Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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Acknowledgements
A full list of acknowledgments appears in the Supplementary Note. Funding was provided by the Aarno Koskelo Foundation; the Academy of Finland; the Agency for Science, Technology and Research of Singapore; the Australian National Health and Medical Research Council; the Australian Research Council; BDA Research; the BioSHaRE Consortium; the British Heart Foundation; the Cedars-Sinai Board of Governors' Chair in Medical Genetics; the Centre for Clinical Research at the University of Leipzig; the Centre of Excellence in Genomics and the University of Tartu; the Chief Scientist Office of the Scottish government; the City of Kuopio and the Social Insurance Institution of Finland; the Department of Educational Assistance, the University and Research of the Autonomous Province of Bolzano; the Donald W. Reynolds Foundation; the Dutch Ministry for Health, Welfare and Sports; the Dutch Ministry of Education, Culture and Science; Dutch BBRMI-NL; the Dutch Brain Foundation; the Dutch Centre for Medical Systems Biology; the Dutch Diabetes Research Foundation; the Dutch Government Economic Structure–Enhancing Fund; the Dutch Inter-University Cardiology Institute; the Dutch Kidney Foundation; the Dutch Ministry of Economic Affairs; the Dutch Ministry of Justice; the Dutch Research Institute for Diseases in the Elderly; Eleanor Nichols endowments; the Emil Aaltonen Foundation; Erasmus Medical Center and Erasmus University; the Estonian government; the European Commission; the European Regional Development Fund; the European Research Council; the European Science Foundation; the Faculty of Biology and Medicine of Lausanne; Finland's Slot Machine Association; the Finnish Cultural Foundation; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Funding Agency for Technology and Innovation; the Finnish Heart Association; the Finnish Medical Society; the Finnish Ministry of Education and Culture; the Finnish Ministry of Health and Social Affairs; the Finnish National Institute for Health and Welfare; the Finnish Social Insurance Institution; Finska Läkaresällskapet; the Folkhälsan Research Foundation; the Foundation for Life and Health in Finland; the French Ministry of Research; the French National Research Agency; the Genetic Association Information Network; the German Diabetes Association; the German Federal Ministry of Education and Research; the German Ministry of Cultural Affairs; the German National Genome Research Network; the German Research Foundation; GlaxoSmithKline; the Göteborg Medical Society; the Greek General Secretary of Research and Technology; the Gyllenberg Foundation; Health Care Centers in Vasa, Närpes and Korsholm; the Heinz Nixdorf Foundation; Helmholtz Zentrum München–German Research Center for Environmental Health; the Icelandic Heart Association; the Icelandic Parliament; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, the National Cancer Institute, NIH; Italian Ministry of Education, Universities and Research; Italian Ministry of Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; the Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds; the Leducq Foundation; the Lundberg Foundation; the March of Dimes; the Munich Center of Health Sciences as part of LMUinnovativ; the Municipal Health Care Center and Hospital in Jakobstad; the Municipality of Rotterdam; the Närpes Health Care Foundation; National Alliance for Research on Schizophrenia and Depression Young Investigator Awards; the Netherlands Genomics Initiative; the Netherlands Organization for Health Research and Development; UK NHSBT; US National Institutes of Health; the Nordic Center of Cardiovascular Research; the Nordic Center of Excellence in Disease Genetics; the Nordic Centre of Excellence on Systems Biology in Controlled Dietary Interventions and Cohort Studies; the Northern Netherlands Collaboration of Provinces; the Novo Nordisk Foundation; the Ollqvist Foundation; the Orion-Farmos Research Foundation; the Paavo Nurmi Foundation; the Päivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Petrus and Augusta Hedlunds Foundation; the Province of Groningen; the Republic of Croatia Ministry of Science, Education and Sport; the Reynold's Foundation; the Royal Society; Samfundet Folkhälsan; the Signe and Ane Gyllenberg Foundation; the Sigrid Juselius Foundation; the Social Ministry of the Federal State of Mecklenburg–West Pomerania; the Sophia Foundation for Medical Research; the South Tyrolean Sparkasse Foundation; the Southern California Diabetes Endocrinology Research Center; the Stockholm County Council; the Strategic Cardiovascular Program of Karolinska Institutet; Strategic Support for Epidemiological Research at Karolinska Institutet; the Susan G. Komen Breast Cancer Foundation; the Swedish Ministry for Higher Education; the Swedish Cancer Society; the Swedish Cultural Foundation in Finland; the Swedish Diabetes Association; the Swedish Foundation for Strategic Research; the Swedish Heart-Lung Foundation; the Swedish Medical Research Council; the Swedish Ministry of Education; the Swedish Research Council; the Swedish Royal Academy of Science; the Swedish Society for Medical Research; the Swedish Society of Medicine; the Swiss National Science Foundation; the Tampere Tuberculosis Foundation; The Great Wine Estates of the Margaret River Region of Western Australia; The Paul Michael Donovan Charitable Foundation; the Torsten and Ragnar Söderberg Foundation; Cancer Research UK; the UK Diabetes Association; the UK Heart Foundation; the UK MRC; the UK NIHR, Biomedical Research Centre; UK West Anglia Primary and Community Care; the University Medical Center Groningen and the University of Groningen; the Västra Götaland Foundation; VU University: the Institute for Health and Care Research and the Neuroscience Campus Amsterdam; the Wellcome Trust; and the Yrjö Jahnsson Foundation.
