Suchergebnisse

AbstractThe amount of available DNA is often a limiting factor in pursuing genetic analyses of large-scale population cohorts. An association between higher DNA yield from blood and several phenotypes associated with inflammatory states has recently been demonstrated, suggesting that exclusion of samples with very low DNA yield may lead to biased results in statistical analyses. Whole genome amplification (WGA) could present a solution to the DNA concentration-dependent sample selection. The aim was to thoroughly assess WGA for samples with low DNA yield, using the multiply-primed rolling circle amplification method. Fifty-nine samples were selected with the lowest DNA yield (less than 7.5µg) among 799 samples obtained for one population cohort. The genotypes obtained from two replicate WGA samples and the original genomic DNA were compared by typing 24 single nucleotide polymorphisms (SNPs). Multiple genotype discrepancies were identified for 13 of the 59 samples. The largest portion of discrepancies was due to allele dropout in heterozygous genotypes in WGA samples. Pooling the WGA DNA replicates prior to genotyping markedly improved genotyping reproducibility for the samples, with only 7 discrepancies identified in 4 samples. The nature of discrepancies was mostly homozygote genotypes in the genomic DNA and heterozygote genotypes in the WGA sample, suggesting possible allele dropout in the genomic DNA sample due to very low amounts of DNA template. Thus, WGA is applicable for low DNA yield samples, especially if using pooled WGA samples. A higher rate of genotyping errors requires that increased attention be paid to genotyping quality control, and caution when interpreting results.

Aims Genetics plays an important role in coronary heart disease (CHD) but the clinical utility of genomic risk scores (GRSs) relative to clinical risk scores, such as the Framingham Risk Score (FRS), is unclear. Our aim was to construct and externally validate a CHD GRS, in terms of lifetime CHD risk and relative to traditional clinical risk scores. Methods and results We generated a GRS of 49 310 SNPs based on a CARDIoGRAMplusC4D Consortium meta-analysis of CHD, then independently tested it using five prospective population cohorts (three FINRISK cohorts, combined n = 12 676, 757 incident CHD events; two Framingham Heart Study cohorts (FHS), combined n = 3406, 587 incident CHD events). The GRS was associated with incident CHD (FINRISK HR = 1.74, 95% confidence interval (CI) 1.61–1.86 per S.D. of GRS; Framingham HR = 1.28, 95% CI 1.18–1.38), and was largely unchanged by adjustment for known risk factors, including family history. Integration of the GRS with the FRS or ACC/AHA13 scores improved the 10 years risk prediction (meta-analysis C-index: +1.5–1.6%, P < 0.001), particularly for individuals ≥60 years old (meta-analysis C-index: +4.6–5.1%, P < 0.001). Importantly, the GRS captured substantially different trajectories of absolute risk, with men in the top 20% of attaining 10% cumulative CHD risk 12–18 y earlier than those in the bottom 20%. High genomic risk was partially compensated for by low systolic blood pressure, low cholesterol level, and non-smoking. Conclusions A GRS based on a large number of SNPs improves CHD risk prediction and encodes different trajectories of lifetime risk not captured by traditional clinical risk scores. ; National Health and Medical Research Council Early Career Fellowship (1090462 to G.A.); National Health and Medical Research Council and the National Heart Foundation of Australia (1061435 and 1062227 to M.I.); Finnish Foundation for Cardiovascular Research to V.S; British Heart Foundation and NIHR to N.J.S.; AP and SR are supported by the Academy of Finland (grant no. 251704, 286500, 293404 to AP, and 251217, 285380 to SR), Juselius Foundation, Finnish Foundation for Cardiovascular Research, NordForsk e-Science NIASC (grant no 62721) and Biocentrum Helsinki (to SR). The MI Genetics (MIGen) Consortium Study was funded by the National Heart, Lung, and Blood Institute of the United States National Institutes of Health (R01 HL087676). Genotyping was partially funded by The Broad Institute Center for Genotyping and Analysis, which was supported by grant U54 RR02027 from the National Center for Research Resources. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113 and 085475. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 261433 (Biobank Standardisation and Harmonisation for Research Excellence in the European Union—BioSHaRE-EU). We are grateful to the CARDIoGRAMplusC4D consortium for making their large-scale genetic data available. A list of members of the consortium and the contributing studies is available at www.cardiogramplusc4d.org.

