Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

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Abstract

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk ( q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control.

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Most cited references 104

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Quantifying heterogeneity in a meta-analysis.

Julian P T Higgins, Simon G Thompson (2002)

The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. Copyright 2002 John Wiley & Sons, Ltd.

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PLINK: a tool set for whole-genome association and population-based linkage analyses.

Shaun Purcell, Benjamin M. Neale, Kathe Todd-Brown … (2007)

Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.

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METAL: fast and efficient meta-analysis of genomewide association scans

Cristen Willer, Yun Li, Gonçalo R Abecasis (2010)

Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/ Contact: goncalo@umich.edu

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 9 August 2012

Publication date (Electronic): 12 August 2012

Publication date (Print): September 2012

Publication date PMC-release: 01 March 2013

Volume: 44

Issue: 9

Pages: 991-1005

Affiliations

[1 ]Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.

[2 ]Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.

[3 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

[4 ]Bioinformatics Graduate Program, University of Michigan Medical School, Ann Arbor, Michigan, USA.

[5 ]Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

[6 ]Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

[7 ]Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

[8 ]Division of Endocrinology, Diabetes and Nutrition, University of Maryland, School of Medicine, Baltimore, Maryland, USA.

[9 ]Estonian Genome Center, University of Tartu, Tartu, Estonia.

[10 ]Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

[11 ]Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

[12 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

[13 ]Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

[14 ]Universite Lille Nord de France, Lille, France.

[15 ]Le Centre national de la recherche scientifique (CNRS) UMR8199, Institut Pasteur de Lille, France.

[16 ]Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.

[17 ]Department of Public Health & Clinical Medicine, Umeå University, Umeå, Sweden.

[18 ]Department of Odontology, Umeå University, Umeå, Sweden.

[19 ]Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato, Italy.

[20 ]Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.

[21 ]Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.

[22 ]Interuniversity Cardiology Institute of the Netherlands (ICIN), Durrer Center for Cardiogenetic Research, Utrecht, The Netherlands.

[23 ]Departmentt of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.

[24 ]Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK.

[25 ]The Genome Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK.

[26 ]Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands.

[27 ]deCODE genetics, Rekjavik, Iceland.

[28 ]Department of Biological Psychology, VU University & EMGO+ Institute, Amsterdam, The Netherlands.

[29 ]University College London Genetics Institute (UGI), University College London, London, UK.

[30 ]Icelandic Heart Association, Kopavogur, Iceland.

[31 ]Faculty of Medicine, University of Iceland, Reykjavìk, Iceland.

[32 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.

[33 ]Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

[34 ]University of Helsinki, Institute of Molecular Medicine, Finland (FIMM), Helsinki, Finland.

[35 ]MRC Council Centre for Causal Analyses in Translational Epidemiology (CAiTE) Centre, School of Social and Community Medicine, University of Bristol, UK.

[36 ]School of Social and Community Medicine, University of Bristol, UK.

[37 ]Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

[38 ]Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

[39 ]Busselton Population Medical Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

[40 ]School of Population Health, The University of Western Australia, Nedlands, Western Australia, Australia.

[41 ]School of Pathology and Laboratory Medicine, The University of Western Australia, Nedlands, Western Australia, Australia.

[42 ]PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia.

[43 ]Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

[44 ]MRC Human Genetics Unit at the Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.

[45 ]Centre for Medical Systems Biology (CMSB), Leiden, The Netherlands.

[46 ]Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

[47 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

[48 ]Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, UK.

[49 ]The Broad Institute of Harvard and MIT, Boston, Massachusetts, USA.

[50 ]Department of Pharmacology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

[51 ]Divisions of Genetics & Rheumatology, Brigham and Women’s Hospital, Boston, Massachusetts, USA.

[52 ]Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

[53 ]Boston University Data Coordinating Center, Boston, Massachusetts, USA.

[54 ]Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

[55 ]The Service of Medical Genetics, CHUV, University Hospital, Lausanne Switzerland.

[56 ]Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.

[57 ]Genetics, GlaxoSmithKline, Upper Merion, Pennsylvania, USA.

[58 ]Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

[59 ]Illumina Inc., Chesterford Research Park, Essex, UK.