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Authors and Affiliations
Contributions
Steering committee (oversaw the consortium): G.R.A., T.L.A., I.B., S.I.B., M. Boehnke, I.B.B., P.D., C.S.F., T. Frayling, L.C.G., T.H., I.M.H., D.H., E.I., R.C.K., R.J.F.L., M.I.M., K.L. Mohlke, K.E.N., J.R.O., D. Schlessinger, D.P.S., U.T. and C.M.v.D. Writing group (drafted and edited the manuscript): S.I.B., M.F.F., A. Ganna, S.G., E.I., A.E.J., C.M.L., R.J.F.L., R.M., M.I.M., D. Meyre, K.L. Monda, A.P.M., K.E.N., A. Scherag, E.K.S., E. Wheeler and C.J.W. Data cleaning and preparation: S.I.B., D.C.C.-C., F.R.D., T.E., T. Fall, T. Ferreira, S.G., I.M.H., E.I., A.U.J., C.M.L., J. Luan, R.M., J.C.R., A. Scherag, E.K.S., G.T., S.V., T.W.W. and A.R.W. Statistical advisors: S.H.L., B.M.N., Y.P., P.M.V., J.Y., D.-Y.L. and Y.-J.H. Gene expression (eQTL) analyses: L. Liang, W.O.C., M.F.M., G.R.A., V. Steinthorsdottir, G.T., J.L.M., G. Nicholson, F. Karpe., M.I.M. and E.E.S.
Project design, management and coordination of contributing studies
Stage 1—GWAS: (ADVANCE) T.L.A. and C.I.; (AGES) V.G., T.B.H. and L.J.L.; (ARIC) E.B. and K.E.N.; (B58C) D.P.S.; (BRIGHT Study) M.J.C. and P.B.M.; (CAPS) E.I.; (CHS) B.M. and B.M.P.; (CoLaus) V.M., P.V. and G. Waeber; (COROGENE) M.S.N. and J. Sinisalo; (deCODE) K. Stefansson and U.T.; (DGI) L.C.G. and J.N.H.; (EGCUT) A.M.; (EPIC) K.-T.K., R.J.F.L. and N.J.W.; (ERF) B.A.O. and C.M.v.D.; (FamHS) I.B.B. and M.A.P.; (Fenland) R.J.F.L. and N.J.W.; (FRAM) L.A.C. and C.S.F.; (FUSION GWAS) M. Boehnke and K.L. Mohlke; (Genmets) A.J., S.R. and V. Salomaa; (GerMIFS1) J.E. and H. Schunkert; (GerMIFS2) C. Hengstenberg and K. Stark; (GOOD) C.O.; (HBCS) J.G.E.; (KORA S3) H.-E.W.; (KORA S4) C.G., T.I., W.K. and A. Peters; (MGS) P.V.G. and D.F.L.; (MICROS (SOUTH TYROL)) P.P.P.; (MIGEN) J.N.H. and S. Kathiresan; (NESDA) B.P.; (NFBC 1966) M.-R.J.; (NHS) L.Q.; (Nijmegen Biomedical Study) L.A.K.; (NSPHS) U.G.; (NTR) D.I.B.; (ORCADES) J.F.W. and A.F.W.; (PLCO) S.J.C. and S.I.B.; (PROCARDIS) M.F. and H. Watkins; (RS-I) F.R. and A.G.U.; (RUNMC) L.A.K.; (SardiNIA) D. Schlessinger; (SASBAC) E.I.; (SHIP) H. Wallaschofski; (Sorbs) M.S. and A. Tönjes; (TwinsUK) T.D.S.; (VIS) I.R.; (WGHS) P.M.R.; (WTCC-T2D) M.I.M.; (WTCCC-CAD) A.J.B., A.S.H. and N.J.S.; and (YFS) M. Kähönen, T.L., O.R. and J. Viikari. Stage 2—Metabochip and in silico replication: (AMC-PAS) K.G.H.; (B58C) C. Power; (BHS) L.J.P.; (DILGOM) K. Kuulasmaa and V. Salomaa; (DPS) M.U.; (DR's EXTRA) T.A.L. and R.R.; (EPIC, Fenland and Ely) C. Langenberg, R.J.F.L. and N.J.W.; (FIN-D2D 2007) S.M.K.-K. and T.E.S.; (GLACIER) P.W.F.; (Go-DARTS (Dundee)) A.D.M. and C.N.A.P.; (HNR) K.