© 2010 Nature America, Inc. All rights reserved. A A full list of authors and affiliations appear at the end of the paper. Methods, (Online individuals 1 Fig. 123,865 to up studies 46 from data using SNPs genotyped or imputed We first conducted a of meta-analysis GWAS of BMI and ~2.8 Stage RESULTS ancestry. European of individuals of 249,796 a total include to meta-analysis association genome-wide the expanded we Genetic Investigation BMI, of Anthropometric with Traits (GIANT) associated Consortium loci additional identify To of additional to lead the discovery likely would size sample the increasing that suggested have variants of established sizes effect of the variation in BMI. Furthermore, power calculations based on the obesity to tibility to are play a known role in major suscep balance, or energy appetite of regulation in involved and hypothalamus the in expressed those particularly genes, neuronal which in obesity human monogenic of studies and models animal in results with consistent is pattern This lighting a likelyhigh neuronal componentsystem, in the predisposition nervous to obesity central the in act to known or expressed are NEGR1 ciations ( significant genome-wide with loci ten identified obesity. of basis biological the of understanding a to better lead could of BMI determinants genetic complications related of risk the predicts that obesity risk obesity to ( estimates heritability (with contribution genetic substantial a for evidence provide studies heritability epidemic to proportions, prevalence its driven have changes lifestyle disease Although cardiovascular and diabetes 2 type including disorders, for multiple factor risk prevalent increasingly and a is major Obesity human these GPRC5B. and with for Obesity 18 new loci associated with body mass index Association analyses of 249,796 individuals reveal Nature Ge Nature Received 13 May; accepted 15 September; published online 10 October 2010; The ten previously identified loci account for only a small fraction for account only fraction a loci small identified The ten previously (GWAS) studies association Genome-wide of BMI have pr

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P , rs1805081, 1.75 ×10 1.17 ×10 5.53 ×10 4.35 ×10 1.82 ×10 2.42 ×10 2.05 ×10 1.31 ×10 4.79 ×10 7.61 ×10 7.04 ×10 1.20 ×10 7.65 ×10 2.38 ×10 1.11 ×10 9.81 ×10 2.69 ×10 1.04 ×10 1.88 ×10 4.76 ×10 1.37 ×10 1.36 ×10 3.18 ×10 1.15 ×10 4.20 ×10 1.80 ×10 2.03 ×10 3.96 ×10 5.97 ×10 1.66 ×10 2.81 ×10 7.57 ×10 = 0.64; and and 0.64; = Stage 1 P −22 −62 −10 −14 −13 −17 −22 −13 −9 −11 −14 −6 −8 −7 −7 −7 −7 −8 −8 −6 −7 −8 −8 −7 –9 −7 −10 −11 −7 −7 −11 −16 2 obtainedfromstage2 cohortsonly. P = 0.0025; 7.89 ×10 2.29 ×10 1.17 ×10 1.45 ×10 3.19 ×10 4.42 ×10 1.01 ×10 2.40 ×10 1.10 ×10 1.15 ×10 1.88 ×10 8.24 ×10 4.48 ×10 9.47 ×10 2.25 ×10 5.32 ×10 1.72 ×10 1.59 ×10 3.19 ×10 8.29 ×10 1.93 ×10 7.04 ×10 1.40 ×10 1.59 ×10 8.13 ×10 1.44 ×10 2.86 ×10 7.82 ×10 2.40 ×10 2.41 ×10 7.39 ×10 1.00 ×10 TNKS-MSRA Stage 2 P P −12 −9 −14 −15 −21 −30 −60 −2 −3 −6 −11 −4 −3 −4 −4 −5 −5 −4 −5 −7 −6 −6 −7 −7 −6 −10 −9 −12 −16 −5 −8 −6 MAF < 5 × 10 204,309 198,380 204,158 197,008 203,600 197,806 192,344 192,872 191,943 196,221 179,414 249,777 249,791 241,999 198,577 243,013 209,068 241,667 237,404 242,807 233,512 216,916 231,729 245,378 227,900 194,564 227,950 239,715 230,748 183,022 200,064 195,776 r , rs473034, rs473034, ,