[60 ]Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

[61 ]Centre for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy - Affiliated Institute of the University of Lübeck, Lübeck, Germany.

[62 ]Division of Statistical Genomics, Washington University School of Medicine, St. Louis, Missouri, USA.

[63 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

[64 ]Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.

[65 ]Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

[66 ]Department of Evolutionary Biology, Genetic Section, University of Ferrara, Ferrara, Italy.

[67 ]Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

[68 ]Interdisciplinary Center for Pathology of Emotions, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

[69 ]University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

[70 ]Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.

[71 ]Carolina Center for Genome Sciences, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

[72 ]Department of Epidemiology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.

[73 ]Department of Public Health and Clinical Medicine, Section for Nutritional Research, Umeå University Hospital, Umeå, Sweden.

[74 ]Pirkanmaa Hospital District, Tampere, Finland.

[75 ]Laboratory of Genetics, National Institute on Aging, NIH, Baltimore, Maryland, USA.

[76 ]Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

[77 ]Department of Epidemiology and Public Health, University College London, London UK.

[78 ]Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

[79 ]Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

[80 ]Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK.

[81 ]Department of Epidemiology, Center for Aging and Population Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

[82 ]Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

[83 ]Institute of Biomedicine, Physiology, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.

[84 ]University of Leipzig, IFB Adiposity Diseases, Leipzig, Germany.

[85 ]Pediatric Research Center, Department of Women’s & Child Health, University of Leipzig, Leipzig, Germany.

[86 ]School of Medicine and Pharmacology, The University of Western Australia, Nedlands, Western Australia, Australia.

[87 ]Pulmonary Physiology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.

[88 ]Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

[89 ]Netherlands Consortium for Healthy Ageing of the Netherlands (NCHAH) of the Genomics Initiative (NGI), Leiden, The Netherlands.

[90 ]Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

[91 ]Medical Research Institute, University of Dundee, Dundee, UK.

[92 ]Department of Psychiatry, VU University Medical Centre, Amsterdam, The Netherlands.

[93 ]Faculty of Medicine, University of Split, Split, Croatia.

[94 ]U557 Institut National de la Santé et de la Recherche Médicale, U1125 Institut National de la Recherche Agronomique, Université Paris 13, Bobigny, France.

[95 ]Department of Dietetics-Nutrition, Harokopio University, Athens, Greece.

[96 ]Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

[97 ]University of Leipzig, Interdisciplinary Center for Clinical Research, Leipzig, Germany.

[98 ]National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland.

[99 ]Geriatric Department Azienda Sanitaria Firenze, Florence Italy.

[100 ]Department Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.

[101 ]Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

[102 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.

[103 ]The members of this consortium are listed in the Supplementary Note.

[104 ]Synlab Academy, Mannheim, Germany.

[105 ]Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany.

[106 ]Ludwigshafen Risk and Cardiovascular Health (LURIC) Study nonprofit LLC, Freiburg, Germany.

[107 ]Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, Ulm, Germany.

[108 ]Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.

[109 ]Department of Neurology, General Central Hospital, Bolzano, Italy.

[110 ]Department of Neurology, University of Lübeck, Lübeck, Germany.

[111 ]Department of Medicine, University of Leipzig, Leipzig, Germany.

[112 ]Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

[113 ]Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

[114 ]South Ostrobothnia Central Hospital, Seinäjoki, Finland.

[115 ]Red RECAVA Grupo RD06/0014/0015, Hospital Universitario La Paz, Madrid, Spain.

[116 ]Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.

[117 ]Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California, USA.

[118 ]Department of Physiology & Biophysics, Keck School of Medicine of USC, Los Angeles, California, USA.

[119 ]Cardiovascular Health Research Unit, Departments of Medicine, University of Washington, Seattle, Washington, USA.

[120 ]Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA.

[121 ]Department of Epidemiology, University of Washington, Seattle, Washington, USA.

[122 ]Department of Health Services, University of Washington, Seattle, Washington, USA.

[123 ]Department of Internal Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.

[124 ]Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.

[125 ]Research Unit, Kuopio University Hospital, Kuopio, Finland.

[126 ]Odense Patient data Explorative Network (OPEN), Odense, Denmark.

[127 ]Institute of Regional Health Services Research, Odense, Denmark.

