Department of Health Studies, University of Chicago, Chicago, IL, USA Yonglan Zheng, Department of Medicine, University of Chicago, Chicago, IL, USA Nancy J. Cox, Department of Medicine, University of Chicago, Chicago, IL, USA Olufunmilayo I. Olopade, Department of Medicine, University of Chicago, Chicago, IL, USA Temidayo O. Ogundiran, Department of Surgery, College of Medicine, University of Ibadan, Ibadan, Nigeria Clement Adebamowo, Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, MD, USA Katherine L. Nathanson, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Susan M. Domchek, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Michael S. Simon, Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA Anselm Hennis, Chronic Disease Research Centre, Tropical Medicine Research Institute, University of the West Indies, Bridgetown, Barbados Barbara Nemesure, Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA Suh-Yuh Wu, Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA M. Cristina Leske, Department of Preventive Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA Stefan Ambs, Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD, USA Carolyn M. Hutter, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Alicia Young, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Charles Kooperberg, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Ulrike Peters, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Suhn K. Rhie, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Peggy Wan, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Xin Sheng, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Loreall C. Pooler, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA David J. Van Den Berg, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Loic Le Marchand, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA Laurence N. Kolonel, Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI, USA Brian E. Henderson, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Christopher A. Haiman, Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Central corneal thickness (CCT) has become an endophenotype of major interest for the genetically complex disorder glaucoma. CCT has a high heritability, and thin CCT is an independent risk factor for the diagnosis and progression of open-angle glaucoma. Genome-wide association studies thus provide genetic loci associated with CCT and potentially related to open-angle glaucoma. The distribution of CCT and prevalence of glaucoma in population-based studies have demonstrated ethnic differences suggesting ethnic-dependent variations in the genetic determinants of CCT. We conducted a genome-wide association study in Caucasians ( n  = 3,931) from the Gutenberg Health Study (Germany) followed by replication of 30 genome-wide significant SNPs or SNPs of interest ( P  〈 10 −5 ) in the Rotterdam Study (The Netherlands, n  = 1,418). In a combined analysis, we confirmed quantitative trait loci on chromosomes 9q34 and 16q24 for association with CCT. On chromosome 16q24, the locus is located in an intergenic region near the ZNF469 gene (top SNP: rs9938149, P  = 1.45 × 10 −12 ). ZNF469 missense mutation is involved in a syndrome with very thin cornea (brittle cornea syndrome). The second locus on chromosome 9q34 represents the intergenic region between the RXRA and COL5A1 gene (top SNP: rs3132306, P  = 2.71 × 10 −10 ). Collagen type 5 determines the diameter of the corneal collagen fibrils. In our Caucasian population-based GWA study, we reinforce the involvement of collagen-related genes influencing CCT in Caucasians. We could not confirm the collagen type 8 locus on chromosome 1 as reported in Asian studies. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1201-3 Authors René Hoehn, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Tanja Zeller, Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany Virginie J. M. Verhoeven, Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands Franz Grus, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Max Adler, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Roger C. Wolfs, Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands André G. Uitterlinden, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands Raphaële Castagne, INSERM UMRS 937, Pierre and Marie Curie University and Medical School, Paris, France Arne Schillert, Institute of Medical Biometry and Statistics, University Hospital Schleswig–Holstein, Luebeck, Germany Caroline C. W. Klaver, Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands Norbert Pfeiffer, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Alireza Mirshahi, Department of Ophthalmology, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Statins reduce the risk of cardiovascular events by lowering the blood cholesterol. Many genes involved in the pharmacodynamic pathway of statins have been part of pharmacogenetic research in patients with hypercholesterolemia, with an emphasis on genes involved in the cholesterol pathway. The present study was carried out with an aim to evaluate the association between the genetic variants of lipoprotein lipase gene [ Hin dIII (+/+)/ Hin dIII (−/−)], multiple drug resistance gene (C3435T) and endothelial nitric oxide synthase gene (4a/4b) with clinical outcome including an increased risk of recurrent stroke or death in ischemic stroke patients on atorvastatin therapy. 525 stroke patients and 500 healthy controls were involved in the study. Follow-up telephone interviews were conducted with patients post-event to determine stroke outcome. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. A significant association of MDR1 and LPL gene variants with bad outcome in stroke patients on atorvastatin therapy was found. However, there was no significant association of 27 bp VNTR polymorphism of eNOS gene with outcome. MDR analysis was carried out to analyze gene–gene interaction involving these gene variants contributing to clinical outcome of patients on stratin therapy but no significant interaction between these variants was observed. In conclusion the individuals with Hin dIII (−/−) genotype of LPL and CC genotype of MDR1 gene would benefit more from atorvastatin therapy. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1202-2 Authors Anjana Munshi, Department of Molecular Biology, Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet, Hyderabad, 500016 India Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Heritability, the fraction of phenotypic variation explained by genetic variation, has been estimated for many phenotypes in a range of populations, organisms, and time points. The recent development of efficient genotyping and sequencing technology has led researchers to attempt to identify the genetic variants responsible for the genetic component of phenotype directly via GWAS. The gap between the phenotypic variance explained by GWAS results and those estimated from classical heritability methods has been termed the “missing heritability problem”. In this work, we examine modern methods for estimating heritability, which use the genotype and sequence data directly. We discuss them in the context of classical heritability methods, the missing heritability problem, and describe their implications for understanding the genetic architecture of complex phenotypes. Content Type Journal Article Category Review Paper Pages 1-10 DOI 10.1007/s00439-012-1199-6 Authors Noah Zaitlen, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA Peter Kraft, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Millions of genetic variants have been assessed for their effects on the trait of interest in genome-wide association studies (GWAS). The complex traits are affected by a set of inter-related genes. However, the typical GWAS only examine the association of a single genetic variant at a time. The individual effects of a complex trait are usually small, and the simple sum of these individual effects may not reflect the holistic effect of the genetic system. High-throughput methods enable genomic studies to produce a large amount of data to expand the knowledge base of the biological systems. Biological networks and pathways are built to represent the functional or physical connectivity among genes. Integrated with GWAS data, the network- and pathway-based methods complement the approach of single genetic variant analysis, and may improve the power to identify trait-associated genes. Taking advantage of the biological knowledge, these approaches are valuable to interpret the functional role of the genetic variants, and to further understand the molecular mechanism influencing the traits. The network- and pathway-based methods have demonstrated their utilities, and will be increasingly important to address a number of challenges facing the mainstream GWAS. Content Type Journal Article Category Review Paper Pages 1-10 DOI 10.1007/s00439-012-1198-7 Authors Yan V. Sun, Department of Epidemiology, Emory University, Rollins School of Public Health, 1518 Clifton Road NE #3049, Atlanta, 30322 GA, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. The present study aimed to evaluate whether OPG gene (TNFRSF11B) polymorphisms are involved in ischemic stroke in an Italian population with diabetes. Participants in a retrospective case–control study included 364 diabetic patients (180 males, 184 females) with history of ischemic stroke and 492 diabetic subjects without history of ischemic stroke (252 males, 240 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism. We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (34.1 vs. 9.5 %, P  〈 0.0001; 30.8 vs. 6.3 %, P  〈 0.0001 and 26.4 vs. 11.6 % P  〈 0.0001, respectively) and independently (adjusted OR 5.15 [3.46–7.68], OR 6.63 [4.26–10.31], and OR 3.03 [2.04–4.50], respectively) associated with history of ischemic stroke. We also found