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© 2010 Nature America, Inc. All rights reserved. European Fund; Social Eve Appeal; Finnish Diabetes Research Foundation; Finnish 01ZZ0403 and Federal 03ZIK012); State of Mecklenburg-West Pomerania; 01GS0825, 01GS0830, 01GS0831, 01IG07015, 01KU0903, 01ZZ9603, 01ZZ0103, 01GI0823, 01GI0826, 01GP0209, 01GP0259, 01GS0820, 01GS0823, 01GS0824, ofFederal Ministry Education and Research (Germany) (01AK803, 01EA9401, 2013, 205419, 212111, 245536, 95201408 05F02 SOC and WLRT-2001-01254); ENGAGE, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550, FP7/2007- 518153, LSHM-CT-2007-037273,LSH-2006-037593, HEALTH-F2-2008- QLG2-CT-2002-01254, LSHC-CT-2005, LSHG-CT-2006-018947, LSHG-CT-2004- University (Rotterdam); European Commission XII; (DG QLG1-CT-2000-01643, Vera Foundation;Cornell Erasmus Medical Center (Rotterdam); Erasmus Reynolds Foundation; Dresden University of Technology Funding Grant; Emil and Health (UK); Diabetes UK; Diabetes and InflammationDonald W.Laboratory; Deutsche Council; Forschungsgemeinschaft (DFG; HE Department 1446/4-1); of Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Danish Centre for Health Technology Assessment; Danish Diabetes Association; ofScientist Office the Scottish Government; Contrat Plan Etat Région (France); Centre for Neurogenomics and Cognitive Research (The Netherlands); Chief Cancer Research UK; Centre for Medical Systems (The Biology Netherlands); Research (NIHR) Comprehensive Biomedical Research Centre; CamStrad (UK); Cambridge Institute for Medical Research; Cambridge National Institute of Health (97020; BusseltonPG/02/128); Population Medical Research Foundation; Research British Center; Diabetes Association (1192); British Heart Foundation Biocenter (Finland); Biomedicum Helsinki Foundation; Boston Obesity Nutrition Australian Research Council (ARC grant DP0770096); Foundation;Becket 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485 and 613672); Australian National Health and Medical Research Council (241944, 389875, Althingi (the Icelandic Parliament); AugustinusAstraZeneca; Foundation; and Research of Singapore (A*STAR); ALF/LUA research grant in Gothenburg; Mentor-Based Postdoctoral Fellowship; Amgen; Agency for TechnologyScience, 129494, 129680, 130326, 209072, 210595, 213225, 213506 and 216374); ADA 117797, 120315, 121584, 124243, 126775, 126925, 127437, 129255, 129269, 129306, A list full of acknowledgments appears in the Note: Supplementary information is available on the of the paper at http://www.nature.com/naturegenetics/. Methods and any associated references are available in M the online version http://www URLs. interventions. and therapies future of application and development the guide to needed critically are obesity of biology the into insights obesity growing of challenges the addressing in ineffective are largely interventions lifestyle of current measure obesity. Because common a BMI, in variation with associated loci genetic numerous obesity. of biology the into insights new uncover could function assign to designed studies experimental and genomic and a combinationthrough of resequencing loci and fine mapping to find associated causal variants the of examination further particular, In investigation. for point and entry important uncovered an GWAS that provide may be to remains obesity underlies that biology the of much that suggest results these Thus, levels). lipid or diseases mune results from equivalent studies of other certain traits (such as autoim the with contrast striking in is and traits obesity-related and BMI of our regulation. This reflects limited still of understanding the biology of weight biology the to connections clear with any, genes annotated few, harbor if study present by the identified loci the instances, most In obesity. of development the in secretion insulin postprandial in near variants common and BMI between association the is regard this in as obesity such of conditions Nature Ge Nature Foundation for Cardiovascular Research; Finnish Foundation for Pediatric Acknowledgments et Funding was provided by Academy of Finland (10404, 77299, 104781, 114382, In conclusion, we performed GWAS in large samples to identify identify to samples large GWASin performed we conclusion, In h GIPR LocusZoom, LocusZoom, ods , which may indicate a causal contribution of variation variation of contribution causal a indicate may which , n .sph.umich.edu/csg/a etics

ADVANCE ONLINE PUBLICATION ONLINE ADVANCE http: //csg.sph.umich.edu/ 4 2 . One particularly noteworthy finding finding noteworthy . particularly One becasis/Metal Supplementary Supplementary Note N ature Genetic / locuszoo .

