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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Abstract

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

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Figure 1: Genome-wide association results for GIANT (stage 1).
Figure 2: Regional association plots showing signals in stage 1 samples for replicating loci around TMEM18, GNPDA2, SH2B1, MTCH2, KCTD15 and NEGR1.
Figure 3: Combined impact of risk alleles on average BMI in the population-based EPIC-Norfolk cohort.
Figure 4: Contribution of copy number polymorphism to BMI.

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Acknowledgements

We are extremely grateful to all of the participants in each of the studies contributing to this effort. Full acknowledgments can be found in the Supplementary Note.

Support for this research was provided by: US National Institutes of Health grants CA65725, CA87969, CA49449, CA67262, CA50385, DK062370, DK072193, DK075787, HG02651, HL084729, HL087679 (through STAMPEED, 1RL1MH083268), 5UO1CA098233, 1Z01 HG000024, 1RL1MH083268, T32 DK07191, F32 DK079466, K23 DK080145, K23 DK067288, CIDR NIH Contract Number N01-HG-65403, NIA contract NO1-AG-1-2109; the Intramural Research Program of the Division of Cancer Epidemiology and Genetics; contracts from the Division of Cancer Prevention, National Cancer Institute and EU FP6 funding (contract no LSHM-CT-2003-503041); GlaxoSmithKline; the Faculty of Biology and Medicine of Lausanne, Switzerland; the Intramural Research Program of the National Institute on Aging (NIA); Cancer Research United Kingdom; the UK Medical Research Council (including grants G0000649, G0000934 and G0601261); the Wellcome Trust (including Strategic Award 076113, grants 068545/Z/02 and 076467/Z/05/Z); the NIHR through the Biomedical Research Centres at Oxford, King's College London; Guys and St. Thomas' Foundation Hospitals' Trust; the British Heart Foundation (including grant FS/05/061/19501), European Community's Seventh Framework Programme (ENGAGE:HEALTH-F4-2007-201413); Diabetes UK; Unilever Corporate Research; American Diabetes Association including a Smith Family Foundation Pinnacle Program Project Award #7-03-PPG-04R; the Academy of Finland (grants 118065 and 124243); National Genome Research Net Germany; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; the Helmholtz Center Munich; the Sigrid Juselius Foundation; University of Bristol; Linné grant from Swedish Research Council; Wallenberg Foundation; Folkhälsan Research Foundation; University of Southampton; Netherlands Organisation of Scientific Research NWO (nr. 175.010.2005.011); Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry for Health, Welfare and Sports; the European Commision (DG XII) and the Municipality of Rotterdam. G.R.A. and K.L.M. are Pew Scholars for the Biomedical Sciences; A.L.E. is supported by a Sarnoff Cardiovascular Research Foundation Fellowship; C.M.L. is a Nuffield Department of Medicine Scientific Leadership Fellow; S.A.M. is supported by a Life Sciences Research Fellowship; M.K. is supported by the Finnish Cultural Foundation; N.J.S. holds a BHF Chair; M.N.W. is a Vandervell Foundation Research Fellow; C.J.W. is supported by an American Diabetes Association postdoctoral fellowship; and E.Z. is a Wellcome Trust-RD Fellow (grant number 079557).

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The writing team consisted of G.R.A., I.B., M.B., I.M.H., J.N.H., S.L., C.M.L., R.J.F.L., M.I.McC., E.K.S. and C.J.W. Full author contributions and roles are listed in the Supplementary Note.

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Correspondence to Mark I McCarthy, Michael Boehnke, Inês Barroso, Gonçalo R Abecasis or Joel N Hirschhorn.

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Peter Vollenweider and Gérard Waeber received financial support from GlaxoSmithKline to build the CoLaus study; Dawn Waterworth, Kijoung Song, Noha Lim and Vincent Mooser are full-time employees of GlaxoSmithKline (GSK); Inês Barroso owns stock in the companies GlaxoSmithKline (CSK) and Incyte (INCY).

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the GIANT Consortium. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 41, 25–34 (2009). https://doi.org/10.1038/ng.287

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