that these three polymorphisms act synergistically in patients with stroke history. The TNFRSF11B gene polymorphisms studied are associated with history of ischemic stroke and synergistic effects between these genotypes might be potential markers for cerebrovascular disorders. Content Type Journal Article Category Original Investigation Pages 1-7 DOI 10.1007/s00439-012-1224-9 Authors Federico Biscetti, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy Giuseppe Straface, Vascular Medicine and Atherothrombosis Laboratory, Department of Experimental Medicine, Sapienza University of Rome, Polo Pontino, Italy Silvia Giovannini, Department of Gerontology and Geriatrics, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy Angelo Santoliquido, Department of Internal Medicine, Complesso Integrato Columbus, School of Medicine, Rome, Italy Flavia Angelini, Laboratory of Vascular Biology and Genetics, Catholic University School of Medicine, Rome, Italy Luca Santoro, Department of Internal Medicine, Complesso Integrato Columbus, School of Medicine, Rome, Italy Carlo Filippo Porreca, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy Giovanni Pecorini, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy Giovanni Ghirlanda, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy Andrea Flex, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Preterm birth (PTB) is the leading cause of infant mortality. PTB pathophysiology overlaps with those of adult cardiovascular, immune and metabolic disorders (CIMD), with mechanisms including inflammation, immunotolerance, thrombosis, and nutrient metabolism. Whereas many genetic factors for CIMD have been identified, progress in PTB has lagged. We hypothesized that highly validated genetic risk factors for CIMD may also be associated with PTB. We conducted case–control study of four female cohorts with spontaneous PTB ( n  = 673) versus term ( n  = 1119). Of 35 SNPs genotyped, there were 13 statistically significant associations ( P  〈 0.05), which were more than expected (binomial test; P  = 0.02). In US White (307 cases/342 controls), the G allele of HLA-DQA1 (A/G) rs9272346 was protective for PTB in the initial discovery cohort ( P  = 0.02; OR = 0.65; 95 % CI 0.46, 0.94). This protective association replicated ( P  = 0.02; OR = 0.85; 95 % CI 0.75, 0.97) nominally in the Danish Cohort (883 cases, 959 controls), but lost significance upon multiple testing correction. We observed more statistically significant associations than expected, suggesting that chance is an unlikely explanation for one or more of the associations. Particularly, a protective association of the G allele of HLA - DQA1 was found in two independent cohorts, and in previous studies, this same allele was found to protect against type-1-diabetes (meta-analysis P value 5.52 × 10 –219 ). Previous investigations have implicated HLA phenotypic variation in recurrent fetal loss and in chronic chorioamnionitis. Given the limited sample size in his study, we suggest larger studies to further investigate possible HLA genetic involvement in PTB. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1223-x Authors Nadia Falah, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA Jude McElroy, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA Victoria Snegovskikh, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA Charles J. Lockwood, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA Errol Norwitz, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT, USA Jeffey C. Murray, Department of Pediatrics, University of Iowa, Iowa City, IA, USA Edward Kuczynski, Biology and Biochemistry Department, University of Houston, Houston, TX, USA Ramkumar Menon, Department of Obstetrics and Gynecology, University of Texas, Galveston, TX, USA Kari Teramo, Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland Louis J. Muglia, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA Thomas Morgan, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Protein C (PC) is a well-characterized anticoagulant enzyme. However, the association between PC and ischemic stroke (IS) remains controversial. The aim of the present study was to investigate whether any genetic variant in the human protein C gene (PROC) was associated with susceptibility to IS in the Chinese Han population. All exons and the 5′- and 3′-untranslated regions of PROC were initially sequenced to identify informative variants. Potential abnormal variants were analyzed in a population of 788 IS patients and 1,200 healthy controls. The analysis was stratified by stroke etiology, and the results were replicated in 262 IS patients and 288 healthy controls. Finally, functional studies were performed to evaluate the effects of the variant. A three-nucleotide duplication/deletion variant (c.574_576del) was identified and found to be significantly associated with IS (OR 2.56, 95 % CI 1.45-4.52, P  = 0.001). Stratification by stroke etiology after adjustment for IS risk factors showed that this association persisted in the lacunar and cardioembolic subtypes ( P  〈 0.001 and P  = 0.008, respectively) but not in the atherothrombotic and undetermined subtypes ( P  = 0.070 and P  = 0.998, respectively). The functional studies showed a significant difference in the anticoagulant activity of PC in c.574_576del carriers and non-carriers ( P  〈 0.001). Our results suggested that the novel PROC c.574_576del variant is a possible genetic determinant of an increased risk of IS and diminished anticoagulant activity of PC. Content Type Journal Article Category Original Investigation Pages 1-9 DOI 10.1007/s00439-012-1225-8 Authors Xuan Lu, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Liang Tang, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Kang Xu, Neurology Department, Hubei Xinhua Hospital, Wuhan, China Jie Ma, Department of Laboratory Medicine, Hubei Xinhua Hospital, Wuhan, China Tao Guo, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Heng Mei, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Rui Yang, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Jianming Yu, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Qingyun Wang, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Yan Yang, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Xiaorong Jian, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Yu Hu, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Hepatitis C virus (HCV) modulates host lipid metabolism as part of its lifecycle and is dependent upon VLDL for co-assembly and secretion. HCV dyslipidemia is associated with steatosis, insulin resistance, IL28B genotype and disease progression. Apolipoprotein E (ApoE) is an important lipid transport protein, a key constituent of VLDL, and is involved in immunomodulation. Our aims were to determine the role of APOE regional polymorphisms on host lipids, IL28B genotype and disease severity in chronic HCV (CHC) patients. The study cohort included 732 CHC patients with available DNA for genotype determination of four polymorphisms in the chromosome 19 region that encompasses the TOMM40, APOE and APOC1 genes. Serum lipid analysis and apolipoproteins levels were measured using an immunoturbidimetric assay. APOE rs7412 polymorphism (capturing the ε2 isoform) was significantly associated with serum ApoE levels in both Caucasians and African-American patients ( p  = 2.3 × 10 −11 ) and explained 7 % of variance in serum ApoE. Among I L28B -CC patients ( n  = 196), the rs429358 (defines ε4 isoform) and TOMM40 ‘523’ S polymorphisms were associated with 12 % of variance in ApoB levels. Patients homozygous for the APOE ε3 isoform had a greater than twofold increased odds of F2–F4 fibrosis ( p  = 1.8 × 10 −5 ), independent of serum lipid and lipoprotein levels. There were no associations between APOE polymorphisms and serum HDL-C, APO-CIII and triglycerides. In CHC patients, genetic heterogeneity in the APOE/TOMM40 genomic region is significantly associated with variation in serum ApoE and ApoB levels, and also with fibrosis suggesting a pleiotropic attribute of this genomic region. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1220-0 Authors Ornit Chiba-Falek, Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA Colton Linnertz, Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA John Guyton, Division of Endocrinology, Duke University Medical Center, Durham, NC 27710, USA Stephen D. Gardner, GlaxoSmithKline Research and Development, Research Triangle Park, NC, USA Allen D. Roses, Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA Jeanette J. McCarthy, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA Keyur Patel, Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC 27710, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Study designs and methods post genome-wide association studies Content Type Journal Article Category Editorial Pages 1-7 DOI 10.1007/s00439-012-1209-8 Authors Andreas Ziegler, Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig–Holstein, Campus Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany Yan V. Sun, Department of Epidemiology, Department of Biomedical Informatics, Emory University, Atlanta, GA, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H + -ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients’ dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-β signalling and increased TGF-β1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2 -related ARCL. Content Type Journal Article Category Original Investigation Pages 1-13 DOI 10.1007/s00439-012-1197-8 Authors Björn Fischer, Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany Aikaterini Dimopoulou, Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany Johannes Egerer, Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany Thatjana Gardeitchik, Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Alexa Kidd, Central