ALBERT

Description: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P 〈 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185210/" 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/PMC4185210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perry, John R B -- Day, Felix -- Elks, Cathy E -- Sulem, Patrick -- Thompson, Deborah J -- Ferreira, Teresa -- He, Chunyan -- Chasman, Daniel I -- Esko, Tonu -- Thorleifsson, Gudmar -- Albrecht, Eva -- Ang, Wei Q -- Corre, Tanguy -- Cousminer, Diana L -- Feenstra, Bjarke -- Franceschini, Nora -- Ganna, Andrea -- Johnson, Andrew D -- Kjellqvist, Sanela -- Lunetta, Kathryn L -- McMahon, George -- Nolte, Ilja M -- Paternoster, Lavinia -- Porcu, Eleonora -- Smith, Albert V -- Stolk, Lisette -- Teumer, Alexander -- Tsernikova, Natalia -- Tikkanen, Emmi -- Ulivi, Sheila -- Wagner, Erin K -- Amin, Najaf -- Bierut, Laura J -- Byrne, Enda M -- Hottenga, Jouke-Jan -- Koller, Daniel L -- Mangino, Massimo -- Pers, Tune H -- Yerges-Armstrong, Laura M -- Hua Zhao, Jing -- Andrulis, Irene L -- Anton-Culver, Hoda -- Atsma, Femke -- Bandinelli, Stefania -- Beckmann, Matthias W -- Benitez, Javier -- Blomqvist, Carl -- Bojesen, Stig E -- Bolla, Manjeet K -- Bonanni, Bernardo -- Brauch, Hiltrud -- Brenner, Hermann -- Buring, Julie E -- Chang-Claude, Jenny -- Chanock, Stephen -- Chen, Jinhui -- Chenevix-Trench, Georgia -- Collee, J Margriet -- Couch, Fergus J -- Couper, David -- Coviello, Andrea D -- Cox, Angela -- Czene, Kamila -- D'adamo, Adamo Pio -- Davey Smith, George -- De Vivo, Immaculata -- Demerath, Ellen W -- Dennis, Joe -- Devilee, Peter -- Dieffenbach, Aida K -- Dunning, Alison M -- Eiriksdottir, Gudny -- Eriksson, Johan G -- Fasching, Peter A -- Ferrucci, Luigi -- Flesch-Janys, Dieter -- Flyger, Henrik -- Foroud, Tatiana -- Franke, Lude -- Garcia, Melissa E -- Garcia-Closas, Montserrat -- Geller, Frank -- de Geus, Eco E J -- Giles, Graham G -- Gudbjartsson, Daniel F -- Gudnason, Vilmundur -- Guenel, Pascal -- Guo, Suiqun -- Hall, Per -- Hamann, Ute -- Haring, Robin -- Hartman, Catharina A -- Heath, Andrew C -- Hofman, Albert -- Hooning, Maartje J -- Hopper, John L -- Hu, Frank B -- Hunter, David J -- Karasik, David -- Kiel, Douglas P -- Knight, Julia A -- Kosma, Veli-Matti -- Kutalik, Zoltan -- Lai, Sandra -- Lambrechts, Diether -- Lindblom, Annika -- Magi, Reedik -- Magnusson, Patrik K -- Mannermaa, Arto -- Martin, Nicholas G -- Masson, Gisli -- McArdle, Patrick F -- McArdle, Wendy L -- Melbye, Mads -- Michailidou, Kyriaki -- Mihailov, Evelin -- Milani, Lili -- Milne, Roger L -- Nevanlinna, Heli -- Neven, Patrick -- Nohr, Ellen A -- Oldehinkel, Albertine J -- Oostra, Ben A -- Palotie, Aarno -- Peacock, Munro -- Pedersen, Nancy L -- Peterlongo, Paolo -- Peto, Julian -- Pharoah, Paul D P -- Postma, Dirkje S -- Pouta, Anneli -- Pylkas, Katri -- Radice, Paolo -- Ring, Susan -- Rivadeneira, Fernando -- Robino, Antonietta -- Rose, Lynda M -- Rudolph, Anja -- Salomaa, Veikko -- Sanna, Serena -- Schlessinger, David -- Schmidt, Marjanka K -- Southey, Mellissa C -- Sovio, Ulla -- Stampfer, Meir J -- Stockl, Doris -- Storniolo, Anna M -- Timpson, Nicholas J -- Tyrer, Jonathan -- Visser, Jenny A -- Vollenweider, Peter -- Volzke, Henry -- Waeber, Gerard -- Waldenberger, Melanie -- Wallaschofski, Henri -- Wang, Qin -- Willemsen, Gonneke -- Winqvist, Robert -- Wolffenbuttel, Bruce H R -- Wright, Margaret J -- Australian Ovarian Cancer Study -- GENICA Network -- kConFab -- LifeLines Cohort Study -- InterAct Consortium -- Early Growth Genetics (EGG) Consortium -- Boomsma, Dorret I -- Econs, Michael J -- Khaw, Kay-Tee -- Loos, Ruth J F -- McCarthy, Mark I -- Montgomery, Grant W -- Rice, John P -- Streeten, Elizabeth A -- Thorsteinsdottir, Unnur -- van Duijn, Cornelia M -- Alizadeh, Behrooz Z -- Bergmann, Sven -- Boerwinkle, Eric -- Boyd, Heather A -- Crisponi, Laura -- Gasparini, Paolo -- Gieger, Christian -- Harris, Tamara B -- Ingelsson, Erik -- Jarvelin, Marjo-Riitta -- Kraft, Peter -- Lawlor, Debbie -- Metspalu, Andres -- Pennell, Craig E -- Ridker, Paul M -- Snieder, Harold -- Sorensen, Thorkild I A -- Spector, Tim D -- Strachan, David P -- Uitterlinden, Andre G -- Wareham, Nicholas J -- Widen, Elisabeth -- Zygmunt, Marek -- Murray, Anna -- Easton, Douglas F -- Stefansson, Kari -- Murabito, Joanne M -- Ong, Ken K -- 098381/Wellcome Trust/United Kingdom -- 10118/Cancer Research UK/United Kingdom -- G0701863/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106179472/Medical Research Council/United Kingdom -- MC_UU_12013/1/Medical Research Council/United Kingdom -- MC_UU_12013/3/Medical Research Council/United Kingdom -- MC_UU_12015/1/Medical Research Council/United Kingdom -- MC_UU_12015/2/Medical Research Council/United Kingdom -- MR/J012165/1/Medical Research Council/United Kingdom -- P50 CA116201/CA/NCI NIH HHS/ -- R01 AG041517/AG/NIA NIH HHS/ -- UL1 TR001108/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Oct 2;514(7520):92-7. doi: 10.1038/nature13545. Epub 2014 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. [3] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [4] Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. [5]. ; 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2]. ; 1] deCODE Genetics, Reykjavik IS-101, Iceland. [2]. ; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. ; 1] Department of Epidemiology, Indiana University Richard M Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA. [2] Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202, USA. ; 1] Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. [2] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [3] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA. [4] Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Institute of Genetic Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-85764 Neuherberg, Germany. ; School of Women's and Infants' Health, The University of Western Australia, WA-6009, Australia. ; 1] Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland. [2] Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland. ; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. ; Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark. ; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599-7400, USA. ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden. ; NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA. ; Science for Life Laboratory, Karolinska Institutet, Stockholm, Box 1031, 17121 Solna, Sweden. ; 1] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA. [2] Boston University School of Public Health, Department of Biostatistics, Boston, Massachusetts 02118, USA. ; 1] MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. [2] School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. ; Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; 1] Institute of Genetics and Biomedical Research, National Research Council, Cagliari, 09042 Sardinia, Italy. [2] University of Sassari, Department of Biomedical Sciences, 07100 Sassari, Italy. ; 1] Icelandic Heart Association, IS-201 Kopavogur, Iceland. [2] University of Iceland, IS-101 Reykjavik, Iceland. ; 1] Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands. [2] Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands. ; Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany. ; 1] Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. [2] Department of Biotechnology, University of Tartu, 51010 Tartu, Estonia. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Hjelt Institute, University of Helsinki, FI-00014, Finland. ; Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy. ; Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, 3015 GE, Rotterdam, the Netherlands. ; Department of Psychiatry, Washington University, St Louis, Missouri 63110, USA. ; 1] The University of Queensland, Queensland Brain Institute, St Lucia, Queensland 4072, Australia. [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. ; Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands. ; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-3082, USA. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; 1] Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA. [2] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA. [3] Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical 142 University of Denmark, DK-2800 Lyngby, Denmark. ; Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. ; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. ; 1] Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; Department of Epidemiology, University of California Irvine, Irvine, California 92697-7550, USA. ; Sanquin Research, 6525 GA Nijmegen, The Netherlands. ; 1] Tuscany Regional Health Agency, Florence, Italy, I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, 50134 Florence, Italy. [2] Geriatric Unit, Azienda Sanitaria di Firenze, 50122 