-H.J.; (HUNT 2) K.H.; (Hypergenes) D.C.; (IMPROVE) U.d.F., A. Hamsten and E.T.; (KORA S3) I.M.H.; (LifeLines Cohort Study) H. Snieder, M.M.V.d.K. and B.H.R.W.; (LURIC) B.O.B., W.M. and B.R.W.; (METSIM) J.K. and M. Laakso; (MORGAM) P.A., P.B., M.M.F., J.F., F. Kee, D.-A.T. and J. Virtamo; (NSHD) D.K.; (PIVUS) E.I.; (PLCO2) S.I.B. and S.J.C.; (PREVEND) P.v.d.H.; (QIMR) N.G.M., G.W.M., A.C.H. and P.M.; (RS-II) A. Hofman and J.B.J.v.M.; (RS-III) C.M.v.D. and J.C.M.W.; (Swedish Twin Registry) E.I.; (THISEAS/AMCPAS/CARDIOGENICS) P.D.; (THISEAS) G.V.D.; (TRAILS) A.J.O.; (Tromsø 4) I.N.; (TWINGENE) E.I.; (UKBS2) W.H.O.; (ULSAM) E.I.; (Whitehall II) A. Hingorani and M. Kivimäki; and (WTCC-T2D) M.I.M. and C.M.L. Other contributing studies, clinical extremes: (French Extreme Obesity Study) D. Meyre and P.F.; (GEO-IT) A.M.D.B.; (Essen Obesity Study, Essen Case-Control & Essen Obesity Trio GWAS) J.H. and A. Hinney; and (GOYA) T.I.A.S. and E.A.N.
Genotyping of contributing studies
Stage 1—GWAS: (ADVANCE) D.A.; (ARIC) E.B.; (B58C) W.L.M.; (CAPS) H. Grönberg; (CHS) T.H.; (CoLaus) V.M.; (COROGENE) M. Perola; (EGCUT) T.E. and L.M.; (EPIC) I.B.; (ERF) B.A.O. and C.M.v.D.; (FamHS) I.B.B., M.A.P. and A.T.K.; (Fenland) J. Luan; (Genmets) S.R.; (GOOD) C.O., J.-O.J. and M. Lorentzon; (HBCS) A. Palotie and E. Widén; (MGS) P.V.G. and A.R.S.; (MICROS (SOUTH TYROL)) A.A.H.; (NHS) F.B.H. and D.H.; (NSPHS) Å.J.; (NTR and NESDA) J.-J.H.; (ORCADES) J.F.W.; (PLCO) S.J.C. and K.B.J.; (RS-I) F.R., A.G.U., K.E. and C.M.-G.; (SardiNIA) M. Dei; (SASBAC) P.H. and J. Liu; (SHIP) G.H.; (TwinsUK) M.M., S.-Y.S. and N.S.; (VIS) C. Hayward and V.V.; (WGHS) D.I.C.; (WTCC-T2D) M.I.M.; (WTCCC-CAD) A.J.B., A.S.H. and N.J.S.; and (YFS) T.L. Stage 2—Metabochip and in silico replication: (BHS) L.J.P. and J.B.; (CARDIOGENICS) S.E. and S.E.H.; (DPS) A.J.S.; (DR's EXTRA) M.A.; (EPIC, Fenland and Ely) J. Luan and K.K.O.; (FIN-D2D 2007) P.S.C.; (FUSION) F.S.C., J. Saramies and J. Tuomilehto; (GLACIER) I.B. and S.E.; (Go-DARTS (Dundee)) C.N.A.P.; (HNR) T.W.M.; (HUNT 2) N.N.; (Hypergenes) F.F.; (KORA S3) H. Grallert; (KORA S4) T.I.; (LifeLines Cohort Study) H. Snieder, B.H.R.W., M. Bruinenberg and L.F.; (NSHD) D.K., K.K.O. and A.W.; (PIVUS) E.I. and L. Lind; (PLCO2) S.J.C., K.B.J. and Z.W.; (PREVEND) P.v.d.H. and F.W.A.; (QIMR) N.G.M., G.W.M., A.C.H. and P.A.M.; (RS-II) M.J.P. and M. Dei; (Swedish Twin Registry) E.I., P.K.M. and N.P.; (THISEAS/AMCPAS/CARDIOGENICS) K. Stirrups; (TRAILS) A.J.O., I.M.N. and J.V.V.V.-O.; (Tromsø 4) L.L.B.; (TWINGENE) E.I., A. Hamsten and N.P.; (ULSAM) E.I.; (Whitehall II) C. Langenberg; and (WTCC-T2D) M.I.M. Other contributing studies, clinical extremes: (French Extreme Obesity Study) D. Meyre and P.F.; (GEO-IT) D.G.; and (GOYA) L.P. and D.M.E.