and Southern Regional Genetic Services, Wellington Hospital, Wellington South, New Zealand Dominik Jost, Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany Hülya Kayserili, Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Yasemin Alanay, Department of Child Health and Diseases, Acibadem University, Istanbul, Turkey Iliana Tantcheva-Poor, Department of Dermatology, University of Cologne, Cologne, Germany Elisabeth Mangold, Institute of Human Genetics, University of Bonn, Bonn, Germany Cornelia Daumer-Haas, Prenatal Medicine Munich, Munich, Germany Shubha Phadke, Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Reto I. Peirano, Beiersdorf AG, R&D, Skin Research Center, Unnastrasse 48, 20253 Hamburg, Germany Julia Heusel, Beiersdorf AG, R&D, Skin Research Center, Unnastrasse 48, 20253 Hamburg, Germany Charu Desphande, Department of Clinical Genetics, Guy’s Hospital, London, UK Neerja Gupta, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Arti Nanda, Pediatric Dermatology Unit, Asad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait City, Kuwait Emma Felix, Central and Southern Regional Genetic Services, Wellington Hospital, Wellington South, New Zealand Elisabeth Berry-Kravis, Department of Pediatrics, Neurological Sciences and Biochemistry, Rush University Medical Center, Chicago, IL, USA Madhulika Kabra, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Ron A. Wevers, Laboratory of Genetic, Endocrine and Metabolic Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Lionel van Maldergem, Cutis laxa, Debré type Study Group, Centre de Génétique Humaine, Centre Hospitalier Universitaire, Université de Franche-Comté, 25000 Besançon, France Stefan Mundlos, Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany Eva Morava, Department of Pediatrics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands Uwe Kornak, Institut fuer Medizinische Genetik und Humangenetik, Charité-Universitaetsmedizin Berlin, Berlin, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Trisomies 18 and 21 are the two most common live born autosomal aneuploidies in humans. While the anatomic abnormalities in affected fetuses are well documented, the dysregulated biological pathways associated with the development of the aneuploid phenotype are less clear. Amniotic fluid (AF) cell-free RNA is a valuable source of biological information obtainable from live fetuses. In this study, we mined gene expression data previously produced by our group from mid-trimester AF supernatant samples. We identified the euploid, trisomy 18 and trisomy 21 AF transcriptomes, and analyzed them with a particular focus on the nervous system. We used multiple bioinformatics resources, including DAVID, Ingenuity Pathway Analysis, and the BioGPS Gene Expression Atlas. Our analyses confirmed that AF supernatant from aneuploid fetuses is enriched for nervous system gene expression and neurological disease pathways. Tissue analysis showed that fetal brain cortex and Cajal–Retzius cells were significantly enriched for genes contained in the AF transcriptomes. We also examined AF transcripts known to be dysregulated in aneuploid fetuses compared with euploid controls and identified several brain-specific transcripts among them. Many of these genes play critical roles in nervous system development. NEUROD2 , which was downregulated in trisomy 18, induces neurogenic differentiation. SOX11 , downregulated in trisomy 21, is a transcription factor that is essential for pan-neuronal protein expression and axonal growth of sensory neurons. Our results show that whole transcriptome analysis of cell-free RNA in AF from live pregnancies permits discovery of biomarkers of abnormal human neurodevelopment and advances our understanding of the pathophysiology of aneuploidy. Content Type Journal Article Category Original Investigation Pages 1-9 DOI 10.1007/s00439-012-1195-x Authors Lisa Hui, Mother Infant Research Institute and the Division of Genetics, Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA Donna K. Slonim, Department of Computer Science, Tufts University, Medford, MA, USA Heather C. Wick, Department of Computer Science, Tufts University, Medford, MA, USA Kirby L. Johnson, Mother Infant Research Institute and the Division of Genetics, Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA Keiko Koide, Mother Infant Research Institute and the Division of Genetics, Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA Diana W. Bianchi, Mother Infant Research Institute and the Division of Genetics, Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA 02111, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The interest in performing gene–environment interaction studies has seen a significant increase with the increase of advanced molecular genetics techniques. Practically, it became possible to investigate the role of environmental factors in disease risk and hence to investigate their role as genetic effect modifiers. The understanding that genetics is important in the uptake and metabolism of toxic substances is an example of how genetic profiles can modify important environmental risk factors to disease. Several rationales exist to set up gene–environment interaction studies and the technical challenges related to these studies—when the number of environmental or genetic risk factors is relatively small—has been described before. In the post-genomic era, it is now possible to study thousands of genes and their interaction with the environment. This brings along a whole range of new challenges and opportunities. Despite a continuing effort in developing efficient methods and optimal bioinformatics infrastructures to deal with the available wealth of data, the challenge remains how to best present and analyze genome-wide environmental interaction (GWEI) studies involving multiple genetic and environmental factors. Since GWEIs are performed at the intersection of statistical genetics, bioinformatics and epidemiology, usually similar problems need to be dealt with as for genome-wide association gene–gene interaction studies. However, additional complexities need to be considered which are typical for large-scale epidemiological studies, but are also related to “joining” two heterogeneous types of data in explaining complex disease trait variation or for prediction purposes. Content Type Journal Article Category Review Paper Pages 1-23 DOI 10.1007/s00439-012-1192-0 Authors Hugues Aschard, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Sharon Lutz, Departments of Epidemiology & Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Bärbel Maus, Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium Eric J. Duell, Unit of Nutrition, Environment and Cancer, Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain Tasha E. Fingerlin, Departments of Epidemiology & Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA Nilanjan Chatterjee, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA Peter Kraft, Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA Kristel Van Steen, Systems and Modeling Unit, Montefiore Institute, University of Liège, Liège, Belgium Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    After an association between genetic variants and a phenotype has been established, further study goals comprise the classification of patients according to disease risk or the estimation of disease probability. To accomplish this, different statistical methods are required, and specifically machine-learning approaches may offer advantages over classical techniques. In this paper, we describe methods for the construction and evaluation of classification and probability estimation rules. We review the use of machine-learning approaches in this context and explain some of the machine-learning algorithms in detail. Finally, we illustrate the methodology through application to a genome-wide association analysis on rheumatoid arthritis. Content Type Journal Article Category Review Paper Pages 1-16 DOI 10.1007/s00439-012-1194-y Authors Jochen Kruppa, Institut für Medizininsche Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany Andreas Ziegler, Institut für Medizininsche Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany Inke R. König, Institut für Medizininsche Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Biomarkers are of increasing importance for personalized medicine, with applications including diagnosis, prognosis, and selection of targeted therapies. Their use is extremely diverse, ranging from pharmacodynamics to treatment monitoring. Following a concise review of terminology, we provide examples and current applications of three broad categories of biomarkers—DNA biomarkers, DNA tumor biomarkers, and other general biomarkers. We outline clinical trial phases for identifying and validating diagnostic and prognostic biomarkers. Predictive biomarkers, more generally termed companion diagnostic tests predict treatment response in terms of efficacy and/or safety. We consider suitability of clinical trial designs for predictive biomarkers, including a detailed discussion of validation study designs, with emphasis on interpretation of study results. We specifically discuss the interpretability of treatment effects if a large set of DNA biomarker profiles is available and the number of therapies is identical to the number of different profiles. Content Type Journal Article Category Review Paper Pages 1-12 DOI 10.1007/s00439-012-1188-9 Authors Andreas Ziegler, Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig–Holstein, Campus Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany Armin Koch, Institut für Biometrie, Medizinische Hochschule Hannover, OE 8410, 30625 Hannover, Germany Katja Krockenberger, Zentrum für Klinische Studien, Universität zu Lübeck, Lübeck, Germany Anika Großhennig, Institut für Biometrie, Medizinische Hochschule Hannover, OE 