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  • 1
    Publication Date: 2012-02-22
    Description: Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299548/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299548/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉MacArthur, Daniel G -- Balasubramanian, Suganthi -- Frankish, Adam -- Huang, Ni -- Morris, James -- Walter, Klaudia -- Jostins, Luke -- Habegger, Lukas -- Pickrell, Joseph K -- Montgomery, Stephen B -- Albers, Cornelis A -- Zhang, Zhengdong D -- Conrad, Donald F -- Lunter, Gerton -- Zheng, Hancheng -- Ayub, Qasim -- DePristo, Mark A -- Banks, Eric -- Hu, Min -- Handsaker, Robert E -- Rosenfeld, Jeffrey A -- Fromer, Menachem -- Jin, Mike -- Mu, Xinmeng Jasmine -- Khurana, Ekta -- Ye, Kai -- Kay, Mike -- Saunders, Gary Ian -- Suner, Marie-Marthe -- Hunt, Toby -- Barnes, If H A -- Amid, Clara -- Carvalho-Silva, Denise R -- Bignell, Alexandra H -- Snow, Catherine -- Yngvadottir, Bryndis -- Bumpstead, Suzannah -- Cooper, David N -- Xue, Yali -- Romero, Irene Gallego -- 1000 Genomes Project Consortium -- Wang, Jun -- Li, Yingrui -- Gibbs, Richard A -- McCarroll, Steven A -- Dermitzakis, Emmanouil T -- Pritchard, Jonathan K -- Barrett, Jeffrey C -- Harrow, Jennifer -- Hurles, Matthew E -- Gerstein, Mark B -- Tyler-Smith, Chris -- 085532/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- BB/I02593X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- RG/09/012/28096/British Heart Foundation/United Kingdom -- U54 HG003273/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2012 Feb 17;335(6070):823-8. doi: 10.1126/science.1215040.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Hinxton, UK. macarthur@atgu.mgh.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22344438" target="_blank"〉PubMed〈/a〉
    Keywords: Disease/genetics ; Gene Expression ; Gene Frequency ; *Genetic Variation ; *Genome, Human ; Humans ; Phenotype ; Polymorphism, Single Nucleotide ; Proteins/*genetics ; Selection, Genetic
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-11-07
    Description: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491803/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491803/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jostins, Luke -- Ripke, Stephan -- Weersma, Rinse K -- Duerr, Richard H -- McGovern, Dermot P -- Hui, Ken Y -- Lee, James C -- Schumm, L Philip -- Sharma, Yashoda -- Anderson, Carl A -- Essers, Jonah -- Mitrovic, Mitja -- Ning, Kaida -- Cleynen, Isabelle -- Theatre, Emilie -- Spain, Sarah L -- Raychaudhuri, Soumya -- Goyette, Philippe -- Wei, Zhi -- Abraham, Clara -- Achkar, Jean-Paul -- Ahmad, Tariq -- Amininejad, Leila -- Ananthakrishnan, Ashwin N -- Andersen, Vibeke -- Andrews, Jane M -- Baidoo, Leonard -- Balschun, Tobias -- Bampton, Peter A -- Bitton, Alain -- Boucher, Gabrielle -- Brand, Stephan -- Buning, Carsten -- Cohain, Ariella -- Cichon, Sven -- D'Amato, Mauro -- De Jong, Dirk -- Devaney, Kathy L -- Dubinsky, Marla -- Edwards, Cathryn -- Ellinghaus, David -- Ferguson, Lynnette R -- Franchimont, Denis -- Fransen, Karin -- Gearry, Richard -- Georges, Michel -- Gieger, Christian -- Glas, Jurgen -- Haritunians, Talin -- Hart, Ailsa -- Hawkey, Chris -- Hedl, Matija -- Hu, Xinli -- Karlsen, Tom H -- Kupcinskas, Limas -- Kugathasan, Subra -- Latiano, Anna -- Laukens, Debby -- Lawrance, Ian C -- Lees, Charlie W -- Louis, Edouard -- Mahy, Gillian -- Mansfield, John -- Morgan, Angharad R -- Mowat, Craig -- Newman, William -- Palmieri, Orazio -- Ponsioen, Cyriel Y -- Potocnik, Uros -- Prescott, Natalie J -- Regueiro, Miguel -- Rotter, Jerome I -- Russell, Richard K -- Sanderson, Jeremy D -- Sans, Miquel -- Satsangi, Jack -- Schreiber, Stefan -- Simms, Lisa A -- Sventoraityte, Jurgita -- Targan, Stephan R -- Taylor, Kent D -- Tremelling, Mark -- Verspaget, Hein W -- De Vos, Martine -- Wijmenga, Cisca -- Wilson, David C -- Winkelmann, Juliane -- Xavier, Ramnik J -- Zeissig, Sebastian -- Zhang, Bin -- Zhang, Clarence K -- Zhao, Hongyu -- International IBD Genetics Consortium (IIBDGC) -- Silverberg, Mark S -- Annese, Vito -- Hakonarson, Hakon -- Brant, Steven R -- Radford-Smith, Graham -- Mathew, Christopher G -- Rioux, John D -- Schadt, Eric E -- Daly, Mark J -- Franke, Andre -- Parkes, Miles -- Vermeire, Severine -- Barrett, Jeffrey C -- Cho, Judy H -- 