Phenotyping of contributing studies
Stage 1—GWAS: (ARIC) E.B.; (B58C) D.P.S.; (BRIGHT Study) J.M.C.; (CAPS) H. Grönberg; (CHS) B.M.P.; (CoLaus) P.V. and G. Waeber; (COROGENE) J. Sinisalo, M.-L.L.; (EGCUT) A.M. and K.F.; (EPIC) R.J.F.L.; (ERF) B.A.O. and C.M.v.D.; (FamHS) I.B.B., M.A.P. and M.F.F.; (Fenland) R.J.F.L.; (FRAM) C.S.F.; (Genmets) A.J. and V. Salomaa; (GerMIFS1) S. Schreiber; (GerMIFS2) A. Peters; (GOOD) C.O., J.-O.J., M. Lorentzon and L.V.; (MGS) P.V.G., A.R.S. and D.F.L.; (NFBC 1966) A.-L.H., J.H.L. and A. Pouta; (NHS) L.Q.; (Nijmegen Biomedical Study) F.d.V., M.d.H. and S.H.V.; (NSPHS) Å.J. and U.G.; (NTR and NESDA) G. Willemsen; (ORCADES) H.C. and S.H.W.; (PLCO) S.I.B.; (RS-I) F.R. and A.G.U.; (SASBAC) P.H.; (SHIP) S. Schipf; (Sorbs) A. Tönjes; (TwinsUK) M.M. and T.D.S.; (VIS) O.P.; (WTCC-T2D) M.I.M.; (WTCCC-CAD) A.J.B., A.S.H. and N.J.S.; and (YFS) M. Kähönen, O.R. and J. Viikari. Stage 2—Metabochip and in silico replication: (AMC-PAS) H.B. and M.D.T.; (B58C) C. Power and E.H.; (BHS) L.J.P., J.B. and A.W.M.; (DPS) J. Lindström; (EPIC, Fenland and Ely) R.J.F.L.; (GLACIER) P.W.F. and D. Shungin; (Go-DARTS (Dundee)) C.N.A.P. and A.D.M.; (Hypergenes) D.C. and P.M.; (KORA S3) B.T.; (KORA S4) A. Peters; (LifeLines Cohort Study) B.H.R.W. and M.M.V.d.K.; (METSIM) A. Stančáková and P.V.G.; (NSHD) D.K.; (PIVUS) E.I. and L. Lind; (PLCO2) S.I.B.; (PREVEND) G. Navis; (QIMR) N.G.M., A.C.H. and P.M.; (RS-II) M.C.Z.; (RS-III) J.C.M.W.; (Swedish Twin Registry) E.I., P.K.M. and N.P.; (THISEAS) M. Dimitriou and E.V.T.; (TRAILS) R.P.S.; (TWINGENE) E.I. and N.P.; (UKBS2) A. Rendon; (ULSAM) E.I.; (Whitehall II) M. Kumari; and (WTCC-T2D) M.I.M. Other contributing studies, clinical extremes: (Essen Obesity Study, Essen Case-Control GWAS & Essen Obesity Trio GWAS) J.H. and A. Hinney; (GEO-IT) A.L. and S. Signorini; and (GOYA) T.I.A.S. and E.A.N.