Florence, Italy. ; University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany. ; 1] Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain. [2] Centro de Investigacion en Red de Enfermedades Raras (CIBERER), E-46010 Valencia, Spain. ; Department of Oncology, University of Helsinki and Helsinki University Central Hospital, FI-00100 Helsinki, Finland. ; 1] Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark. [2] Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark. ; Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), 20139 Milan, Italy. ; 1] DrMargarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany. [2] University of Tubingen, D-72074 Tubingen, Germany. ; 1] Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. [2] German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany. ; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany. ; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA. ; 1] Departments of Anatomy and Neurological Surgery, Indiana University school of Medicine, Indianapolis, Indiana 46202, USA. [2] Stark Neuroscience Research Center, Indiana University school of Medicine, Indianapolis, Indiana 46202, USA. ; Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006 Australia. ; Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA. ; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599-7420, USA. ; Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, Massachusetts 02118, USA. ; Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK. ; 1] Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", 34137 Trieste, Italy. [2] Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, 34149 Trieste, Italy. ; 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Department of Human Genetics &Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands. ; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge CB1 8RN, UK. ; Icelandic Heart Association, IS-201 Kopavogur, Iceland. ; 1] National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of General Practice and Primary health Care, University of Helsinki, FI-00014 Helsinki, Finland. [3] Helsinki University Central Hospital, Unit of General Practice, FI-00029 HUS Helsinki, Finland. [4] Folkhalsan Research Centre, FI-00290 Helsinki, Finland. ; Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 20892, USA. ; Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, D-20246 Hamburg, Germany. ; Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark. ; Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands. ; National Insitute on Aging, National Institutes of Health, Baltimore, Maryland 20892, USA. ; 1] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. [2] Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK. ; 1] Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands. [2] EMGO + Institute for Health and Care Research, VU University Medical Centre, Van der Boechorststraat 7, 1081 Bt, Amsterdam, The Netherlands. ; 1] Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia. [2] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. ; 1] deCODE Genetics, Reykjavik IS-101, Iceland. [2] Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. ; 1] Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, F-94807 Villejuif, France. [2] University Paris-Sud, UMRS 1018, F-94807 Villejuif, France. ; Department of Obstetrics and Gynecology, Southern Medical University, 510515 Guangzhou, China. ; Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany. ; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. ; Department of Psychiatry, University of Groningen, University Medical Center Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands. ; Washington University, Department of Psychiatry, St Louis, Missouri 63110, USA. ; Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands. ; Department of Medical Oncology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. ; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia. ; 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; 1] Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA. [2] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [3] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts 02131, USA. ; 1] Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts 02131, USA. [2] Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada. ; 1] School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland. [2] Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, P.O. Box 