8410, 30625 Hannover, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Signaling by the glial cell line-derived neurotrophic factor (GDNF)-RET receptor tyrosine kinase and SPRY1, a RET repressor, is essential for early urinary tract development. Individual or a combination of GDNF , RET and SPRY1 mutant alleles in mice cause renal malformations reminiscent of congenital anomalies of the kidney or urinary tract (CAKUT) in humans and distinct from renal agenesis phenotype in complete GDNF or RET -null mice. We sequenced GDNF , SPRY1 and RET in 122 unrelated living CAKUT patients to discover deleterious mutations that cause CAKUT. Novel or rare deleterious mutations in GDNF or RET were found in six unrelated patients. A family with duplicated collecting system had a novel mutation, RET - R831Q , which showed markedly decreased GDNF-dependent MAPK activity. Two patients with RET - G691S polymorphism harbored additional rare non-synonymous variants GDNF - R93W and RET - R982C . The patient with double RET - G691S/R982C genotype had multiple defects including renal dysplasia, megaureters and cryptorchidism. Presence of both mutations was necessary to affect RET activity. Targeted whole-exome and next-generation sequencing revealed a novel deleterious mutation G443D in GFRα1 , the co-receptor for RET, in this patient. Pedigree analysis indicated that the GFRα1 mutation was inherited from the unaffected mother and the RET mutations from the unaffected father. Our studies indicate that 5 % of living CAKUT patients harbor deleterious rare variants or novel mutations in GDNF-GFR α 1-RET pathway. We provide evidence for the coexistence of deleterious rare and common variants in genes in the same pathway as a cause of CAKUT and discovered novel phenotypes associated with the RET pathway. Content Type Journal Article Category Original Investigation Pages 1-14 DOI 10.1007/s00439-012-1181-3 Authors Rajshekhar Chatterjee, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Enrique Ramos, Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Mary Hoffman, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Jessica VanWinkle, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Daniel R. Martin, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Thomas K. Davis, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Masato Hoshi, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Stanley P. Hmiel, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Anne Beck, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Keith Hruska, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Doug Coplen, Department of Surgery (Urology), Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Helen Liapis, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Robi Mitra, Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Todd Druley, Department of Pediatrics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Paul Austin, Department of Surgery (Urology), Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA Sanjay Jain, Department of Internal Medicine (Renal Division), Washington University School of Medicine, Box 8126, 660 S. Euclid Ave, St. Louis, MO 63110, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Both environmental and genetic factors impact lipid traits. Environmental modifiers of known genotype–phenotype associations may account for some of the “missing heritability” of these traits. To identify such modifiers, we genotyped 23 lipid-associated variants identified previously through genome-wide association studies (GWAS) in 2,435 non-Hispanic white, 1,407 non-Hispanic black, and 1,734 Mexican-American samples collected for the National Health and Nutrition Examination Surveys (NHANES). Along with lipid levels, NHANES collected environmental variables, including fat-soluble macronutrient serum levels of vitamin A and E levels. As part of the Population Architecture using Genomics and Epidemiology (PAGE) study, we modeled gene–environment interactions between vitamin A or vitamin E and 23 variants previously associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. We identified three SNP × vitamin A and six SNP × vitamin E interactions at a significance threshold of p  〈 2.2 × 10 −3 . The most significant interaction was APOB rs693 × vitamin E ( p  = 8.9 × 10 −7 ) for LDL-C levels among Mexican-Americans. The nine significant interaction models individually explained 0.35–1.61 % of the variation in any one of the lipid traits. Our results suggest that vitamins A and E may modify known genotype–phenotype associations; however, these interactions account for only a fraction of the overall variability observed for HDL-C, LDL-C, and TG levels in the general population. Content Type Journal Article Category Original Investigation Pages 1-10 DOI 10.1007/s00439-012-1186-y Authors Logan Dumitrescu, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Robert Goodloe, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Kristin Brown-Gentry, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Ping Mayo, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Melissa Allen, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Hailing Jin, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Niloufar B. Gillani, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Nathalie Schnetz-Boutaud, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Holli H. Dilks, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Dana C. Crawford, Center for Human Genetics Research, Vanderbilt University, 2215 Garland Avenue, 515B Light Hall, Nashville, TN 37232, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT ( P  〈 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 ( P  = 0.031) and 17q12-21.32 SPOP rs650461 ( P  = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 ( P  = 0.0001), SOX5 rs7305773 ( P  = 0.0001) and STKY1 rs2418087 ( P  = 0.0003), and 17q12-21.32 SPOP rs6504618 ( P  = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set ( P trend 〈1.0 × 10 −8 ). The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1187-x Authors Yanhong Liu, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA Beatrice S. Melin, Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden Preetha Rajaraman, Division of Cancer Epidemiology and Genetics, Department Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Zhaoming Wang, Division of Cancer Epidemiology and Genetics, Department Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Martha Linet, Division of Cancer Epidemiology and Genetics, Department Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Sanjay Shete, Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Christopher I. Amos, Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Ching C. Lau, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA Michael E. Scheurer, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA Spiridon Tsavachidis, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA Georgina N. Armstrong, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA Richard S. Houlston, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK Fay J. Hosking, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK Elizabeth B. Claus, Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT, USA Jill Barnholtz-Sloan, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA Rose Lai, The Neurological Institute of Columbia University, New York, NY, USA Dora Il’yasova, Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA Joellen Schildkraut, Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA Siegal Sadetzki, Cancer and Radiation Epidemiology Unit, Chaim Sheba Medical Center, Gertner Institute, Tel Hashomer, Israel Christoffer Johansen, Department of Neurology, Danish Cancer Society, Copenhagen, Denmark Jonine L. Bernstein, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Sara H. Olson, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Robert B. Jenkins, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA Daniel LaChance, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA Nicholas A. Vick, Evanston Kellogg Cancer Care Center, North Shore University Health System, Evanston, IL, USA Margaret Wrensch, Department of Neurological Surgery, University of California, San Francisco, CA, USA Faith Davis, Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, USA Bridget J. McCarthy, Division of Epidemiology and Biostatistics, University of Illinois at Chicago, Chicago, IL, USA Ulrika Andersson, Department of Radiation Sciences Oncology, Umeå University, Umeå, Sweden Patricia A. Thompson, Arizona Cancer Center, University of Arizona, Tucson, AZ, USA Stephen Chanock, Division of Cancer Epidemiology and Genetics, Department Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA The Gliogene Consortium Melissa L. Bondy, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Oocyte loss has a significant impact on fertility and somatic health. Yet, we know little about factors that impact this process. We sought to identify genetic variants associated with ovarian reserve (oocyte number as measured by antral follicle count, AFC). Based on recently published genome-wide scans that identified loci associated with age of menopause, we also sought to test our hypothesis that follicle number and menopausal age share underlying genetic associations. We analyzed menopause-related variants for association with follicle number in an independent population of approximately 450 reproductive-aged women of European and African ancestry; these women were assessed for AFC, anthropometric, clinical, and lifestyle factors. One SNP strongly associated with later menopausal age in Caucasian women (+1.07 ± 0.11 years) in previous work was also associated with higher follicle counts in Caucasians (+2.79 ± 1.67 follicles) in our study. This variant is within the Minichromosome Maintenance Complex Component 8 ( MCM8 ) gene, which we found was expressed within oocytes in follicles of the human ovary. In genome-wide scans of AFC, we also identified one marginally genome-wide and several nominally significant SNPs within several other genes associated with follicle number in both ethnic groups. Further, there were overlapping variants associated with multiple ovarian reserve markers (AFC, serum hormone levels, menopausal age). This study provides the first evidence for direct genetic associations underlying both follicle number and menopause and identifies novel candidate genes. Genetic variants associated with ovarian reserve may facilitate discovery of genetic markers to predict reproductive health and lifespan in women. Content Type Journal Article Category Original Investigation Pages 1-16 DOI 10.1007/s00439-012-1184-0 Authors Sonya M. Schuh-Huerta, Department of Obstetrics and Gynecology, Institute for Stem Cell Biology and Regenerative Medicine, Center for Human Embryonic Stem Cell Research and Education, School of Medicine, Stanford University, 265 Campus Drive, Lorry I. Lokey Stem Cell Research Building Rm G1165, Stanford, CA 94305, USA Nicholas A. Johnson, Department of Statistics, Stanford University, Stanford, CA 94305, USA Mitchell P. Rosen, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94115, USA Barbara Sternfeld, Division of Research, Kaiser Permanente, Oakland, CA 94612, USA Marcelle I. Cedars, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, CA 94115, USA Renee A. Reijo Pera, Department of Obstetrics and Gynecology, Institute for Stem Cell Biology and Regenerative Medicine, Center for Human Embryonic Stem Cell Research and Education, School of Medicine, Stanford University, 265 Campus Drive, Lorry I. Lokey Stem Cell Research Building Rm G1165, Stanford, CA 94305, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    As whole genome sequence becomes a routine component of gene discovery studies in humans, we will have an exhaustive catalog of genetic variation and the challenge becomes understanding the phenotypic consequences of these variants. Statistical genetic methods and analytical approaches that are concerned with optimizing phenotypes for gene discovery for complex traits offer two general categories of advantages. They may increase power to localize genes of interest and also aid in interpreting associations between genetic variants and disease outcomes by suggesting potential mechanisms and pathways through which genes may affect outcomes. Such phenotype optimization approaches include use of allied phenotypes such as symptoms or ages of onset to reduce genetic heterogeneity within a set of cases, study of quantitative risk factors or endophenotypes, joint analyses of related phenotypes, and derivation of new phenotypes designed to extract independent measures underlying the correlations among a set of related phenotypes through approaches such as principal components. New opportunities are also presented by technological advances that permit efficient collection of hundreds or thousands of phenotypes on an individual, including phenotypes more proximal to the level of gene action such as levels of gene expression, microRNAs, or metabolic and proteomic profiles. Content Type Journal Article Category Review Paper Pages 1-8 DOI 10.1007/s00439-012-1191-1 Authors Laura Almasy, Department of Genetics, Texas Biomedical Research Institute, PO Box 760549, San Antonio, TX 78245-0549, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Rare disruptions of FOXP2 have been strongly implicated in deficits in language development. Research over the past decade has suggested a role in the formation of underlying neural circuits required for speech. Until recently no evidence existed to suggest that the closely related FOXP1 gene played a role in neurodevelopmental processes. However, in the last few years, novel rare disruptions in FOXP1 have been reported in multiple cases of cognitive dysfunction, including intellectual disability and autism spectrum disorder, together with language impairment. As FOXP1 and FOXP2 form heterodimers for transcriptional regulation, one may assume that they co-operate in common neurodevelopmental pathways through the co-regulation of common targets. Here we compare the phenotypic consequences of FOXP1 and FOXP2 impairment, drawing on well-known studies from the past as well as recent exciting findings and consider what these tell us regarding the functions of these two genes in neural development. Content Type Journal Article Category Review Paper Pages 1-12 DOI 10.1007/s00439-012-1193-z Authors Claire Bacon, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany Gudrun A. Rappold, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena. Content Type Journal Article Category Review Paper Pages 1-25 DOI 10.1007/s00439-012-1189-8 Authors Victoria K. Cortessis, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA Duncan C. Thomas, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., SSB-202F, Los Angeles, CA 90089-9234, USA A. Joan Levine, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA Carrie V. Breton, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., Los Angeles, CA 90089-9234, USA Thomas M. Mack, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA Kimberly D. Siegmund, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, 2001 N. Soto St., Los Angeles, CA 90089-9234, USA Robert W. Haile, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089, USA Peter W. Laird, Departments of Surgery, Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, USC Norris Comprehensive Cancer Center, Epigenome Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9601, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Vitamin D deficiency is becoming more apparent in many populations. Genetic factors may play a role in the maintenance of vitamin D levels. The objective of this study was to perform a genome-wide analysis (GWAS) of vitamin D levels, including replication of prior GWAS results. We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected at the time of enrollment and at year 4 in 572 Caucasian children with asthma, who were part of a multi-center clinical trial, the Childhood Asthma Management Program. Replication was performed in a second cohort of 592 asthmatics from Costa Rica and a third cohort of 516 Puerto Rican asthmatics. In addition, we attempted replication of three SNPs that were previously identified in a large GWAS of Caucasian individuals. The setting included data from a clinical trial of childhood asthmatics and two cohorts of asthmatics recruited for genetic studies of asthma. The main outcome measure was circulating 25(OH)D levels. The 25(OH)D levels at the two time-points were only modestly correlated with each other (intraclass correlation coefficient = 0.33) in the CAMP population. We identified SNPs that were nominally associated with 25(OH)D levels at two time-points in CAMP, and replicated four SNPs in the Costa Rican cohort: rs11002969, rs163221, rs1678849, and rs4864976. However, these SNPs were not significantly associated with 25(OH)D levels in a third population of Puerto Rican asthmatics. We were able to replicate the SNP with the strongest effect, previously reported in a large GWAS: rs2282679 ( GC ), and we were able to replicate another SNP, rs10741657 ( CYP2R1 ), to a lesser degree. We were able to replicate two of three prior significant findings in a GWAS of 25(OH)D levels. Other SNPs may be additionally associated with 25(OH)D levels in certain populations. Content Type Journal Article Category Original Investigation Pages 1-11 DOI 10.1007/s00439-012-1185-z Authors Jessica Lasky-Su, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA Nancy Lange, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA John M. Brehm, Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Amy Damask, Novartis Institutes for Biomedical Research, Cambridge, MA, USA Manuel Soto-Quiros, Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica Lydiana Avila, Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica Juan C. Celedón, Division of Pediatric Pulmonary Medicine, Allergy and Immunology, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA Glorisa Canino, Behavioral Sciences Institute, University of Puerto Rico, San Juan, PR, USA Michelle M. Cloutier, University of Connecticut Health Center, Farmington, CT, USA Bruce W. Hollis, Darby Children’s Research Institute, Medical University of South Carolina, Charleston, SC, USA Scott T. Weiss, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA Augusto A. Litonjua, Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Recent studies have identified PRDM9, a zinc finger (ZF) protein, as a key regulator of meiotic recombination. As both recurrent genomic disorders and chromosomal non-disjunction are known to be associated with specific unusual patterns of recombination, we hypothesized a possible link between PRDM9 ZF variation and susceptibility to microdeletion syndromes and/or trisomy. We sequenced the PRDM9 ZF domain in 271 parents of patients with de novo microdeletions of known parental origin (velocardiofacial syndrome, the 17q21.31 microdeletion syndrome, Prader-Willi/Angelman syndrome and Williams-Beuren syndrome), and in 61 parents of individuals with a supernumerary X chromosome. We compared PRDM9 ZF genotype frequencies between parents in whose germ line the de novo rearrangement occurred and their spouses. We observed a significantly increased frequency ( p  = 0.006) of PRDM9 variants in parents who transmitted de novo 7q11.23 deletions to their offspring. These data suggest that certain PRDM9 alleles may be associated with an increased susceptibility to recurrent 7q11.23 microdeletions that cause Williams-Beuren syndrome. However, as the majority of parents who transmitted a de novo microdeletion/supernumerary