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples. ; This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence 'Inflammation at Interfaces'. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre.

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes. ; Artika Nath was supported by an Australian Postgraduate Award. This research was supported in part by the Victorian Government's OIS Program. Michael Inouye was supported by an NHMRC and Australian Heart Foundation Career Development Fellowship (no. 1061435). Gad Abraham was supported by an NHMRC Early Career Fellowship (no. 1090462). Qin Qin Huang is supported by the Melbourne International Research Scholarship. The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; The Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS); and European Research Council (grant 742927 for MULTIEPIGEN project); Tampere University Hospital Supporting Foundation. Peter Würtz is supported by the Novo Nordisk Foundation (15998) and Academy of Finland (312476 and 312477).

Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies. Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively. Interpretation: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. Funding: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

OBJECTIVE: To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. DESIGN: Individual participant data meta-analysis. DATA SOURCES: Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. REVIEW METHODS: Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. RESULTS: Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I2=7.1%, τ2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I2=18.0%, τ2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, τ2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I2=25.9%, τ2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. CONCLUSIONS: These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk. ; The EPIC-InterAct study received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). We thank all EPIC participants and staff for their contribution to the study. We thank Nicola Kerrison (MRC Epidemiology Unit, University of Cambridge, Cambridge, UK) for managing the data for the InterAct Project. In addition, InterAct investigators acknowledge funding from the following agencies: MT: Health Research Fund (FIS) of the Spanish Ministry of Health; the CIBER en Epidemiología y Salud Pública (CIBERESP), Spain; Murcia Regional Government (N° 6236); JS: JS was supported by a Heisenberg-Professorship (SP716/2-1), a Clinical Research Group (KFO218/1) and a research group (Molecular Nutrition to JS) of the Bundesministerium für Bildung und Forschung (BMBF); YTvdS, JWJB, PHP, IS: Verification of diabetes cases was additionally funded by NL Agency grant IGE05012 and an Incentive Grant from the Board of the UMC Utrecht; HBBdM: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); MDCL: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (N° 6236); FLC: Cancer Research UK; PD: Wellcome Trust; LG: Swedish Research Council; GH: The county of Västerbotten; RK: Deutsche Krebshilfe; TJK: Cancer Research UK; KK: Medical Research Council UK, Cancer Research UK; AK: Medical Research Council (Cambridge Lipidomics Biomarker Research Initiative); CN: Health Research Fund (FIS) of the Spanish Ministry of Health; Murcia Regional Government (N° 6236); KO: Danish Cancer Society; OP: Faculty of Health Science, 47 University of Aarhus, Denmark; JRQ: Asturias Regional Government; LRS: Asturias Regional Government; AT: Danish Cancer Society; RT: AIRE-ONLUS Ragusa, AVIS-Ragusa, Sicilian Regional Government; DLvdA, WMMV: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); MMC: Wellcome Trust (083270/Z/07/Z), MRC (G0601261).

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) 350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. ; The ENGAGE Project was funded under the European Union Framework 7 – Health Theme (HEALTH-F4-2007- 201413). The InterAct project received funding from the European Union (Integrated Project LSHM-CT-2006-037197 in the Framework Programme 6 of the European Community). The EPIC-CVD study was supported by core funding from the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG/13/13/30194; RG/18/13/33946), the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the National Institute for Health Research [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust]. C.P.N is funded by the BHF. V.C., C.P.N. and N.J.S. are supported by the NIHR Leicester Cardiovascular Biomedical Research Centre and N.J.S. holds an NIHR Senior Investigator award. Chen Li is support by a 4-year Wellcome Trust PhD Studentship; CL, LAL, NJW are funded by the Medical Research Council (MC_UU_12015/1). NJW is an NIHR Senior Investigator. JD is funded by the National Institute for Health Research [Senior Investigator Award]. Cohort specific and further acknowledgements are given in the Supplemental Data.