100, FI-70029 Kuopio, Finland. ; Institute of Genetics and Biomedical Research, National Research Council, Cagliari, 09042 Sardinia, Italy. ; 1] Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium. [2] Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium. ; Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden. ; Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia. ; School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. ; 1] Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark. [2] Department of Medicine, Stanford School of Medicine, Stanford, California 94305-5101, USA. ; Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 100, FI-00029 HUS Helsinki, Finland. ; KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, 3000 Leuven, Belgium. ; Research Unit of Obstetrics &Gynecology, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark. ; Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. ; 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland. [2] Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Psychiatric &Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy. ; Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. ; University Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands. ; 1] National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. [2] Department of Obstetrics and Gynecology, Oulu University Hospital, P.O. Box 10, FI-90029 OYS Oulu, Finland. ; Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital/NordLab Oulu, P.O. Box 3000, FI-90014 Oulu, Finland. ; Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy. ; 1] Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands. [2] Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands. [3] Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland. ; National Institute on Aging, Intramural Research Program, Baltimore, Maryland 21224-6825, USA. ; Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Postbus 90203, 1006 BE Amsterdam, The Netherlands. ; Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia. ; 1] Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. [2] Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK. ; 1] Institute of Epidemiology II, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-8576 Neuherberg, Germany. [2] Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians-University, D-81377 Munich, Germany. ; Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands. ; Department of Internal Medicine, Lausanne University Hospital, CH-1015 Lausanne, Switzerland. ; 1] Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. ; Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen - German Research Center for Environmental Health, D-8576 Neuherberg, Germany. ; 1] Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany. ; Department of Endocrinology, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands. ; Queensland Insitute of Medical Research, Brisbane, Queensland 4029, Australia. ; 1] Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-3082, USA. [2] Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. ; Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 0QQ, UK. ; 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, Box 1003, New York, New York 10029, USA. ; 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. [2] NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK. [3] Oxford Centre for Diabetes, Endocrinology, &Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. ; 1] Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. [2] Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, Baltimore, Maryland 21201, USA. ; 1] Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands. [2] Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, 3015 GE, Rotterdam, the Netherlands. [3] Centre of Medical Systems Biology, PO Box 9600, 2300 RC Leiden, the Netherlands. ; Human Genetics Center and Divof Epidemiology, University of Houston, P.O. Box 20186, Texas 77025 USA. ; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Box 256, 751 05 Uppsala, Sweden. ; 1] Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK. [2] Institute of Health Sciences, University of Oulu, P.O. Box 5000, FI-90014 Oulu, Finland. [3] Biocenter Oulu, University of Oulu, P.O. Box 5000, Aapistie 5A, FI-90014 Oulu, Finland. [4] Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland. [5] Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, FI-90220 