s website. . m ; METAL, ; 43,44 , new new , - Cancer Cancer Institute; National Health and Medical Research Council of Australia; Jakobstad; Municipality of Rotterdam; Närpes Health Care Foundation; National Heart Institute Foundation; Municipal Health Care Center and Hospital in of 0302); Ministry Research Science, and the Arts Baden-Württemberg; Montreal of Ministry EducationScience, and Sport of the Republic of Croatia (216-1080315- (The Science Netherlands); of Ministry Internal Affairs and Health (Denmark); Netherlands); of Ministry Education (Finland); of Ministry Education, Culture and of Mecklenburg-West Pomerania; for Ministry Health, Welfare and Sports (The PrevMetSyn); of Ministry Cultural ofAffairs andMinistry the Federal Social State (UK) G0000934, (G0000649, G9521010D, G0500539, G0600331 and G0601261, Foundation; Marie Curie Intra-European Fellowship; Medical Research Council Personalized Prediction, Disease Prevention and Care (LUCAMP); Lundberg Foundation; Lundbeck Foundation Centre of Applied Medical Genomics for Karolinska Institute; Knut and Alice Wallenberg Foundation; Leenaards Foundation; Juvenile Diabetes Research Foundation International (JDRF); Forschung (IZKF) (B27); Jalmari and Rauha Ahokas Foundation; Juho Vainio (France); Ib Henriksen Foundation; Interdisziplinäres für Zentrum Klinische Hospital,Central Hjartavernd (the Icelandic Heart Association); INSERM Healthway, Western Australia; Helmholtz Center Munich; Helsinki University Gyllenberg Foundation; Health Care Centers in Vasa, Närpes and Korsholm; GreatGlaxoSmithKline; Göteborg Medical WineSociety; Estates Auctions; Research Center for Environmental Health; Giorgi-Cavaglieri Foundation; German National Genome Research Net ‘NGFNplus’ (FKZ German 01GS0823); AssociationGenetic Information Network; German Research Council (KFO-152); for Life and Health in Finland; Foundation for Strategic Research (Sweden); Développement Régional (France); Fondation (Paris,LeDucq France); Foundation Foundation,Sohlberg Folkhälsan Research Foundation; Fond Européen pour le Research, Finska Finnish Päivikki Läkaresällskapet, Medical and Society; Sakari Research Council; Research SwedishCouncil; of Society Medicine; Swiss National FoundationScience and K2010-54X-09894-19-3 Swedish 2006-3832); 01-3, K2010-54X-09894-19-3, Lung Foundation; Swedish Medical Research Council (8691, K2007-66X-20270- Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Heart- Komen Breast Cancer Foundation; SwedishSwedish Cultural Cancer Society; Foundation; State of Bavaria; Stockholm County Council (560183); Susan G. 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 © 2010 Nature America, Inc. All rights reserved. T Valgerdur S Anne U Jackson E 17. 16. 15. 14. 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. reprintsandpermissions/. http://npg.nature.com/ at online available is information permissions and Reprints Published online at http://www.nature.com/naturegenetics/. HTML version of the paper at http://www.nature.com/naturegenetics/. The authors declare competing interests:financial details accompany the full-text A list full of author contributions appears in the Foundation. Western Australian Epidemiology Genetic Resource; and Yrjö Jahnsson 079895, 081682, 083270, 085301 and 086596); Western Australian DNA Bank; endowments; Wellcome Trust (068545, 072960, 075491, 076113, 077016, 079557, Västra Götaland Foundation; Walter E. Nichols, M.D., and Eleanor Nichols Tampere; University Hospital Oulu, Finland; University of Oulu, Finland (75617); Communauté Urbaine du Grand UniversityNancy; Hospital Medical funds to Söderberg’s Foundation; Université Henri Poincaré-Nancy 1, Région Lorraine, and310000-112552 (33CSCO-122661, 3100AO-116323/1); Torsten and Ragnar s e l c i t r A  COM AU ailaja ailaja Vedantam eresa eresa Ferreira

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T cea, A. Scherag, D. Meyre, Heard-Costa, N.L. C.M. Lindgren, central the of disorder heritable a as obesity Human I.S. Farooqi, & S. O’Rahilly, Huszar, D. D. Ren, G. Thorleifsson, Willer,C.J. R.J. Loos, A. Scuteri, T.M. Frayling, Taylor,A.E. Maes, H.H., Neale, M.C. & Eaves, L.J. Genetic and environmental factors in relative T.T.Foch, A.J., Stunkard, obesity.human of study twin A Z. Hrubec, & Lewis, C.E. of treatment and evaluation, identification, the on guidelines Clinical Anonymous. nlss f eoewd ascain tde fr al-ne etee bst in obesity extreme early-onset groups. study for German and French studies association genome-wide of analysis populations. inEuropean loci (2009). 157–159 risk new three identifies obesity (2009). Consortium. CHARGE the from study association wide fat distribution. and (2009). adiposity influencing loci balance. energy of control mice. in homeostasis. obesity. of measures with (2009). associate that loci seven at regulation. weight body on influence obesity. of risk and traits. obesity-related with associated are gene (2007). mass index and predisposes to childhood and adult obesity. (2010). cohorts. UK 4 from data using study a mortality: of central adiposity and fat mass with coronary heart disease, diabetes, and all-cause adiposity. human and weight body Assoc. (2009). 3263–3271 Association. Heart American the from advisory science a range: comment Res. Obes. Health. of Institutes National report. evidence adults–the in obesity and overweight H P O ET R R

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Department Department of Oncology, University of Cambridge, Cambridge, UK. 50 24 K 61 haw avid avid P Department Department of Biological Psychology, Vrije Universiteit (VU) University Amsterdam, Department Department of Harvard Biostatistics, School of Public Health, Boston, Massachusetts, National National Institute for Health and Welfare, Department of Chronic Disease Prevention, aplan E D 148 29 rdmann 34 6 D