[128 ]Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland.

[129 ]National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Helsinki, Finland.

[130 ]U872 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Paris, France.

[131 ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

[132 ]Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

[133 ]Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.

[134 ]Department of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.

[135 ]Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.

[136 ]Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.

[137 ]Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina, USA.

[138 ]Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.

[139 ]Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

[140 ]Faculty of Medicine, Institute of Health Sciences, University of Oulu, Oulu, Finland.

[141 ]Unit of General Practice, Oulu University Hospital, Oulu, Finland.

[142 ]Finnish Diabetes Association, Tampere, Finland.

[143 ]National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, USA.

[144 ]British Heart Foundation (BHF) Building, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.

[145 ]Laboratory of Epidemiology, Demography, and Biometry, National Institute on Ageing, Bethesda, Maryland, USA.

[146 ]Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.

[147 ]Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland.

[148 ]Wellcome Trust Sanger Institute, Hinxton, UK.

[149 ]Unit of Chronic Disease Epidemiology and Prevention, National Institute for Health and Welfare, Helsinki, Finland.

[150 ]Inserm, Centre de recherche en Épidémiologie et Santé des Populations (CESP) Center for Research in Epidemiology and Public Health, U1018, Epidemiology of diabetes, obesity and chronic kidney disease over the lifecourse, Villejuif, France.

[151 ]University Paris Sud 11, UMRS 1018, Villejuif, France.

[152 ]Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

[153 ]Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland.

[154 ]Department of Lifecourse and Services, National Institute for Health and Welfare, Oulu, Finland.

[155 ]Biocenter Oulu, University of Oulu, Oulu, Finland.

[156 ]Department of Epidemiology and Biostatistics, School of Public Health, MRC-HPA Centre for Environment and Health, Faculty of Medicine, Imperial College London, London, UK.

[157 ]Institute of Health Sciences, University of Oulu, Oulu, Finland.

[158 ]Inserm U970, Paris Cardiovascular Research Center PARCC, Paris, France.

[159 ]Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Churchill Hospital, Oxford, UK.

[160 ]Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

[161 ]General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA.

[162 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

[163 ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

[164 ]Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

[165 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

[166 ]NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.

[167 ]University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.

Author notes

Correspondence should be addressed to J.C.F. ( jcflorez@ 123456partners.org ), C.L. ( claudia.langenberg@ 123456mrc-epid.cam.ac.uk ), E.I. ( erik.ingelsson@ 123456ki.se ), I.P. ( inga@ 123456well.ox.ac.uk ) or I.B. ( ib1@ 123456sanger.ac.uk )

[168]

These authors contributed equally to this work.

AUTHOR CONTRIBUTIONS Writing group: R.A.S, V.La, R.P.W, E.Wh, M.M, R.J.S, N.Bo, M.I.M, P.W.F, J.B.M, T.M.T, J.C.F, C.L, E.In, I.P and I.Ba wrote the manuscript. All authors reviewed the manuscript.