068545/Z/02/Wellcome Trust/United Kingdom -- 083948/Z/07/Z/Wellcome Trust/United Kingdom -- 085475/B/08/Z/Wellcome Trust/United Kingdom -- 085475/Z/08/Z/Wellcome Trust/United Kingdom -- 089120/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- AI062773/AI/NIAID NIH HHS/ -- CA141743/CA/NCI NIH HHS/ -- CZB/4/540/Chief Scientist Office/United Kingdom -- DK043351/DK/NIDDK NIH HHS/ -- DK062413/DK/NIDDK NIH HHS/ -- DK062420/DK/NIDDK NIH HHS/ -- DK062422/DK/NIDDK NIH HHS/ -- DK062423/DK/NIDDK NIH HHS/ -- DK062429/DK/NIDDK NIH HHS/ -- DK062429-S1/DK/NIDDK NIH HHS/ -- DK062431/DK/NIDDK NIH HHS/ -- DK062432/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK076984/DK/NIDDK NIH HHS/ -- DK084554/DK/NIDDK NIH HHS/ -- DK83756/DK/NIDDK NIH HHS/ -- ETM/137/Chief Scientist Office/United Kingdom -- ETM/75/Chief Scientist Office/United Kingdom -- G0000934/British Heart Foundation/United Kingdom -- G0600329/Medical Research Council/United Kingdom -- G0800675/Medical Research Council/United Kingdom -- G0800759/Medical Research Council/United Kingdom -- G1002033/Medical Research Council/United Kingdom -- K23 DK097142/DK/NIDDK NIH HHS/ -- M01-RR00425/RR/NCRR NIH HHS/ -- P01 DK046763/DK/NIDDK NIH HHS/ -- P01DK046763/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 CA141743/CA/NCI NIH HHS/ -- R01 DK055731/DK/NIDDK NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- T32GM07205/GM/NIGMS NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 DK062420/DK/NIDDK NIH HHS/ -- U01 DK062422/DK/NIDDK NIH HHS/ -- U01 DK062429/DK/NIDDK NIH HHS/ -- U01 DK062431/DK/NIDDK NIH HHS/ -- U01 DK062432/DK/NIDDK NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- UL1 TR000124-01/TR/NCATS NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23128233" target="_blank"〉PubMed〈/a〉
    Keywords: Colitis, Ulcerative/genetics/immunology/microbiology/physiopathology ; Crohn Disease/genetics/immunology/microbiology/physiopathology ; Genetic Predisposition to Disease/*genetics ; Genome, Human/genetics ; *Genome-Wide Association Study ; Haplotypes/genetics ; *Host-Pathogen Interactions/genetics/immunology ; Humans ; Inflammatory Bowel Diseases/*genetics/immunology/*microbiology/physiopathology ; Mycobacterium/*immunology/pathogenicity ; Mycobacterium Infections/genetics/microbiology ; Mycobacterium tuberculosis/immunology/pathogenicity ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-04-25
    Description: The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180223/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180223/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉MacArthur, D G -- Manolio, T A -- Dimmock, D P -- Rehm, H L -- Shendure, J -- Abecasis, G R -- Adams, D R -- Altman, R B -- Antonarakis, S E -- Ashley, E A -- Barrett, J C -- Biesecker, L G -- Conrad, D F -- Cooper, G M -- Cox, N J -- Daly, M J -- Gerstein, M B -- Goldstein, D B -- Hirschhorn, J N -- Leal, S M -- Pennacchio, L A -- Stamatoyannopoulos, J A -- Sunyaev, S R -- Valle, D -- Voight, B F -- Winckler, W -- Gunter, C -- P30 DK020595/DK/NIDDK NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- R01 HG007022/HG/NHGRI NIH HHS/ -- R01 HL117626/HL/NHLBI NIH HHS/ -- R01 MH101810/MH/NIMH NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Apr 24;508(7497):469-76. doi: 10.1038/nature13127.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Division of Genetics, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. ; 1] Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, Cambridge, Massachusetts 02139, USA [2] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98115, USA. ; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] NIH Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland 20892, USA [2] Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Departments of Bioengineering & Genetics, Stanford University, Stanford, California 94305, USA. ; 1] Department of Genetic Medicine, University of Geneva Medical School, 1211 Geneva, Switzerland [2] iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland. ; Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, Stanford, California 94305, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK. ; Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; Departments of Genetics, Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA. ; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. ; 1] Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06520, USA [2] Departments of Computer Science, Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA. ; Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina 27708, USA. ; 1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [2] Divisions of Genetics and Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA [2] US Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA. ; Department of Genome Sciences, University of Washington, 1705 Northeast Pacific Street, Seattle, Washington 98195, USA. ; 1] Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ; Department of Pharmacology and Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA. ; 1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [2] Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.). ; 1] HudsonAlpha Institute for Biotechnology, 601 Genome Way, Huntsville, Alabama 35806, USA [2] Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA (W.W.); Marcus Autism Center, Children's Healthcare of Atlanta, Atlanta, Georgia 30329, USA (C.G.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759409" target="_blank"〉PubMed〈/a〉
    Keywords: *Disease ; False Positive Reactions ; Genes/genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; *Guidelines as Topic ; Humans ; Information Dissemination ; Publishing ; Reproducibility of Results ; Research Design ; Translational Medical Research/standards
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 1995-05-12
    Description: A gene from human chromosome 11p11.2 was isolated and was shown to suppress metastasis when introduced into rat AT6.1 prostate cancer cells. Expression of this gene, designated KAI1, was reduced in human cell lines derived from metastatic prostate tumors. KAI1 specifies a protein of 267 amino acids, with four hydrophobic and presumably transmembrane domains and one large extracellular hydrophilic domain with three potential N-glycosylation sites. KAI1 is evolutionarily conserved, is expressed in many human tissues, and encodes a member of a structurally distinct family of leukocyte surface glycoproteins. Decreased expression of this gene may be involved in the malignant progression of prostate and other cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, J T -- Lamb, P W -- Rinker-Schaeffer, C W -- Vukanovic, J -- Ichikawa, T -- Isaacs, J T -- Barrett, J C -- CA 58236/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1995 May 12;268(5212):884-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7754374" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antigens, CD/chemistry/*genetics/physiology ; Antigens, CD82 ; Base Sequence ; Biological Evolution ; *Chromosomes, Human, Pair 11 ; Gene Expression ; *Genes, Tumor Suppressor ; Humans ; Male ; Membrane Glycoproteins/chemistry/*genetics/physiology ; Mice ; Mice, SCID ; Molecular Sequence Data ; Neoplasm Metastasis/*genetics ; Prostatic Neoplasms/*genetics/pathology ; *Proto-Oncogene Proteins ; Rats ; Transfection ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2007-04-17
    Description: Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646098/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frayling, Timothy M -- Timpson, Nicholas J -- Weedon, Michael N -- Zeggini, Eleftheria -- Freathy, Rachel M -- Lindgren, Cecilia M -- Perry, John R B -- Elliott, Katherine S -- Lango, Hana -- Rayner, Nigel W -- Shields, Beverley -- Harries, Lorna W -- Barrett, Jeffrey C -- Ellard, Sian -- Groves, Christopher J -- Knight, Bridget -- Patch, Ann-Marie -- Ness, Andrew R -- Ebrahim, Shah -- Lawlor, Debbie A -- Ring, Susan M -- Ben-Shlomo, Yoav -- Jarvelin, Marjo-Riitta -- Sovio, Ulla -- Bennett, Amanda J -- Melzer, David -- Ferrucci, Luigi -- Loos, Ruth J F -- Barroso, Ines -- Wareham, Nicholas J -- Karpe, Fredrik -- Owen, Katharine R -- Cardon, Lon R -- Walker, Mark -- Hitman, Graham A -- Palmer, Colin N A -- Doney, Alex S F -- Morris, Andrew D -- Smith, George Davey -- Hattersley, Andrew T -- McCarthy, Mark I -- 079557/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0500070/Medical Research Council/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- Z99 AG999999/Intramural NIH HHS/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2007 May 11;316(5826):889-94. Epub 2007 Apr 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17434869" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue ; Adolescent ; Adult ; Aged ; Alleles ; Birth Weight ; *Body Mass Index ; Case-Control Studies ; Child ; Cohort Studies ; Diabetes Mellitus, Type 2/*genetics ; Female ; *Genetic Predisposition to Disease ; Great Britain ; Homozygote ; Humans ; Infant, Newborn ; Male ; Middle Aged ; Obesity/*genetics ; Overweight/genetics ; *Polymorphism, Single Nucleotide