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© 2010 Nature America, Inc. All rights reserved. Unit Unit of General Practice, Helsinki, Finland. Primary Health Care, University of Helsinki, Helsinki, Finland. Medica D’investigacio and Centro de Biomédica Investigación en Red CIBER y Epidemiología Salud Pública, Barcelona, Spain. India. Evanston, Healthsystem, Illinois, USA. Nijmegen, The Netherlands. Dundee, Ninewells Hospital and Medical School, Dundee, UK. Oxford, UK. Warwick, Warwick Medical School, Coventry, UK. Ricerche (CNR), Monserrato, Cagliari, Italy. School of Medicine, University of Southern California, Los Angeles, California, USA. Dresden, Dresden, Germany. Germany. 80 79 Nature Ge Nature Oulu, Oulu, University of Oulu, Oulu, Finland. Department of Chronic Disease Prevention, Population Studies Unit, Turku, Finland. University Hospital, Glostrup, Denmark. Germany. Inc., National Cancer Institute Frederick, Maryland, (NCI)-Frederick, USA. San Francisco, San Francisco, California, USA. 127 Western Australia, Australia. University Greifswald, Greifswald, Germany. Child and Adolescent Psychiatry, University of Essen, Duisburg-Essen, Germany. Medizin II, Universität Regensburg, Regensburg, Germany. of Psychiatry and Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, Missouri, USA. Helsinki, Finland. Oulu, Oulu, Finland. 116 Oxford, UK. Maryland School of Medicine, Baltimore, Maryland, USA. Greifswald, Germany. School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. Endocrinology, Diabetes and Obesity Unit, Department of Pediatrics and Adolescent Medicine, Ulm, Germany. Neurology, General Central Hospital, Bolzano, Italy. Medicine, European Academy (EURAC), Bozen-Bolzano Italy,Bolzano-Bozen, Affiliated Institute of the University of Lübeck, Lübeck, Germany. Laboratory, Queensland Institute of Medical Research, Queensland, Australia. des Hôpitaux de Paris, Paris, France. Related Traits Consortium) investigators. Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK. Finland. 154 Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland. 151 Technology, Levanger, Norway. Finland. Centre for Clinical Research, University of Leipzig, Leipzig, Germany. School of Medicine, Stanford, California, USA. USA. Massachusetts, National, Heart, Lung, and Blood Institute and Boston University, Framingham, USA. Massachusetts, USA. Helsinki and Uusimaa (HUS), Helsinki, Finland. Hospital, Hospital, Cambridge, UK. Institutes of Health, Framingham, USA. Massachusetts, Croatia. Laboratory, Queensland Institute of Medical Research, Queensland, Australia. Research Center for Health, Environmental Neuherberg, Germany. Genetics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany. of Social Medicine, University of Bristol, Bristol, UK. University University Medical Center, Leiden, The Netherlands. Helsinki, Finland. Germany. Road, Leicester, UK. NIHR Biomedical Research Unit in Disease, Cardiovascular Glenfield Hospital, Leicester, UK. Haematology, University of Cambridge, Cambridge, UK. Psychiatry, Instituut voor Extramuraal Geneeskundig Onderzoek (EMGO) Institute, VU University Medical Center, Amsterdam, The Netherlands. University Central Hospital, Helsinki, Finland. Internal Medicine I, Kiel, Germany. Medicine, Greifswald, Germany. Central Hospital, Finland. Lappeenranta, Finland. Psychology and Psychotherapy, University of Marburg, Marburg, Germany. Medicine, Cardiovascular University of Turku, Turku, Finland. Finland. Medicine, Levanger Hospital, The Nord-Trøndelag Health Trust, Levanger, Norway. of Helsinki, Helsinki, Finland. McMaster University, Hamilton, Ontario, Canada. Department Department of Social Medicine, University of Bristol, Bristol, UK. Research Cardiovascular Centre Multidisciplinary (MCRC), Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK. Division Division of Research, Kaiser Permanente Northern California, Oakland, California, USA. Merck Research Merck Laboratories, and Co., Inc., Boston, USA. Massachusetts, Human Human Genetics, Genome Institute of Singapore, Singapore, Singapore. Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. 140 98 169 MRC-Health MRC-Health Protection Agency (HPA) Centre for Environment and Health, London, UK. 156 148 185 180 Cardiovascular Research Cardiovascular Center and Cardiology Division, General Massachusetts Hospital, Boston, USA. Massachusetts, 82 132 200 Neurogenetics Laboratory,Neurogenetics Queensland Institute of Medical Research, Queensland, Australia. Department Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Nord-Trøndelag Health Study (HUNT) Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Ludwig-Maximilians-Universität, Institute of Medical Ludwig-Maximilians-Universität, Informatics, Biometry and Epidemiology, Chair of Epidemiology, Munich, Germany. Department of Sciences, Cardiovascular University of Leicester, Glenfield Hospital, Leicester, UK. Department Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK. 91 114 Institut Institut für und Epidemiologie Universität Sozialmedizin, Greifswald, Greifswald, Germany. Department Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland. n Department Department of Epidemiology and School Biostatistics, of Public Health, Faculty of Medicine, Imperial College London, London, UK. etics Montreal Montreal Heart Institute, Montreal, Quebec, Canada. 119 202 118 198 MRC MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, UK. Department Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 111 143