Project design, management and coordination: (AGES) V.Gu., T.B.H.; (ALSPAC) G.D.S.; (AMC-PAS) G.K.H.; (Amish) A.R.S.; (ASAP) L.Fo.; (ASCOT) M.Ca., P.B.M.; (BLSA) L.Fe.; (BSN) J.P.B.; (CHS) B.M.P.; (CLHNS) L.S.A., K.L.M.; (CoLaus) P.Vo.; (CROATIA-Vis) N.D.H., I.Ru.; (deCODE) K.St.; (DESIR) B.Ba., P.Fr.; (DIAGEN) S.R.B., P.E.H.S.; (DPS) M.Uu.; (DR’s EXTRA) T.A.L., R.Ra.; (EAS) J.F.P.; (EGCUT) A.Me.; (Ely/Fenland) N.J.W., N.G.F, C.La., R.J.F.L., ; (ERF) B.A.O.; (FIN-D2D 2007) S.M.K., T.E.S.; (FINRISK/DILGOM) S.Ri., V.Sa.; (FamHS) M.A.P., I.B.B.; (Framingham Heart Study) J.B.M.; (FUSION) R.N.B., M.Boe., F.S.C., K.L.M., J. Tu., R.M.W.; (GEMs) D.M.W.; (GENOA) P.A.P.; (GenomEUtwin) D.I.B., J.Ka., K.O.K., P.K.E.M., N.L.P.; (GLACIER) I.Ba., P.W.F., T.V.V.; (GRAIL) S.Ra.; (Health ABC) T.B.H.; (InChianti) L.Fe.; (KORA F3) A.Pe.; (KORA F4) T.Il.; (LEIPZIG_ADULT_IFB) A.To.; (LEIPZIG_CHILDHOOD_IFB) A.Kö., W.Ki., ; (LURIC) W.Ma., B.O.B; (METSIM) J.Ku., M.La.; (MICROS) P.P.P.; (NFBC66) M.Ja., M.I.M.; (NFBC86) M.Ja., M.I.M., A.Po.; (NTRNESDA) D.I.B., E.J.C.D., B.W.P.; (ORCADES-Discovery) H.Ca.; (ORCADES-Metabochip) J.F.W., A.F.W.; (PIVUS) E.In., L.Li.; (PREVEND) P.Va.; (PROCARDIS) M.Fa., H.Wa.; (PROSPER) N.Sa.; (Rotterdam) A.Ho., C.M.V.; (SardiNIA) F.Cu.; (SCARFSHEEP) U.De., A.Ha.; (SORBS) I.Pr., M.St., A.To.; (SUVIMAX) P.Me.; (Swedish Twin Reg.) E.In.; (THISEAS) G.V.D.; (THISEAS-PROMIS-AMCPAS) P.De.; (TRAILS) A.J.O.; (TwinsUK) T.D.S.; (GoDARTS) A.Mo.; (ULSAM) E.In.; (Whitehall II) A.Hi., M.Ki.

Sample collection and phenotyping: (AGES) V.Gu., T.B.H.; (AMC-PAS) H.V.B.; (Amish) A.R.S.; (ARIC) J.S.P.; (BSN) J.P.B., J.Hu., A.L.J.; (CHS) B.M.P.; (CLHNS) L.S.A.; (CoLaus) P.Vo.; (CROATIA-Korcula) O.Po.; (DESIR) B.Ba.; (DPS) J.Li.; (EAS) G.R.F., J.F.P.; (EGCUT) A.Me.; (Ely/Fenland) N.J.W, N.G.F.; (ERF) B.A.O.; (FINRISK/DILGOM) H.Ok., V.Sa.; (Framingham Heart Study) J.C.F., J.B.M.; (GEMs) D.M.W.; (GenomEUtwin) D.I.B., J.Ka., K.O.K., P.K.E.M., N.L.P.; (GLACIER) G.Ha.; (Health ABC) I.Mi.; (Health 2000) J.An., M.Pe.; (InChianti) S.Ba.; (KORA F3) W.Ra.; (KORA F4) C.He.; (LEIPZIG_ADULT_IFB) P.Ko., A.To.; (LEIPZIG_CHILDHOOD_IFB) W.Ki., A.Kö.; (METSIM) J.Ku., M.La.; (MICROS) P.P.P.; (NTRNESDA) J.H.S., G.Wi.; (ORCADES-Discovery) S.H.W.; (ORCADES-Metabochip) J.F.W.; (PIVUS) E.In., L.Li.; (PREVEND) S.J.L.B.; (PROSPER) J.W.J.; (Rotterdam) A.Ho., C.M.V.; (SORBS) A.To.; (SUVIMAX) S.He.; (Swedish Twin Reg.) E.In., N.L.P.; (THISEAS) M.Di.; (TwinsUK) T.D.S.; (GoDARTS) A.Do., C.Pa.; (ULSAM) E.In.