X chromosome to their offspring have the common AA genotype, we conclude that none of the rearrangements we have studied are dependent on specific non-A PRDM9 alleles. Content Type Journal Article Category Short Report Pages 1-6 DOI 10.1007/s00439-012-1180-4 Authors Christelle Borel, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA Fanny Cheung, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA Helen Stewart, Department of Clinical Genetics, Churchill Hospital, Oxford, OX3 7LJ UK David A. Koolen, Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Christopher Phillips, Forensic Genetics Unit, Institute of Legal Medicine, Faculty of Medicine, University of Santiago de Compostela, Galicia, Spain N. Simon Thomas, Wessex Regional Genetics Laboratory, Salisbury, SP2 8BJ UK Patricia A. Jacobs, Wessex Regional Genetics Laboratory, Salisbury, SP2 8BJ UK Stephan Eliez, Service Médico-Pédagogique, Department of Psychiatry, University of Geneva School of Medicine, Geneva, Switzerland Andrew J. Sharp, Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Beta-microseminoprotein (MSP)/MSMB is an immunoglobulin superfamily protein synthesized by prostate epithelial cells and secreted into seminal plasma. Variants in the promoter of the MSMB gene have been associated with the risk of prostate cancer (PCa) in several independent genome-wide association studies. Both MSMB and an adjacent gene, NCOA4, are subjected to transcriptional control via androgen response elements. The gene product of NCOA4 interacts directly with the androgen receptor as a co-activator to enhance AR transcriptional activity. Here, we provide evidence for the expression of full-length MSMB - NCOA4 fusion transcripts regulated by the MSMB promoter. The predominant MSMB - NCOA4 transcript arises by fusion of the 5′UTR and exons 1–2 of the MSMB pre-mRNA, with exons 2–10 of the NCOA4 pre-mRNA, producing a stable fusion protein, comprising the essential domains of NCOA4. Analysis of the splice sites of this transcript shows an unusually strong splice acceptor at NCOA4 exon 2 and the presence of Alu repeats flanking the exons potentially involved in the splicing event. Transfection experiments using deletion clones of the promoter coupled with luciferase reporter assays define a core MSMB promoter element located between −27 and −236 of the gene, and a negative regulatory element immediately upstream of the start codon. Computational network analysis reveals that the MSMB gene is functionally connected to NCOA4 and the androgen receptor signaling pathway. The data provide an example of how GWAS-associated variants may have multiple genetic and epigenetic effects. Content Type Journal Article Category Original Investigation Pages 1-14 DOI 10.1007/s00439-012-1182-2 Authors Hong Lou, Human Genetics Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA Hongchuan Li, Molecular Immunology Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA Meredith Yeager, Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA Kate Im, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA Bert Gold, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA Thomas D. Schneider, Gene Regulation and Chromosome Biology Laboratory, Molecular Information Theory Group, Frederick, MD 21702, USA Joseph F. Fraumeni Jr., Division of Cancer Epidemiology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA Stephen J. Chanock, Division of Cancer Epidemiology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA Stephen K. Anderson, Molecular Immunology Section, Basic Research Program, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, MD 21702, USA Michael Dean, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Smallpox is a deadly and debilitating disease that killed hundreds of millions of people in the past century alone. The use of Vaccinia virus-based smallpox vaccines led to the eradication of smallpox. These vaccines are remarkably effective, inducing the characteristic pustule or “take” at the vaccine site in 〉97 % of recipients, and inducing a wide spectrum of long-lasting humoral and cellular immune responses. The mechanisms behind inter-individual vaccine-response variability are likely to involve host genetic variation, but have not been fully characterized. We report here the first smallpox vaccine response genome-wide association study of over 1,000 recent recipients of Dryvax ® . The data presented here focus on cellular immune responses as measured by both production of secreted IFNγ and quantitation of IFNγ secreting cells by ELISPOT assay. We identified multiple significant SNP associations in genes (RASA1, ADRA1D, TCF7L1, FAS) that are critical components of signaling pathways that directly control lymphocyte IFNγ production or cytotoxic T cell function. Similarly, we found many associations with SNPs located in genes integral to nerve cell function; findings that, given the complex interplay between the nervous and immune systems, deserve closer examination in follow-up studies. Content Type Journal Article Category Original Investigation Pages 1-19 DOI 10.1007/s00439-012-1179-x Authors Richard B. Kennedy, Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN, USA Inna G. Ovsyannikova, Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN, USA V. Shane Pankratz, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA Iana H. Haralambieva, Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN, USA Robert A. Vierkant, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA Robert M. Jacobson, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA Gregory A. Poland, Mayo Vaccine Research Group, Mayo Clinic, Guggenheim 611C, 200 First Street SW, Rochester, MN 55905, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Recruiting research participants based on genetic information generated about them in a prior study is a potentially powerful way to study the functional significance of human genetic variation. However, it also presents significant ethical challenges that, to date, have received only minimal consideration. We convened a multi-disciplinary workshop to discuss key issues relevant to the conduct and oversight of genotype-driven recruitment and to translate those considerations into practical policy recommendations. Workshop participants were invited from around the US, and included genomic researchers and study coordinators, research participants, clinicians, bioethics scholars, experts in human research protections, and government representatives. Discussion was directed by experienced facilitators and informed by empirical data collected in a national survey of IRB chairs and in-depth interviews with research participants in studies where genotype-driven recontact occurred. A high degree of consensus was attained on the resulting seven recommendations, which cover informed consent disclosures and choices, the process for how and by whom participants are recontacted, the disclosure of individual genetic research results, and the importance of tailoring approaches based on specific contextual factors. These recommendations are intended to represent a balanced approach—protecting research participants, yet avoiding overly restrictive policies that hinder advancement on important scientific questions. Content Type Journal Article Category Original Investigation Pages 1-9 DOI 10.1007/s00439-012-1177-z Authors Laura M. Beskow, Duke Institute for Genome Sciences and Policy, Duke University, 240 North Building, Campus Box 90141, Durham, NC 27708, USA Stephanie M. Fullerton, Department of Bioethics and Humanities, University of Washington, Seattle, WA, USA Emily E. Namey, Duke Institute for Genome Sciences and Policy, Duke University, 240 North Building, Campus Box 90141, Durham, NC 27708, USA Daniel K. Nelson, Department of Social Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Arlene M. Davis, Department of Social Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Benjamin S. Wilfond, Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Research Institute, Seattle, WA, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10 −12 for SNP rs634990 in Caucasians, and 9.65 × 10 −4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10 −23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P  〈 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P  〈 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly ( P value 5.81 × 10 −2 for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide. Content Type Journal Article Category Original Investigation Pages 1-14 DOI 10.1007/s00439-012-1176-0 Authors Virginie J. M. Verhoeven, Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Pirro G. Hysi, Department of Twin Research and Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London, UK Seang-Mei Saw, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore Veronique Vitart, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK Alireza Mirshahi, Department of Ophthalmology, J. Gutenberg University Medical Center, Mainz, Germany Jeremy A. Guggenheim, School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK Mary Frances Cotch, Division of Epidemiology and Clinical Applications, National Eye Institute, Intramural Research Program, National Institutes of Health, Bethesda, USA Kenji Yamashiro, Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan Paul N. Baird, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia David A. Mackey, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia Robert Wojciechowski, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA M. Kamran Ikram, Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Alex W. Hewitt, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia Priya Duggal, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA Sarayut Janmahasatian, Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, USA Chiea-Chuen