National National Institute for Health and Welfare, Department of Chronic Disease Prevention, Chronic Disease Epidemiology and Prevention Unit, ADVANCE ONLINE PUBLICATION ONLINE ADVANCE Department Department of Medicine, University of Leipzig, Leipzig, Germany. Center Center for Genetics, Neurobehavioral University of California, Los Angeles, California, USA. National National Institute for Health and Welfare, Diabetes Prevention Unit, Helsinki, Finland. 172 94 126 84 Department Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. 176 149 Department Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Clinical Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK. Busselton Busselton Population Medical Research Foundation Inc., Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia. 189 Obesity Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland. Finnish Finnish Institute of Occupational Health, Oulu, Finland. Christian-Albrechts-University, University Institute Hospital for Schleswig-Holstein, Clinical Molecular Biology and Department of 190 160 Universität Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany. 96 138 134 Cardiovascular Genetics Cardiovascular Research Unit, Université Henri 1, Poincaré-Nancy Nancy, France. 159 The The London School of Hygiene and Tropical Medicine, London, UK. 187 Hospital Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Hospital District of Faculty Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark. 103 87 Department Department of Endocrinology, Diabetology and Nutrition, Bernard Bichat-Claude University Hospital, Assistance Publique 125 Department Department of Clinical Sciences and Internal Medicine, University of Oulu, Oulu, Finland. Centre Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, UK. 192 Folkhalsan Folkhalsan Research Centre, Helsinki, Finland. 145 PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands, 129 139 89 174 Departments Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA. Andrija Andrija Stampar School of Public Health, Medical School, University of Zagreb, Zagreb, Croatia. Department Department of Social Services and Health Care, Jakobstad, Finland. Medical Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 107 Massachusetts General Massachusetts Hospital (MGH) Weight Center, General Massachusetts Hospital, Boston, Massachusetts, Amgen, Amgen, Cambridge, USA. Massachusetts, 204 163 Department Department of Internal Medicine B, University,Ernst-Moritz-Arndt Greifswald, Germany. 195 Department Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland. 171 Division Division of Health, Research Board, An Bord Taighde Sláinte, Dublin, Ireland. 113 National National Health Service (NHS) Blood and Transplant, Cambridge Centre, Cambridge, UK. 122 University University of Cambridge Metabolic Research Institute Laboratories, of Metabolic Science, Addenbrooke’s Department Department of Medicine, Cardiovascular University of Oxford, John Radcliffe Hospital, Headington, 182

Regensburg Regensburg University Medical Center, Innere Medizin II, Regensburg, Germany. 101 93 The The Department of Clinical Physiology, Turku University Hospital, Turku, Finland. Department Department of Epidemiology, and Biostatistics HTA, Radboud University Nijmegen Medical Centre, National National Institute for Health and Welfare, Helsinki, Finland. 166 81 115 147 Department Department of Clinical Sciences, Lund University, Malmö, Sweden. Institute Institute of Experimental Paediatric Endocrinology, Berlin, Charité Berlin, Universitätsmedizin Department Department of Medicine III, Pathobiochemistry, University of Dresden, Dresden, Germany. Department Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, 184 131 155 Department Department of Clinical Sciences and Clinical Chemistry, University of Oulu, Oulu, Institute Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, 162 168 Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, 124 110 Croatian Croatian Centre for Global Health, School of Medicine, University of Split, Split, Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department 178 Interfaculty Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt- Institut Institut für Klinische Chemie und Universität Greifswald, Laboratoriumsmedizin, 86 117 136 Gen-Info Gen-Info Ltd, Zagreb, Croatia. 153 Istituto Istituto di e Neurogenetica del Neurofarmacologia Consiglio Nazionale delle Department Department of Clinical Sciences, Obstetrics and Gynecology, University of Institute Institute of Health Sciences, University of Oulu, Oulu, Finland. Department Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. 199 150 128 165 Coordination Coordination Centre for Clinical Trials, University of Leipzig, Leipzig, Institut Institut inter-regional pour la santé (IRSA), La Riche, France. 201 197 Department Department of Epidemiology and University Biostatistics, of California, 158 104 175 Institute Institute of Human Genetics, Helmholtz Zentrum München-German 99 Research Research Program of Molecular Medicine, University of Helsinki, Department Department of Health Sciences, University of Leicester, University On On behalf of the MAGIC of (Meta-Analyses Glucose and Insulin- Vasa Central Hospital, Vasa, Finland. Finnish Finnish Twin Cohort Study, Department of Public Health, University Cardiovascular Epidemiology and Cardiovascular Genetics, Institut Municipal 142 191 133 170 Department Department of Medicine, Harvard Medical School, Boston, 173 Division Division of Cardiology, Laboratory,Cardiovascular Helsinki Research Research Centre for Prevention and Health, Glostrup National National Heart, Lung, and Blood Institute, National 97 Department Department of Pathology and Molecular Medicine, 181 109 South South Asia Network for Chronic Disease, New Dehli, 144 Research Research Centre of Applied and Preventive Division Division of Epidemiology and Community Health, 203 Department Department of Medicine, Stanford University 179 112 Center Center of Medical Systems Biology, Leiden National National Institute for Health and Welfare, Oulu, 130 Department Department of Medicine, University of 135 Core Core Genotyping Facility, SAIC-Frederick, 83 National National Institute for Health and Welfare, Department Department of Medicine III, University of 121 102 85 100 Klinik Klinik und Poliklinik für Innere Division Division of Endocrinology, Keck Helsinki Helsinki University Central Hospital, 141 Department Department of General Practice and 161 Framingham Framingham Heart Study of the 164 188 105 Genetic Genetic Epidemiology 95 167 Institute Institute of Human 90 Institut Institut für Community Institute Institute of Genetic Northshore Northshore University 177 157 Clinical Trial Service Unit, 152 Molecular Molecular Epidemiology Department Department of Department Department of Public 108 123 194 Department Department of Clinical 106 s e l c i t r A 183 Pediatric Pediatric 92 Department Department of Department Department of 146 Department Department of 205 193 186 University University of 196 Clinical Clinical Interdisciplinary Interdisciplinary 88 120 INSERM INSERM Department Department of 137 South South Karelia Leicester Leicester University University of Department Department Biocenter Biocenter 11 © 2010 Nature America, Inc. All rights reserved. ([email protected]), M.I.M. ([email protected]), J.N.H. ([email protected]), E.I. ([email protected]) or E.I. J.N.H. ([email protected]) R.J.F.L. ([email protected]), M.I.M. ([email protected]), ([email protected]), ([email protected]). 250 Prevention and Care of Diabetes, University of Dresden, Dresden, Germany. Paediatric Nutrition Medicine, Vestische Hospital for Children and Adolescents, University of Witten-Herdecke, Datteln, Germany. of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands. of Health Science, University of Aarhus, Aarhus, Denmark. University Nijmegen Medical Centre, Nijmegen, The Netherlands. Adolescent Mental Health, Helsinki, Finland. Center, New York, New York, USA. Texas Health Science Center, Houston, Texas, USA. Hospitalier VaudoisUniversitaire (CHUV) University Hospital, Lausanne, Switzerland. Ursachen umwelt- und Erkrankungen (LIFE) Study lebensstilassoziierter Centre, University of Leipzig, Leipzig, Germany. Psychiatry and Human Behavior, University of California, Irvine (UCI), Irvine, California, USA. University of Tampere and Tampere University Hospital, Tampere, Finland. Oulu, Finland. Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia, Australia. Genomics, Wake Forest University, Winston-Salem, North Carolina, USA. Genetics Cardiovascular team, Centre Clinique Investigation (CIC) 9501, Nancy, France. s e l c i t r A 1 University University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA. Metabolic Research Labs, Institute of Metabolic Science Addenbrooke’s Hospital, Cambridge, UK. London, London, UK. Finland. USA. Heart Study, Framingham, USA. Massachusetts, Washington University School of Medicine, St. Louis, Missouri, USA. Boston, USA. Massachusetts, Broad Institute of Harvard and Institute Massachusetts of Technology (MIT), Cambridge, USA. Massachusetts, Hospital, Seinajoki, Finland. Medical Center, Baltimore, Maryland, USA. 2