Oulu, 90029 OYS, Finland. ; 1] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. [2] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; 1] Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Denmark. [2] Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, DK-2000 Frederiksberg, Denmark. ; Division of Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK. ; Department of Obstetrics and Gynecology, University Medicine Greifswald, D-17475 Greifswald, Germany. ; University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK. ; 1] deCODE Genetics, Reykjavik IS-101, Iceland. [2] Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland. [3]. ; 1] NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA. [2] Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts 02118, USA. [3]. ; 1] MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. [2] Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK. [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25231870" target="_blank"〉PubMed〈/a〉

Description: Mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent-offspring trios at high coverage. We show that in our samples, with an average father's age of 29.7, the average de novo mutation rate is 1.20 x 10(-8) per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father's age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father's age on the risk of diseases such as schizophrenia and autism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548427/" 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/PMC3548427/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kong, Augustine -- Frigge, Michael L -- Masson, Gisli -- Besenbacher, Soren -- Sulem, Patrick -- Magnusson, Gisli -- Gudjonsson, Sigurjon A -- Sigurdsson, Asgeir -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Wong, Wendy S W -- Sigurdsson, Gunnar -- Walters, G Bragi -- Steinberg, Stacy -- Helgason, Hannes -- Thorleifsson, Gudmar -- Gudbjartsson, Daniel F -- Helgason, Agnar -- Magnusson, Olafur Th -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- MH071425/MH/NIMH NIH HHS/ -- R01 MH071425/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Aug 23;488(7412):471-5. doi: 10.1038/nature11396.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland. kong@decode.is〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22914163" target="_blank"〉PubMed〈/a〉

Description: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P 〈 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623669/" 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/PMC3623669/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van der Harst, Pim -- Zhang, Weihua -- Mateo Leach, Irene -- Rendon, Augusto -- Verweij, Niek -- Sehmi, Joban -- Paul, Dirk S -- Elling, Ulrich -- Allayee, Hooman -- Li, Xinzhong -- Radhakrishnan, Aparna -- Tan, Sian-Tsung -- Voss, Katrin -- Weichenberger, Christian X -- Albers, Cornelis A -- Al-Hussani, Abtehale -- Asselbergs, Folkert W -- Ciullo, Marina -- Danjou, Fabrice -- Dina, Christian -- Esko, Tonu -- Evans, David M -- Franke, Lude -- Gogele, Martin -- Hartiala, Jaana -- Hersch, Micha -- Holm, Hilma -- Hottenga, Jouke-Jan -- Kanoni, Stavroula -- Kleber, Marcus E -- Lagou, Vasiliki -- Langenberg, Claudia -- Lopez, Lorna M -- Lyytikainen, Leo-Pekka -- Melander, Olle -- Murgia, Federico -- Nolte, Ilja M -- O'Reilly, Paul F -- Padmanabhan, Sandosh -- Parsa, Afshin -- Pirastu, Nicola -- Porcu, Eleonora -- Portas, Laura -- Prokopenko, Inga -- Ried, Janina S -- Shin, So-Youn -- Tang, Clara S -- Teumer, Alexander -- Traglia, Michela -- Ulivi, Sheila -- Westra, Harm-Jan -- Yang, Jian -- Zhao, Jing Hua -- Anni, Franco -- Abdellaoui, Abdel -- Attwood, Antony -- Balkau, Beverley -- Bandinelli, Stefania -- Bastardot, Francois -- Benyamin, Beben -- Boehm, Bernhard O -- Cookson, William O -- Das, Debashish -- de Bakker, Paul I W -- de Boer, Rudolf A -- de Geus, Eco J C -- de Moor, Marleen H -- Dimitriou, Maria -- Domingues, Francisco S -- Doring, Angela -- Engstrom, Gunnar -- Eyjolfsson, Gudmundur Ingi -- Ferrucci, Luigi -- Fischer, Krista -- Galanello, Renzo -- Garner, Stephen F -- Genser, Bernd -- Gibson, Quince D -- Girotto, Giorgia -- Gudbjartsson, Daniel Fannar -- Harris, Sarah E -- Hartikainen, Anna-Liisa -- Hastie, Claire E -- Hedblad, Bo -- Illig, Thomas -- Jolley, Jennifer -- Kahonen, Mika -- Kema, Ido P -- Kemp, John P -- Liang, Liming -- Lloyd-Jones, Heather -- Loos, Ruth J F -- Meacham, Stuart -- Medland, Sarah E -- Meisinger, Christa -- Memari, Yasin -- Mihailov, Evelin -- Miller, Kathy -- Moffatt, Miriam F -- Nauck, Matthias -- Novatchkova, Maria -- Nutile, Teresa -- Olafsson, Isleifur -- Onundarson, Pall T -- Parracciani, Debora -- Penninx, Brenda W -- Perseu, Lucia -- Piga, Antonio -- Pistis, Giorgio -- Pouta, Anneli -- Puc, Ursula -- Raitakari, Olli -- Ring, Susan M -- Robino, Antonietta -- Ruggiero, Daniela -- Ruokonen, Aimo -- Saint-Pierre, Aude -- Sala, Cinzia -- Salumets, Andres -- Sambrook, Jennifer -- Schepers, Hein -- Schmidt, Carsten Oliver -- Sillje, Herman H W -- Sladek, Rob -- Smit, Johannes H -- Starr, John M -- Stephens, Jonathan -- Sulem, Patrick -- Tanaka, Toshiko -- Thorsteinsdottir, Unnur -- Tragante, Vinicius -- van Gilst, Wiek H -- van Pelt, L Joost -- van Veldhuisen, Dirk J -- Volker, Uwe -- Whitfield, John B -- Willemsen, Gonneke -- Winkelmann, Bernhard R -- Wirnsberger, Gerald -- Algra, Ale -- Cucca, Francesco -- d'Adamo, Adamo Pio -- Danesh, John -- Deary, Ian J -- Dominiczak, Anna F -- Elliott, Paul -- Fortina, Paolo -- Froguel, Philippe -- Gasparini, Paolo -- Greinacher, Andreas -- Hazen, Stanley L -- Jarvelin, Marjo-Riitta -- Khaw, Kay Tee -- Lehtimaki, Terho -- Maerz, Winfried -- Martin, Nicholas G -- Metspalu, Andres -- Mitchell, Braxton D -- Montgomery, Grant W -- Moore, Carmel -- Navis, Gerjan -- Pirastu, Mario -- Pramstaller, Peter P -- Ramirez-Solis, Ramiro -- Schadt, Eric -- Scott, James -- Shuldiner, Alan R -- Smith, George Davey -- Smith, J Gustav -- Snieder, Harold -- Sorice, Rossella -- Spector, Tim D -- Stefansson, Kari -- Stumvoll, Michael -- Tang, W H Wilson -- Toniolo, Daniela -- Tonjes, Anke -- Visscher, Peter M -- Vollenweider, Peter -- Wareham, Nicholas J -- Wolffenbuttel, Bruce H R -- Boomsma, Dorret I -- Beckmann, Jacques S -- Dedoussis, George V -- Deloukas, Panos -- Ferreira, Manuel A -- Sanna, Serena -- Uda, Manuela -- Hicks, Andrew A -- Penninger, Josef Martin -- Gieger, Christian -- Kooner, Jaspal S -- Ouwehand, Willem H -- Soranzo, Nicole -- Chambers, John C -- 092731/Wellcome Trust/United Kingdom -- 097117/Wellcome Trust/United Kingdom -- 14136/Cancer Research UK/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- G1002084/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- HHSN268201100005C/HL/NHLBI NIH HHS/ -- HHSN268201100006C/HL/NHLBI NIH HHS/ -- HHSN268201100007C/HL/NHLBI NIH HHS/ -- HHSN268201100008C/HL/NHLBI NIH HHS/ -- HHSN268201100009C/HL/NHLBI NIH HHS/ -- HHSN268201100010C/HL/NHLBI NIH HHS/ -- HHSN268201100011C/HL/NHLBI NIH HHS/ -- HHSN268201100012C/HL/NHLBI NIH HHS/ -- HHSN271201100005C/DA/NIDA NIH HHS/ -- K12 RR023250/RR/NCRR NIH HHS/ -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- N01AG12109/AG/NIA NIH HHS/ -- P01 HL076491/HL/NHLBI NIH HHS/ -- P01 HL098055/HL/NHLBI NIH HHS/ -- P20 HL113452/HL/NHLBI NIH HHS/ -- P30 DK072488/DK/NIDDK NIH HHS/ -- R01 AG018728/AG/NIA NIH HHS/ -- R01 CA165001/CA/NCI NIH HHS/ -- R01 GM053275/GM/NIGMS NIH HHS/ -- R01 HD042157/HD/NICHD NIH HHS/ -- R01 HL059367/HL/NHLBI NIH HHS/ -- R01 HL086694/HL/NHLBI NIH HHS/ -- R01 HL087641/HL/NHLBI NIH HHS/ -- R01 HL087679/HL/NHLBI NIH HHS/ -- R01 HL088119/HL/NHLBI NIH HHS/ -- R01 HL103866/HL/NHLBI NIH HHS/ -- R01 HL103931/HL/NHLBI NIH HHS/ -- R01 LM010098/LM/NLM NIH HHS/ -- R01 MH081802/MH/NIMH NIH HHS/ -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RL1 MH083268/MH/NIMH NIH HHS/ -- U01 GM074518/GM/NIGMS NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U24 MH068457/MH/NIMH NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1 RR025005/RR/NCRR NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- England -- Nature. 2012 Dec 20;492(7429):369-75. doi: 10.1038/nature11677. Epub 2012 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. p.van.der.harst@umcg.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222517" target="_blank"〉PubMed〈/a〉