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2007-04-28
    Description: The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772310/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772310/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zeggini, Eleftheria -- Weedon, Michael N -- Lindgren, Cecilia M -- Frayling, Timothy M -- Elliott, Katherine S -- Lango, Hana -- Timpson, Nicholas J -- Perry, John R B -- Rayner, Nigel W -- Freathy, Rachel M -- Barrett, Jeffrey C -- Shields, Beverley -- Morris, Andrew P -- Ellard, Sian -- Groves, Christopher J -- Harries, Lorna W -- Marchini, Jonathan L -- Owen, Katharine R -- Knight, Beatrice -- Cardon, Lon R -- Walker, Mark -- Hitman, Graham A -- Morris, Andrew D -- Doney, Alex S F -- Wellcome Trust Case Control Consortium (WTCCC) -- McCarthy, Mark I -- Hattersley, Andrew T -- 083948/Wellcome Trust/United Kingdom -- 090532/Wellcome Trust/United Kingdom -- G0000934/Medical Research Council/United Kingdom -- G0500070/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2007 Jun 1;316(5829):1336-41. Epub 2007 Apr 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17463249" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Case-Control Studies ; Chromosome Mapping ; Diabetes Mellitus, Type 2/*genetics ; Female ; Genes, p16 ; *Genetic Predisposition to Disease ; *Genome, Human ; Great Britain ; Homeodomain Proteins/genetics ; Humans ; Insulin-Like Growth Factor Binding Proteins/genetics ; Introns ; Male ; Meta-Analysis as Topic ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; *Polymorphism, Single Nucleotide ; Transcription Factors/genetics
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2013-10-19
    Description: Genetic mutations cause primary immunodeficiencies (PIDs) that predispose to infections. Here, we describe activated PI3K-delta syndrome (APDS), a PID associated with a dominant gain-of-function mutation in which lysine replaced glutamic acid at residue 1021 (E1021K) in the p110delta protein, the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kdelta), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated families, but not among 3346 healthy subjects. APDS was characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, and reduced immunoglobulin G2 levels in serum and impaired vaccine responses. The E1021K mutation enhanced membrane association and kinase activity of p110delta. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110delta inhibitors IC87114 and GS-1101 reduced the activity of the mutant enzyme in vitro, which suggested a therapeutic approach for patients with APDS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930011/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Angulo, Ivan -- Vadas, Oscar -- Garcon, Fabien -- Banham-Hall, Edward -- Plagnol, Vincent -- Leahy, Timothy R -- Baxendale, Helen -- Coulter, Tanya -- Curtis, James -- Wu, Changxin -- Blake-Palmer, Katherine -- Perisic, Olga -- Smyth, Deborah -- Maes, Mailis -- Fiddler, Christine -- Juss, Jatinder -- Cilliers, Deirdre -- Markelj, Gasper -- Chandra, Anita -- Farmer, George -- Kielkowska, Anna -- Clark, Jonathan -- Kracker, Sven -- Debre, Marianne -- Picard, Capucine -- Pellier, Isabelle -- Jabado, Nada -- Morris, James A -- Barcenas-Morales, Gabriela -- Fischer, Alain -- Stephens, Len -- Hawkins, Phillip -- Barrett, Jeffrey C -- Abinun, Mario -- Clatworthy, Menna -- Durandy, Anne -- Doffinger, Rainer -- Chilvers, Edwin R -- Cant, Andrew J -- Kumararatne, Dinakantha -- Okkenhaug, Klaus -- Williams, Roger L -- Condliffe, Alison -- Nejentsev, Sergey -- 095198/Wellcome Trust/United Kingdom -- 095198/Z/10/Z/Wellcome Trust/United Kingdom -- 095691/Wellcome Trust/United Kingdom -- BB/J004456/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Cambridge, Cambridge, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24136356" target="_blank"〉PubMed〈/a〉