These These authors contributed equally to this work. should Correspondence be addressed to M.B. K. K.E.N. ([email protected]), Stefansson ([email protected]), 241 243 Department Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. Laboratory Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA. 211 School School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. 245 Klinikum Klinikum Grosshadern, Munich, Germany. 233 236 Department Department of Internal Medicine, Centre Hospitalier VaudoisUniversitaire (CHUV) University Hospital, Lausanne, Switzerland. Pacific Pacific Biosciences, Menlo Park, California, USA. 220 National National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Unit for Child and 231 221 Hjelt Hjelt Institute, Department of Public Health, University of Helsinki, Helsinki, Finland. NIHR NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK. 240 218 Department Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, New York, Faculty Faculty of Health Science, University of Southern Denmark, Odense, Denmark. 225 Department Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands. 223 246 239 Institute Institute of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark. Faculty Faculty of Medicine, University of Iceland, Reykjavík, Iceland. Division Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham 208 213 249 230 Department Department of Physiatrics, Lapland Central Hospital, Rovaniemi, Finland. Stanford Stanford University School of Medicine, Stanford, California, USA. Department Department of Genetics, Harvard Medical School, Boston, USA. Massachusetts, Geriatrics Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration 227 237 Department Department of Neurology, University of Lübeck, Lübeck, Germany. 217 Sage Sage Bionetworks, Seattle, Washington, USA. Human Human Genetics Center and Institute of Molecular Medicine, University of 206 244 Steno Steno Diabetes Center, Gentofte, Denmark. 215 Division Division of Community Health Sciences, St. George’s, University of 242 Leipziger Interdisziplinärer Forschungs-komplex zu Forschungs-komplex Leipziger molekularen Interdisziplinärer 248 Department Department of Medical Genetics, University of Helsinki, Helsinki, Carolina Carolina Center for Genome Sciences, School of Public Health, a DVANCE ONLINE PUBLICATION ONLINE DVANCE 210 235 Department Department of Internal Medicine, University of Oulu, Department Department of Psychiatry, Harvard Medical School, 216 222 Service Service of Medical Genetics, Centre 212 Department Department of Urology, Radboud Department Department of Clinical Physiology, 229 238 Department Department of Medicine III, 247 232 219 207 Division Division of Biostatistics, University University of Cambridge South South Ostrobothnia Central New New York University Medical Center Center for Human