Description: The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer's disease. The age-specific prevalence of Alzheimer's disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-beta precursor protein (APP) gene with a significant effect on the risk of Alzheimer's disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease. This substitution is adjacent to the aspartyl protease beta-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer's disease, the two may be mediated through the same or similar mechanisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jonsson, Thorlakur -- Atwal, Jasvinder K -- Steinberg, Stacy -- Snaedal, Jon -- Jonsson, Palmi V -- Bjornsson, Sigurbjorn -- Stefansson, Hreinn -- Sulem, Patrick -- Gudbjartsson, Daniel -- Maloney, Janice -- Hoyte, Kwame -- Gustafson, Amy -- Liu, Yichin -- Lu, Yanmei -- Bhangale, Tushar -- Graham, Robert R -- Huttenlocher, Johanna -- Bjornsdottir, Gyda -- Andreassen, Ole A -- Jonsson, Erik G -- Palotie, Aarno -- Behrens, Timothy W -- Magnusson, Olafur T -- Kong, Augustine -- Thorsteinsdottir, Unnur -- Watts, Ryan J -- Stefansson, Kari -- HL-102924/HL/NHLBI NIH HHS/ -- HL-102925/HL/NHLBI NIH HHS/ -- HL-102926/HL/NHLBI NIH HHS/ -- HL-103010/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):96-9. doi: 10.1038/nature11283.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801501" target="_blank"〉PubMed〈/a〉

Description: Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C〉T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C〉T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C〉T mutation overlaps that of Lgr4 mutant mice.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Styrkarsdottir, Unnur -- Thorleifsson, Gudmar -- Sulem, Patrick -- Gudbjartsson, Daniel F -- Sigurdsson, Asgeir -- Jonasdottir, Aslaug -- Jonasdottir, Adalbjorg -- Oddsson, Asmundur -- Helgason, Agnar -- Magnusson, Olafur T -- Walters, G Bragi -- Frigge, Michael L -- Helgadottir, Hafdis T -- Johannsdottir, Hrefna -- Bergsteinsdottir, Kristin -- Ogmundsdottir, Margret H -- Center, Jacqueline R -- Nguyen, Tuan V -- Eisman, John A -- Christiansen, Claus -- Steingrimsson, Erikur -- Jonasson, Jon G -- Tryggvadottir, Laufey -- Eyjolfsson, Gudmundur I -- Theodors, Asgeir -- Jonsson, Thorvaldur -- Ingvarsson, Thorvaldur -- Olafsson, Isleifur -- Rafnar, Thorunn -- Kong, Augustine -- Sigurdsson, Gunnar -- Masson, Gisli -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- HL-102923/HL/NHLBI NIH HHS/ -- HL-102924/HL/NHLBI NIH HHS/ -- HL-102925/HL/NHLBI NIH HHS/ -- HL-102926/HL/NHLBI NIH HHS/ -- HL-103010/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):517-20. doi: 10.1038/nature12124. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉deCODE Genetics/Amgen, 101 Reykjavik, Iceland. unnurth@decode.is〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644456" target="_blank"〉PubMed〈/a〉

Description: Chronic kidney disease (CKD) is a complex disorder with a strong genetic component. A number of common sequence variants have been found to associate with serum creatinine (SCr), estimated glomerular filtration rate (eGFR) and/or CKD. We imputed 24 million single-nucleotide polymorphisms and insertions/deletions identified by whole-genome sequencing of 2230 Icelanders into 81 656 chip-typed individuals and 112 630 relatives of genotyped individuals over the age of 18 with SCr measurements. The large set of sequenced individuals allowed accurate imputation of variants to a minor allele frequency (MAF) of 0.1%. We tested the imputed variants for association with SCr. In addition to replicating established loci, we discovered missense and loss-of-function variants associating with SCr in three solute carriers ( SLC6A19 , SLC25A45  and SLC47A1 ) and two E3 ubiquitin ligases ( RNF186 and RNF128 ). All the variants are within coding sequences and all but one are rare (MAF 〈2%) with SCr effects between 0.085 and 0.129 standard deviations. These rare variants have a larger effect on SCr than previously reported common variants, explaining 0.5% of the variability of SCr in Icelanders in addition to the 1% already accounted for. We tested the five variants associating with SCr for association with CKD in an Icelandic sample of 15 594 cases and 291 428 controls. Three of the variants also associated with CKD. These variants may either affect kidney function or creatinine synthesis and excretion. Of note were four mutations in SLC6A19 that associate with reduced SCr, three of which have been shown to cause Hartnup disease.

Description: Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 x 10 –11 for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

Description: To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 x 10 –17 , OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 x 10 –13 , OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.

Description: Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ~30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.