Khor, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore Qiao Fan, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore Xin Zhou, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore Terri L. Young, Center for Human Genetics, Duke University Medical Center, Durham, USA E-Shyong Tai, Department of Medicine, National University of Singapore, Singapore, Singapore Liang-Kee Goh, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore Yi-Ju Li, Center for Human Genetics, Duke University Medical Center, Durham, USA Tin Aung, Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore Eranga Vithana, Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore Yik-Ying Teo, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore Wanting Tay, Singapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore Xueling Sim, Centre for Molecular Epidemiology, National University of Singapore, Singapore, Singapore Igor Rudan, Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK Caroline Hayward, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK Alan F. Wright, Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK Ozren Polasek, Faculty of Medicine, University of Split, Split, Croatia Harry Campbell, Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK James F. Wilson, Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK Brian W. Fleck, Princess Alexandra Eye Pavilion, Edinburgh, UK Isao Nakata, Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan Nagahisa Yoshimura, Department of Ophthalmology, Kyoto University Graduate School of Medicine, Kyoto, Japan Ryo Yamada, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Fumihiko Matsuda, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan Kyoko Ohno-Matsui, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan Abhishek Nag, Department of Twin Research and Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London, UK George McMahon, School of Social and Community Medicine, University of Bristol, Bristol, UK Beate St. Pourcain, School of Social and Community Medicine, University of Bristol, Bristol, UK Yi Lu, Department of Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia Jugnoo S. Rahi, Medical Research Council Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, UK Phillippa M. Cumberland, Medical Research Council Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, UK Shomi Bhattacharya, Institute of Ophthalmology, University College London, London, UK Claire L. Simpson, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, USA Larry D. Atwood, Department of Neurology, Boston University School of Medicine, Boston, USA Xiaohui Li, Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, USA Leslie J. Raffel, Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, USA Federico Murgia, Institute of Population Genetics, National Research Council, Sassari, Italy Laura Portas, Institute of Population Genetics, National Research Council, Sassari, Italy Dominiek D. G. Despriet, Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Leonieke M. E. van Koolwijk, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Christian Wolfram, Department of Ophthalmology, J. Gutenberg University Medical Center, Mainz, Germany Karl J. Lackner, Department of Ophthalmology, J. Gutenberg University Medical Center, Mainz, Germany Anke Tönjes, Department of Medicine, University of Leipzig, Leipzig, Germany Reedik Mägi, Estonian Genome Center, University of Tartu, Tartu, Estonia Terho Lehtimäki, Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland Mika Kähönen, Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland Tõnu Esko, Estonian Genome Center, University of Tartu, Tartu, Estonia Andres Metspalu, Estonian Genome Center, University of Tartu, Tartu, Estonia Taina Rantanen, Department of Health Sciences, Gerontology Research Center, University of Jyväskylä, Jyväskylä, Finland Olavi Pärssinen, Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland Barbara E. Klein, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, USA Thomas Meitinger, Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology I, Neuherberg, Germany Timothy D. Spector, Department of Twin Research and Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London, UK Ben A. Oostra, Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands Albert V. Smith, Department of Medicine, University of Iceland, Reykjavik, Iceland Paulus T. V. M. de Jong, Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands Albert Hofman, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Najaf Amin, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Lennart C. Karssen, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Fernando Rivadeneira, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Johannes R. Vingerling, Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Guðný Eiríksdóttir, Icelandic Heart Association, Kopavogur, Iceland Vilmundur Gudnason, Department of Medicine, University of Iceland, Reykjavik, Iceland Angela Döring, Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology II, Neuherberg, Germany Thomas Bettecken, Center for Applied Genotyping, Max Planck Institute of Psychiatry, German Research Institute of Psychiatry, Munich, Germany André G. Uitterlinden, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Cathy Williams, Centre for Child and Adolescent Health, University of Bristol, Bristol, UK Tanja Zeller, Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany Raphaële Castagné, INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, Paris, France Konrad Oexle, Institute of Human Genetics, Technical University Munich, Munich, Germany Cornelia M. van Duijn, Department of Epidemiology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Sudha K. Iyengar, Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, USA Paul Mitchell, Department of Ophthalmology, Centre for Vision Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia Jie Jin Wang, Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Australia René Höhn, Department of Ophthalmology, J. Gutenberg University Medical Center, Mainz, Germany Norbert Pfeiffer, Department of Ophthalmology, J. Gutenberg University Medical Center, Mainz, Germany Joan E. Bailey-Wilson, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, USA Dwight Stambolian, Department of Ophthalmology, University of Pennsylvania, Philadelphia, USA Tien-Yin Wong, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore Christopher J. Hammond, Department of Twin Research and Genetic Epidemiology, King’s College London, St. Thomas’ Hospital, London, UK Caroline C. W. Klaver, Department of Ophthalmology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer. Content Type Journal Article Category Original Investigation Pages 1-14 DOI 10.1007/s00439-012-1183-1 Authors Wigdan Al-Sukhni, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Sarah Joe, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Anath C. Lionel, Program in Genetics and Genome Biology, The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada Nora Zwingerman, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada George Zogopoulos, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Christian R. Marshall, Program in Genetics and Genome Biology, The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada Ayelet Borgida, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Spring Holter, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Aaron Gropper, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Sara Moore, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Melissa Bondy, MD Anderson Cancer Center, Houston, TX, USA Alison P. Klein, The Sol Goldman Pancreatic Research Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA Gloria M. Petersen, Mayo Clinic College of Medicine, Rochester, MN, USA Kari G. Rabe, Mayo Clinic College of Medicine, Rochester, MN, USA Ann G. Schwartz, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA Sapna Syngal, Dana-Farber Cancer Institute, Boston, MA, USA Stephen W. Scherer, Program in Genetics and Genome Biology, The Centre for Applied Genomics, Hospital for Sick Children, Toronto, ON, Canada Steven Gallinger, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Premature to conclude no genetic basis to the association between smoking and major depressive disorder Content Type Journal Article Category Letter to the Editor Pages 1-2 DOI 10.1007/s00439-012-1169-z Authors David Lawrence, Centre for Child Health Research, The University of Western Australia, Telethon Institute for Child Health Research, PO Box 855, West Perth, WA 6872, Australia Francis Mitrou, Centre for Child Health Research, The University of Western Australia, Telethon Institute for Child Health Research, PO Box 855, West Perth, WA 6872, Australia Stephen R. Zubrick, Centre for Child Health Research, The University of Western Australia, Telethon Institute for Child Health Research, PO Box 855, West Perth, WA 6872, Australia Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung: Studies in a consanguineous family reveal a novel locus for stuttering on chromosome 16q Content Type Journal Article Category Short Report Pages 311-313 DOI 10.1007/s00439-011-1134-2 Authors Muhammad Hashim Raza, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, USA Rana Amjad, Allama Iqbal Medical Research Centre, University of Punjab, Lahore, Pakistan Sheikh Riazuddin, Allama Iqbal Medical Research Centre, University of Punjab, Lahore, Pakistan Dennis Drayna, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717 Journal Volume Volume 131 Journal Issue Volume 131, Number 2

