Obesity is a worldwide epidemic, with major health and economic costs. Here we estimate heritability for body mass index (BMI) in 172,000 sibling pairs and 150,832 unrelated individuals and explore the contribution of genotype–covariate interaction effects at common SNP loci. We find evidence for genotype–age interaction (likelihood ratio test (LRT) = 73.58, degrees of freedom (df) = 1, P = 4.83 × 10−18), which contributed 8.1% (1.4% s.e.) to BMI variation. Across eight self-reported lifestyle factors, including diet and exercise, we find genotype–environment interaction only for smoking behavior (LRT = 19.70, P = 5.03 × 10−5 and LRT = 30.80, P = 1.42 × 10−8), which contributed 4.0% (0.8% s.e.) to BMI variation. Bayesian association analysis suggests that BMI is highly polygenic, with 75% of the SNP heritability attributable to loci that each explain <0.01% of the phenotypic variance. Our findings imply that substantially larger sample sizes across ages and lifestyles are required to understand the full genetic architecture of BMI.
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We thank the anonymous reviewers for their insightful comments; the participants of the cohort studies; our colleagues at the Program in Complex Trait Genomics and M. Goddard for comments and suggestions. The authors also wish to thank the staff, contributing research centers and the participants of all studies. The UK Biobank research was conducted using the UK Biobank Resource under project 12505. The University of Queensland group is supported by the Australian Research Council (Discovery Project 160103860), the Australian National Health and Medical Research Council (1080157, 1078037, 1048853, 1050218, and 1113400), and the NIH (R21ESO25052-01 and PO1GMO99568). J.Y. is supported by a Charles and Sylvia Viertel Senior Medical Research Fellowship. M.R.R. is supported by the University of Lausanne. D.C. and M.J. were supported by the Swedish Research Council (421-2013-1061), the Ragnar Söderberg Foundation (E9/11), and the Jan Wallander and Tom Hedelius Foundation (P2015-0001:1). The ARIC study is carried out as a collaborative study supported by the US National Heart, Lung, and Blood Institute (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C). The Estonian Genome Centre of University of Tartu Study was supported by EU Horizon 2020 grants 692145, 676550, and 654248; Estonian Research Council Grant IUT20-60, NIASC, EIT–Health; NIH BMI grant 2R01DK075787-06A1; and the European Regional Development Fund (project 2014-2020.4.01.15-0012 GENTRANSMED). The Health and Retirement Study is supported by the US National Institute on Aging (NIA; U01AG009740). The genotyping was funded separately by the NIA (RC2 AG036495 and RC4 AG039029) and was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the HRS data were performed by the Genetics Coordinating Center at the University of Washington. The LifeLines Cohort Study and generation and management of GWAS genotype data for the LifeLines Cohort Study were supported by the Netherlands Organization of Scientific Research NWO (175.010.2007.006); the Economic Structure Enhancing Fund of the Dutch government; the Ministry of Economic Affairs; the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the Northern Netherlands Collaboration of Provinces; the Province of Groningen; University Medical Center Groningen; the University of Groningen; the Dutch Kidney Foundation; and the Dutch Diabetes Research Foundation. The Nurses Health Study (NHS) and Health Professionals Follow-up Studies (HPFS) received funding support for the GWAS of Gene and Environment Initiatives in Type 2 Diabetes through the NIH Genes, Environment and Health Initiative (GEI) (U01HG004399). The human subjects participating in the GWAS derived from NHS and HPFS and these studies are supported by National Institutes of Health grants CA87969, CA55075 and DK58845. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH GEI (U01HG004424). The Swedish Twin Registry (TWINGENE) was supported by the Swedish Research Council (M-2005-1112), GenomEUtwin (EU/QLRT-2001-01254; QLG2-CT-2002-01254), NIH DK U01-066134, the Swedish Foundation for Strategic Research (SSF), and the Heart and Lung Foundation (20070481).
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Supplementary Figures 1–6, Supplementary Tables 1–6 and Supplementary Note.
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Nature Reviews Genetics (2017)