Nature Ge Nature 214 Department Department of 226 209 228 Department Department School School of 224 Institute Institute for Faculty Faculty n 234 etics The The © 2010 Nature America, Inc. All rights reserved. criteria were criteria as defined Hardy-Weinberg Equilibrium control quality genotyping Minimum excluded. were study by individual each defined criteria control quality the meet not did that SNPs and Samples or TaqManiPLEX ( Sequenom assays using 16 studies 42 SNPs was from available a of from total adults of 79,561 European ancestry up. follow 2 Stage 16 SNPs in ( data CEU by a proxy SNP that was in high LD with it ( substituted and was reasons for technical genotyped not be could association by ent separated when at 1 least Mb. For the some SNP loci, with the strongest 2) ( (stage analyses ( significant most Selection of SNPs for follow up. 1.318. was correction control genomic before results of the results. meta-analyzed The genomic control value for the meta-analyzed correction control genomic final a by followed used were meta-analysis ance vari inverse of the results the variants, of replicating discovery For the 0.99). and the URLs), –log resulting the between correlation the individual werestudies. Both meta-analyses using performed METAL (see and of on is association which the based direction method, results, we also performed of the stage 1 meta-analysis using the consistency weighted Toensure GWAS. individual each from errors standard and on based is which method, variance inverse the using meta-analysis results. association 1 stage of Meta-analysis ( 1.104 to 0.983 from ranged control genomic values study-specific Individual before meta-analysis. rected were excluded for each study. GWASAll individual were genomic control cor × 2 or proper_info < 0.4 in IMPUTE) and those with a minor allele count (MAC = ( scores quality imputation poor SNPs with studies, 46 the for data association genome-wide the meta-analyzing Before covariate. a as sex with combined in and men women relatedness context modeled that model component of the a variance in estimated were coefficients and regression Heart studies, HAPI Heart Amish Family Heart, Framingham SardiNIA, the in relatedness ( diseases) other for (for ascertained samples status case and sex by stratified were Analyses 1. of a deviation and standard 0 of mean a to transformed normally inverse and components) cipal was adjusted for age, age data), unpublished G.R.A., and Merlin Ding P.S. implemented C.J.W., model Li, (Y. genetic MACH2QTL additive in an using BMI with analyses ciation BMI. with analysis Association IMPUTE HapMap SNPs CEU ( European polymorphic of imputation sets, marker different across analysis ( arrays genotyping genome whole Illumina and Affymetrix using genotyped were each, individuals 26,799 and to up with ( studies 46 BMI on data with ancestry European of encompasses individuals adult genotyped 123,865 currently consortium GIANT The meta-analysis. association genome-wide 1 Stage ( 32 SNPs significance identified that genome-wide statistics reached summary 2 stage and 1 stage of Meta-analysis studies. 42 from individuals genotyped 10 × 5 42 SNPs with and from selected 46 studies individuals to genotyped up 123,865 on data of 1) (stage meta-analysis association genome-wide a prising design. Study ONLINE doi:10.1038/ng.686 Supplementary Note Supplementary P r 2 < 5 × 10 × 5 < .hat < 0.3 in MACH, observed/expected dosage variance < 0.3 in BimBam BimBam in < 0.3 variance dosage observed/expected MACH, in < 0.3 .hat N × minor allele frequency) of < 6 in each sex- and case-specific stratum stratum case-specific and sex- each in 6 < of frequency) allele minor × −6 4 8 for follow up in stage 2. Stage 2 comprised up to 125,931 additional additional 125,931 to up comprised 2 Stage 2. stage in up follow for , SNPTEST , 4 6

−8 or BimBam or MET de novo de Supplementary Table 1 Table Supplementary ). We designed a multistage study ( study multistage a We designed H P Supplementary Table 1 Supplementary < 5 × 10 ODS and 18 18 and Samples and genotyping. and Samples 4 6 , ProbAbel , Supplementary Note Supplementary ). The samples from 46 studies, including between 276 between including 46 studies, from samples ). The 4 2 7 and other appropriate covariates (for example, prin . in silico in −6 Supplementary Note Supplementary Forty-two lead SNPs, representing the forty-two ) independent loci, were selected for replication for replication were selected loci, ) independent Each study performed single marker asso marker single performed study Each 4 9 replication studies in stage 2. stage in studies replication , GenABEL , Supplementary Note Supplementary ). We tested the association of these 42 42 these of association the tested We ). Supplementary Note Supplementary ). Loci were considered independ were considered ). Loci r Next, we performed the stage 1 stage the performed we Next, ) was performed using MACH using ) performed was 2 Directly genotyped data for the the for data genotyped Directly > 0.8) according to the HapMap 5 0 Supplementary Fig. 1 Fig. Supplementary , LME in R or PLINK or R in LME , ). Samples and genotyping. and Samples 10 P Supplementary Note Supplementary > 10