Analyses of contributing studies
Stage 1—GWAS: (ADVANCE) L.L.W.; (AGES) A.V.S.; (ARIC) K.E.N., A.E.J. and K.L. Monda; (B58C) D.P.S.; (BRIGHT Study) T.J.; (CAPS) E.I. and R.M.; (CHS) B.M. and G.L.; (CoLaus) D. Marek; (COROGENE) M. Perola; (deCODE) V. Steinthorsdottir and G.T.; (DGI) E.K.S. and S.V.; (EGCUT) K.F., T.E. and E.M.; (EPIC) J.H.Z.; (ERF) N.A.; (FamHS) M.F.F.; (Fenland) J. Luan; (FRAM) L.A.C., N.L.H.-C. and J.S.N.; (Genmets) I.S.; (GerMIFS1) M. Preuss; (GerMIFS2) I.R.K.; (GOOD) C.O., J.-O.J., M. Lorentzon and L.V.; (HBCS) N.E.; (KORA S3) C. Lamina; (KORA S4) E.A.; (MGS) D.F.L. and J. Shi; (MICROS (SOUTH TYROL)) J.E.H. and Å.J.; (MIGEN) E.K.S. and S.V.; (NFBC 1966) A. Pouta, R.M. and J.C.R.; (NHS) L.Q. and T.W.; (NSPHS) Å.J.; (NTR and NESDA) J.- J.H.; (ORCADES) Å.J.; (PLCO) K.B.J. and S.I.B.; (PROCARDIS) M.F., A. Goel and J.F.P.; (RS-I) F.R., K.E. and C.M.-G.; (SardiNIA) J.L.B.-G. and S. Sanna; (SASBAC) E.I. and R.M.; (SEARCH) J. Tyrer; (SHIP) A. Teumer; (Sorbs) R.M. and I.P.; (TwinsUK) M.M. and N.S.; (VIS) Å.J.; (WGHS) D.I.C.; (WTCC-T2D) C.M.L., R.M. and J.C.R.; (WTCCC-CAD) R.M. and J.C.R.; (WTCCC-NBS (UKBS-CC)) A.P.A., R.M., J.C.R., J.G.S. and J.C.S.; and (YFS) O.R. and T.L. Stage 2—Metabochip and in silico replication: (B58C) E.H. and T. Ferreira; (BHS) G.C.; (DILGOM) K. Kristiansson and K. Kuulasmaa; (DPS) A.U.J.; (DR's EXTRA) A.U.J.; (EPIC, Fenland and Ely) J. Luan and K.K.O.; (FIN-D2D 2007) A.U.J.; (FUSION) A.U.J.; (GLACIER) P.W.F. and D. Shungin; (HNR) S.P. and C. Pütter; (HUNT 2) A.U.J.; (Hypergenes) F.F. and Z.K.; (IMPROVE) R.J.S.; (KORA S3) I.M.H. and T.W.W.; (KORA S4) M.M.-N.; (LifeLines Cohort Study) M. Bruinenberg and L.F.; (LURIC) M.E.K.; (METSIM) A.U.J.; (NSHD) A.W. and J. Luan; (PIVUS) E.I., S.G.; (PLCO2) S.I.B., Z.W.; (PREVEND) P.v.d.H. and I.M.L.; (QIMR) S.E.M., J.Y.; (RS-II) M.J.P.; (Swedish Twin Registry) E.I. and S.G.; (THISEAS/AMCPAS/CARDIOGENICS) S. Kanoni; (TRAILS) I.M.N. and J.V.V.V.-O.; (Tromsø 4) A.U.J.; (TWINGENE) E.I. and S.G.; (UKBS2) A. Radhakrishnan; (ULSAM) E.I., A. Ganna and S.G.; (WGHS) L.M.R.; and (WTCC-T2D) R.M. and T. Ferreira. Other contributing studies, clinical extremes: (French Extreme Obesity Study) D. Meyre, C. Lecoeur and B.S.; (GEO-IT) A.M.D.B. and D.G.; (Essen Obesity Study, Essen Case-Control GWAS and Essen Obesity Trio GWAS) A. Scherag and I.J.; and (GOYA) L.P. and D.M.E.
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K. Stefansson, V. Steinthorsdottir, G.T. and U.T. are employed by deCODE Genetics with stock and/or stock options in the company. I.B. and spouse own stock in Incyte, Ltd., and GlaxoSmithKline. E.E.S. is Chief Scientific Officer at Pacific Biosciences. T.I.A.S. has collaborated with Nestlé Research Centre and DSM, The Netherlands, on the metabolomics and genomics of obesity and related traits, respectively.
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Berndt, S., Gustafsson, S., Mägi, R. et al. Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nat Genet 45, 501–512 (2013). https://doi.org/10.1038/ng.2606
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DOI: https://doi.org/10.1038/ng.2606
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