Genotyping: (ARIC) K.E.N.; (BSN) J.P.B., J.Hu.; (CoLaus) J.S.B.; (CROATIA-Korcula) S.Ca.; (CROATIA-Split) C.Ha., T.Ze.; (CROATIA-Vis) N.D.H.; (DESIR) N.Bo., P.Fr.; (DR’s EXTRA) M.At.; (EAS) J.L.B.; (EGCUT) T.Es.; (Ely/Fenland) C.La., R.J.F.L., N.J.W.; (ERF) A.M.I., B.A.O.; (FINRISK/DILGOM) S.Ri.; (Framingham Heart Study) J.Du., J.C.F., J.B.M.; (FUSION) L.L.B.; (GEMs) D.MW.; (GenomEUtwin) D.I.B., J.Ho., J.Ka., K.O.K., P.K.E.M., N.L.P.; (GLACIER) S.Ed.; (Health ABC) Y.Li.; (KORA F3) M.Mü.; (KORA F4) T.Il.; (LEIPZIG_CHILDHOOD_IFB) A.Kö.; (MICROS) A.A.H.; (NTRNESDA) J.Ho., B.W.P., G.Wi.; (ORCADES-Discovery) H.Ca.; (ORCADES-Metabochip) J.F.W., A.F.W.; (PIVUS) E.In.; (PREVEND) P.Va.; (PROSPER) S.Tr., J.W.J.; (Rotterdam) F.Ri., A.G.U.; (SardiNIA) M.An., R.Na.; (SCARFSHEEP) B.Gi.; (Swedish Twin Reg.) E.In., N.L.P.; (THISEAS-PROMIS-AMCPAS) K.St.; (TRAILS) M.Br.; (TwinsUK) M.Ma., K.Sm.; (GoDARTS) A.Do., C.Pa.; (ULSAM) E.In.; (Whitehall II) M.Ku., C.La., N.J.W.

Statistical analysis: (AGES) A.V.S.; (ALSPAC) D.M.E., B.St., N.J.T.; (Amish) M.E.M., J.R.O.; (ARIC) L.J.R.; (ASAP) A.Fr.; (ASCOT) T.Jo.; (BLSA) T.Ta.; (BSN) J.P.B., J.Hu.; (CLHNS) Y.Wu.; (CoLaus) J.S.B.; (CROATIA-Korcula) P.Na.; (CROATIOA-Split) C.Ha., V.Vi.; (deCODE) A.Ko., G.Th.; (DESIR) N.Bu., C.Le., L.Ye.; (EGCUT) T.Es., E.Mi.; (Ely/Fenland) J.Lu., R.A.S.; (ERF) A.M.I.; (FINRISK/DILGOM) S.Ri.; (FamHS) P.An.; (Framingham Heart Study) H.Ch., J.Du., C.Li., D.Ry.; (FUSION) P.S.C., A.U.J., H.Ka., H.M.S., T.M.T., R.P.W.; (GEMs) K.So.; (GENOA) L.F.B., W.Zh; (GenomEUtwin) J.Ho.; (GLACIER) D.Sh., E.Wh.; (Health ABC) J.S.A.; (Health 2000) M.Pe., P.Sa.; (InChianti) T.Ta. (KORA F3) M.Mü.; (KORA F4) C.Gi.; (LEIPZIG_ADULT_IFB) A.Ma.; (LEIPZIG_CHILDHOOD_IFB) A.Ma.; (LURIC) M.E.K.; (MICROS) A.A.H.; (NFBC66) C.M.L., A.P.M., I.Pr.; (NFBC86) V.La., I.Pr., N.W.R., N.Ro.; (NTRNESDA) J.Ho.; (ORCADES-Metabochip) R.M.F.; (PIVUS) E.In., E.Re.; (PREVEND) P.Va., N.Ve.; (PROCARDIS) M.Fa., A.Go, J.F.P.; (PROSPER) I.Fo., P.C.D.J., J.W.J.; (Rotterdam) S.M.W.; (SardiNIA) S.Sa., C.Si.; (SCARFSHEEP) R.J.S.; (SORBS) M.Re.; (SUVIMAX) T.Jo.; (Swedish Twin Reg.) T.Fa., E.In.; (THISEAS-PROMIS-AMCPAS) S.Ka., K.St.; (TRAILS) H.Ja.; (GoDARTS) A.Do., M.Ho., C.Pa.; (ULSAM) S.Gu., E.In., E.Re.; (Whitehall II) J.Lu., S.Sh.

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Manuscript ID: UKMS49338

DOI: 10.1038/ng.2385

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PubMed ID: 22885924

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