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which which is immune to in informa stratification, with 5,507 individuals pedigree analysis, family-based a performed we stratification, population by statistics stratification. population of Assessment METAL. in method inverse-variance the using of statistics the stage the 1 summary and meta-analyzed stage 2 meta-analyses we SNP.Next, this of imputation and genotyping the to relating challenges in for 41 of the 42 individuals for SNPs. For at 179,000 least one SNP (rs6955651 P The meta-analysis using a weighted method. inverse-variance the using studies 2 stage the from errors standard for described the stage 1 studies. We meta-analyzed subsequently each in BMI and SNPs 42 the meta-analysis. and analyses Association excluded. were stratum case-specific and sex- each in 6 < MAC a with SNPs and IMPUTE), in 0.4 < from the scores quality MACH either using imputed Affymetrix and Illumina genome-wide using genotyping arrays. Autosomal HapMapgenotyped SNPs were were and individuals 22,888 and 345 between ( analyses 1 stage the in included been not had GWASthat 18 from ancestry European of individuals 46,370 from SNPs significant most 42 the for obtained also were results Association > studies. in of and each 99% in samples follow-up concordance duplicate the meta-analyses for type 2 diabetes (Diabetes Genetics Replication and and Replication Genetics (Diabetes Consortium (DIAGRAM) diabetes 2 Meta-analysis type association for genome-wide reported meta-analyses related with previously from association extracted the on were data traits and samples, the replication on 2 Data stage the adolescents. from or obtained were weight and height and SNPs 32 children the between obese association extremely and extremely of studies adults obese case-control seven in and SNPs obesity 32 the early-onset or between extreme association for tested we Furthermore, population-based four in studies. examined was adolescents and children in BMI with association and the 2 samples, stage in in assessed BMI was status obese or and weight obesity over and in variants BMI confirmed 32 ability the between Association study. predictive ARIC their assessed and BMI on the in detail in described are analyses follow-up These roles. functional potential their explore to and children and in BMI loci adults of to the impact the estimate 32 low-up analyses confirmed analyses. Follow-up allele examined. strong samples European the have across to differences frequency appear not do BMI with associated are that SNPs the SNPs ( associated non-BMI million 2.1 for Fst from the mean different BMI SNPs for was not significantly the 32 confirmed Cohort, SardiNIA, CoLaus and DeCODE) for this analysis. The mean Fst value large sample sizes (Northern Finland Birth British Cohort (NFBC), 1958 Birth relatively with populations European diverse five Weselected stratification. due to population results SNPs false-positive be BMI might 32 confirmed the by stratification. confounded substantially not are meta- analysis our in associations significant genome-wide the that indicate results These sample. family-based the in size effect larger a had loci) new 18 of out of about stratification, substantial half of the loci (18 out of 32 loci total and 10 ( sample Study Heart and in the Framingham meta-analysis in the overall BMI identical on were essentially sizes effect estimated the particular, in loci new 18 the and general in by For MACH. 32 loci the reported dosages from genotypes best-guess the with those only SNPs, imputed the and the are data Study Heart Framingham the in directions and sizes Effect PLINK. in dure proce QFAM–within the that using Study Heart Framingham the from tion values was >0.99) and included up to 249,796 Data individuals. was available KIAA1505 In brief, we estimated the cumulative effect of the 32 loci combined combined loci 32 the of effect cumulative the estimated we brief, In In addition, we estimated the fixation index (Fst) for all SNPs to test whether P values are empirical and are based on permutation testing. For For testing. permutation on based are and empirical are values β ), ), data was only available for due individuals to 125,672 technical statistics reported by PLINK from the within-family analysis, analysis, within-family the from PLINK by reported statistics Subsequently, we performed an extensive series of fol of series extensive an performed we Subsequently, Supplementary Note Supplementary in

silico in silico in 4 studies ( studies 5 or IMPUTE or r 2 .hat > 0.3 in MACH were analyzed using using analyzed were MACH in 0.3 > .hat Supplementary Note Supplementary z -score -score method was similar (the and and Supplementary Note Supplementary To assess for possible inflation of test test of inflation possible for To assess r We tested the association between between association the tested We 2 .hat .hat < 0.3 in MACH or proper_info 1 de novo de ), and, as expected in the absence absence the in expected as and, ), 8 ), lipid levels (the Global Lipids Lipids Global (the levels lipid ), 4 6 t . SNPs with poor imputation imputation poor with SNPs . test test stage 2 study separately as as separately study 2 stage P = 0.28), suggesting that that suggesting = 0.28), Nature Ge Nature ). Studies included included Studies ). . β values and r between n etics - - - -

© 2010 Nature America, Inc. All rights reserved. whether any of the 32 confirmed BMI loci harbored additional independent independent additional harbored loci BMI confirmed 32 the of any whether analysis. 2 stage and 1 stage combined the in effects those to detect power the and loci BMI established for the observed quencies method new a using exist to likely are that loci susceptibility of number the estimated and loci using a method proposed by the International Schizophrenia Consortium phocytes tissue adipose in genes nearby of expression and the examined We CNVs. common tagged SNPs BMI confirmed 32 the of any whether ated evalu also and boundary exon-intron the of bp 5 within occurred which or having for multiple modest BMI associations using MAGENTA enriched SNPs were BMI confirmed 32 of kb the 300 within gene one at least contain that functions molecular or processes biological predefined whether (MAGIC) Consortium traits Insulin-related and Consortium Genetics Nature Ge Nature We performed a conditional genome-wide association analysis to examine examine to analysis association genome-wide conditional We a performed BMI 32 by the explained variance of phenotypic amount Wethe evaluated tested we BMI, with associated pathways new potentially discover To r 2 36,52

≥ 0.75 with the lead SNP that were likely non-synonymous, nonsense n 3 and brain and 8 etics cis based on the distribution of effect sizes and minor allele fre allele minor and sizes effect of distribution the on based associations between each of the 32 confirmed BMI SNPs SNPs BMI confirmed 32 the of each between associations 2 3 0 5 ) and glycemic traits (Meta-Analyses of Glucose Glucose of (Meta-Analyses traits glycemic and ) . 34,52 19,21 , whole blood whole , 3 ). 3 . . We identified SNPs 3 4 , lym , 3 7 - - -

52. 51. 50. 49. 48. 47. 46. 45. BMI firmed SNPs to test for non-additive effects. the BMI loci. Dominant and recessive analyses were performed for the 32 con signals, and we also examined gene-by-gene and gene-by-sex interactions among

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