Beschreibung:    Smoking and depression are significant public health problems with multiple etiological dimensions and outcomes. Although each condition is important by itself, they are important because they often potentiate each other. Consequently, it is also essential to understand the nature their relationship. This representative review focuses on the genetic etiology of the relationship in the context of reviewing first the epidemiology of depression and smoking, and then by exploring behavioral and molecular genetic studies, and other psychiatric and medical comorbidities. At this point, epidemiological evidence for a relationship between depression and smoking/nicotine dependence is compelling. Although behavioral genetic results differ somewhat by gender and in accordance with specific definitions of depression and smoking variables, recent studies show converging evidence for common genetic factors underlying the relationship, often in addition to non-shared environmental factors. The search for underlying genes and genetic mechanisms is at an early stage, but shows promising candidate genes and genetic approaches for future studies. Content Type Journal Article Category Review Paper Pages 1-11 DOI 10.1007/s00439-012-1170-6 Authors Ming T. Tsuang, Department of Psychiatry, Center for Behavioral Genomics, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA 92039, USA Tracee Francis, Massachusetts Mental Health Center Public Psychiatry Division, Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Kyle Minor, Massachusetts Mental Health Center Public Psychiatry Division, Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Alison Thomas, Department of Psychology, Suffolk University, Boston, MA, USA William S. Stone, Massachusetts Mental Health Center Public Psychiatry Division, Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Epidemiological studies of substance use and substance use disorders (SUDs) have provided an abundance of data on the patterns of substance use in nationally representative samples across the world (Degenhardt et al. in PLoS Med 5(7):e141, 2008 ; Johnston et al. in Monitoring the future national survey results on drug use, 1975–2010, vol I, secondary school students. Institute for Social Research, Ann Arbor, MI, 2011 ; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011 ). This paper presents a summary of the goals, methods, and recent findings on the epidemiology of substance use and disorders in the general population of adults and adolescents and describes the methods and findings on the genetic epidemiology of drug use disorders. The high 12-month prevalence rates of substance dependence in US adults (about 12 % for alcohol and 2–3 % for illicit drugs) approximate those of other mental disorders as well as chronic physical disorders with major public health impact. New findings from the nationally representative samples of US youth reveal that the lifetime prevalence of alcohol use disorders is approximately 8 % and illicit drug use disorders is 2–3 % (Merikangas et al. in J Am Acad Child Adolesc Psychiatry 49(10):980–989, 2010 ; Swendsen et al. in Arch Gen Psychiatry 69(4):390–398, 2012 ; SAMHSA in Results from the 2010 national survey on drug use and health: summary of national findings, vol NSDUH, Series H-41, HHS Publication No. (SMA) 11-4658. Substance Abuse and Mental Health Services Administration, Rockville, 2011 ). The striking increase in prevalence rates from ages 13 to 18 highlight adolescence as the key period of development of SUDs. The application of genetic epidemiological studies has consistently demonstrated that genetic factors have a major influence on progression of substance use to dependence, whereas environmental factors unique to the individual play an important role in exposure and initial use of substances. Identification of specific susceptibility genes and environmental factors that influence exposure and progression of drug use may enhance our ability to prevent and treat SUDs. Content Type Journal Article Category Review Paper Pages 1-11 DOI 10.1007/s00439-012-1168-0 Authors Kathleen R. Merikangas, Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892, USA Vetisha L. McClair, Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD 20892, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    Transgenic systems are widely used to study the cellular and molecular basis of human neurodegenerative diseases. A wide variety of model organisms have been utilized, including bacteria ( Escherichia coli ), plants ( Arabidopsis thaliana ), nematodes ( Caenorhabditis elegans ), arthropods ( Drosophila melanogaster ), fish (zebrafish, Danio rerio ), rodents (mouse, Mus musculus and rat, Rattus norvegicus ) as well as non-human primates (rhesus monkey, Macaca mulatta ). These transgenic systems have enormous value for understanding the pathophysiological basis of these disorders and have, in some cases, been instrumental in the development of therapeutic approaches to treat these conditions. In this review, we discuss the most commonly used model organisms and the methodologies available for the preparation of transgenic organisms. Moreover, we provide selected examples of the use of these technologies for the preparation of transgenic animal models of neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD) and Parkinson’s disease (PD) and discuss the application of these technologies to AD as an example of how transgenic modeling has affected the study of human neurodegenerative diseases. Content Type Journal Article Category Review Paper Pages 535-563 DOI 10.1007/s00439-011-1119-1 Authors Miguel A. Gama Sosa, Research and Development Service, 3F-20, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA Rita De Gasperi, Research and Development Service, 3F-20, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA Gregory A. Elder, Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717 Journal Volume Volume 131 Journal Issue Volume 131, Number 4

Beschreibung:    Here we summarize evidence obtained by our group during the last two decades, and contrasted it with a review of related data from the available literature to show that behavioral syndromes involving attention deficit/hyperactivity disorder (ADHD), externalizing disorders, and substance-use disorder (SUD) share similar signs and symptoms (i.e., have a biological basis as common syndromes), physiopathological and psychopathological mechanisms, and genetic factors. Furthermore, we will show that the same genetic variants harbored in different genes are associated with different syndromes and that non-linear interactions between genetic variants (epistasis) best explain phenotype severity, long-term outcome, and response to treatment. These data have been depicted in our studies by extended pedigrees, where ADHD, externalizing symptoms, and SUD segregate and co-segregate. Finally, we applied here a new formal network analysis using the set of significantly replicated genes that have been shown to be either associated and/or linked to ADHD, disruptive behaviors, and SUD in order to detect significantly enriched gene categories for protein and genetic interactions, pathways, co-expression, co-localization, and protein domain similarity. We found that networks related to pathways involved in axon guidance, regulation of synaptic transmission, and regulation of transmission of nerve impulse are overrepresented. In summary, we provide compiled evidence of complex networks of genotypes underlying a wide phenotype that involves SUD and externalizing disorders. Content Type Journal Article Category Review Paper Pages 1-13 DOI 10.1007/s00439-012-1164-4 Authors Mauricio Arcos-Burgos, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35, Room 1B-209, Bethesda, MD 20892-3717, USA Jorge I. Vélez, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35, Room 1B-209, Bethesda, MD 20892-3717, USA Benjamin D. Solomon, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35, Room 1B-209, Bethesda, MD 20892-3717, USA Maximilian Muenke, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35, Room 1B-209, Bethesda, MD 20892-3717, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717

Beschreibung:    The present study evaluated gene by development interaction in cigarettes smoked per day (CPD) in a longitudinal community-representative sample ( N  = 3,231) of Caucasian twins measured at ages 14, 17, 20, and 24. Biometric heritability analyses show strong heritabilities and shared environmental influences, as well as cross-age genetic and shared environmental correlations. Single nucleotide polymorphisms (SNPs) previously associated with CPD according to meta-analysis were summed to create a SNP score. At best, the SNP score accounted for 1 % of the variance in CPD. The results suggest developmental moderation with a larger significant SNP score effect on CPD at ages 20 and 24, and smaller non-significant effect at ages 14 and 17. These results are consistent with the notion that nicotine-specific genetic substance use risk is less important at younger ages, and becomes more important as individuals age into adulthood. In a complementary analysis, the same nicotine-relevant SNP score was unrelated to the frequency of alcohol use at ages 14, 17, 20, or 24. These results indicate that the SNP score is specific to nicotine in this small sample and that increased exposure to nicotine at ages 20 and 24 does not influence the extent of concurrent or later alcohol use. Increased sample sizes and replication or meta-analysis are necessary to confirm these results. The methods and results illustrate the importance and difficulty of considering developmental processes in understanding the interplay of genes and environment. Content Type Journal Article Category Review Paper Pages 1-11 DOI 10.1007/s00439-012-1167-1 Authors Scott I. Vrieze, University of Minnesota, 75 East River Road, Minneapolis, MN 55455, USA Matt McGue, University of Minnesota, 75 East River Road, Minneapolis, MN 55455, USA William G. Iacono, University of Minnesota, 75 East River Road, Minneapolis, MN 55455, USA Journal Human Genetics Online ISSN 1432-1203 Print ISSN 0340-6717