    Keywords: Class I Phosphatidylinositol 3-Kinases ; *Genetic Predisposition to Disease ; Humans ; Immunologic Deficiency Syndromes/*genetics/immunology/*pathology ; Lymphocytes/immunology ; Mutation ; Pedigree ; Phosphatidylinositol 3-Kinases/*genetics ; Phosphatidylinositol Phosphates/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Respiratory Tract Infections/*genetics/immunology/*pathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 1988-07-01
    Description: Arsenic is a well-established carcinogen in humans, but there is little evidence for its carcinogenicity in animals and it is inactive as an initiator or tumor promoter in two-stage models of carcinogenicity in mice. Two arsenic salts (sodium arsenite and sodium arsenate) induced a high frequency of methotrexate-resistant 3T6 cells, which were shown to have amplified copies of the dihydrofolate reductase gene. The ability of arsenic to induce gene amplification may relate to its carcinogenic effects in humans since amplification of oncogenes is observed in many human tumors. The inability of arsenic to induce gene mutations may relate to the negative results of arsenic in long-term animal studies and suggests that these experiments may not detect some environmental agents that act late in the carcinogenic process in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, T C -- Tanaka, N -- Lamb, P W -- Gilmer, T M -- Barrett, J C -- New York, N.Y. -- Science. 1988 Jul 1;241(4861):79-81.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/3388020" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arsenates/*pharmacology ; Arsenic/*pharmacology ; *Arsenites ; Cell Line ; DNA/genetics ; Drug Resistance ; Gene Amplification/*drug effects ; Humans ; Methotrexate ; Mice ; Neoplasms, Experimental/chemically induced/genetics ; Nucleic Acid Hybridization ; Oncogenes ; *Sodium Compounds ; Tetrahydrofolate Dehydrogenase/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 1990-02-09
    Description: The control of cellular senescence by specific human chromosomes was examined in interspecies cell hybrids between diploid human fibroblasts and an immortal, Syrian hamster cell line. Most such hybrids exhibited a limited life span comparable to that of the human fibroblasts, indicating that cellular senescence is dominant in these hybrids. Karyotypic analyses of the hybrid clones that did not senesce revealed that all these clones had lost both copies of human chromosome 1, whereas all other human chromosomes were observed in at least some of the immortal hybrids. The application of selective pressure for retention of human chromosome 1 to the cell hybrids resulted in an increased percentage of hybrids that senesced. Further, the introduction of a single copy of human chromosome 1 to the hamster cells by microcell fusion caused typical signs of cellular senescence. Transfer of chromosome 11 had no effect on the growth of the cells. These findings indicate that human chromosome 1 may participate in the control of cellular senescence and further support a genetic basis for cellular senescence.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sugawara, O -- Oshimura, M -- Koi, M -- Annab, L A -- Barrett, J C -- New York, N.Y. -- Science. 1990 Feb 9;247(4943):707-10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2300822" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Survival/*genetics ; Chromosome Mapping ; *Chromosomes, Human, Pair 1 ; Clone Cells ; Cricetinae ; Diploidy ; Fibroblasts/*cytology ; Humans ; Hybrid Cells/*cytology ; Hypoxanthine Phosphoribosyltransferase/genetics ; Karyotyping ; Mice ; Ploidies ; Transfection ; Translocation, Genetic ; X Chromosome
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 1996-05-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huff, J -- Bucher, J -- Barrett, J C -- New York, N.Y. -- Science. 1996 May 24;272(5265):1083-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8638144" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carcinogenicity Tests ; Carcinogens/*toxicity ; Female ; Humans ; Liver Neoplasms, Experimental/chemically induced ; Lung Neoplasms/chemically induced ; Male ; Methylene Chloride/*toxicity ; Mice ; Mutagens/*toxicity ; Neoplasms/*chemically induced ; Rats
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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