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation. ; The authors would like to thank the many colleagues who contributed to collection and phenotypic characterisation of the clinical samples, as well as genotyping and analysis of the GWA data. Special mentions are as follows: CGSB participating cohorts: Some of the data utilised in this study were provided by the Understanding Society: The UK Household Longitudinal Study, which is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The data were collected by NatCen and the genome wide scan data were analysed by the Wellcome Trust Sanger Institute. The Understanding Society DAC have an application system for genetics data and all use of the data should be approved by them. The application form is at: https://www.understandingsociety.ac.uk/about/health/data. The Airwave Health Monitoring Study is funded by the UK Home Office, (Grant number 780-TETRA) with additional support from the National Institute for Health Research Imperial College Health Care NHS Trust and Imperial College Biomedical Research Centre. We thank all participants in the Airwave Health Monitoring Study. This work used computing resources provided by the MRC- funded UK MEDical Bioinformatics partnership programme (UK MED-BIO) (MR/L01632X/1). Paul Elliott wishes to acknowledge the Medical Research Council and Public Health England (MR/L01341X/1) for the MRC-PHE Centre for Environment and Health; and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). Paul Elliott is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Paul Elliott is associate director of the Health Data Research UK London funded by a consortium led by the UK Medical Research Council. SHIP (Study of Health in Pomerania) and SHIP-TREND both represent population-based studies. SHIP is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP and SHIP-TREND are part of the Community Medicine Research net (CMR) of the Ernst-Moritz-Arndt University Greifswald (EMAU) which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. SNP typing of SHIP and SHIP-TREND using the Illumina Infinium HumanExome BeadChip (version v1.0) was supported by the BMBF (grant 03Z1CN22). LifeLines authors thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke, Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, René Oostergo, Rosalie Visser, Judith Vonk for their work related to data-collection and validation. The authors are grateful to the study participants, the staff from the LifeLines Cohort Study and Medical Biobank Northern Netherlands, and the participating general practitioners and pharmacists. LifeLines Scientific Protocol Preparation: Rudolf de Boer, Hans Hillege, Melanie van der Klauw, Gerjan Navis, Hans Ormel, Dirkje Postma, Judith Rosmalen, Joris Slaets, Ronald Stolk, Bruce Wolffenbuttel; LifeLines GWAS Working Group: Behrooz Alizadeh, Marike Boezen, Marcel Bruinenberg, Noortje Festen, Lude Franke, Pim van der Harst, Gerjan Navis, Dirkje Postma, Harold Snieder, Cisca Wijmenga, Bruce Wolffenbuttel. The authors wish to acknowledge the services of the LifeLines Cohort Study, the contributing research centres delivering data to LifeLines, and all the study participants. Niek Verweij was supported by NWO VENI (016.186.125). Fenland authors thank Fenland Study volunteers for their time and help, Fenland Study general Practitioners and practice staff for assistance with recruitment, and Fenland Study Investigators, Co-ordination team and the Epidemiology Field, Data and Laboratory teams for study design, sample/data collection and genotyping. We thank all ASCOT trial participants, physicians, nurses, and practices in the participating countries for their important contribution to the study. In particular we thank Clare Muckian and David Toomey for their help in DNA extraction, storage, and handling. We would also like to acknowledge the Barts and The London Genome Centre staff for genotyping the Exome Chip array. The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Centre staff for their assistance with this project. Patricia B. Munroe, Mark J. Caulfield, and Helen R. Warren wish to acknowledge the NIHR Cardiovascular Biomedical Research Unit at Barts and The London, Queen Mary University of London, UK for support. Mark J. Caulfield are Senior National Institute for Health Research Investigators. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Daniel Barrowdale, Debra Frost, Jo Perkins. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Marc Tischkowitz, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire & Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Claire Foo. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Alex Henderson, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Nazneen Rahman, Elizabeth Bancroft, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Jenny Pope, Sibel Saya, Natalie Taylor, Zoe Kemp and Angela George. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. Understanding Society Scientific Group is funded by the Economic and Social Research Council (ES/H029745/1) and the Wellcome Trust (WT098051). Paul D.P. Pharoah is funded by Cancer Research UK (C490/A16561). SHIP is funded by the German Federal Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); see acknowledgements for details. F.W. Asselbergs is funded by the Netherlands Heart Foundation (2014T001) and supported by UCL Hospitals NIHR Biomedical Research Centre. The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) 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 (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Niek Verweij is supported by Horizon 2020, Marie Sklodowska-Curie (661395) and ICIN-NHI. Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK's Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Genotyping was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, and the Royal Society of Edinburgh. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. Paul W. Franks is supported by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, Swedish Heart Lung Foundation (2020389), and Skåne Regional Health Authority. Nicholas J Wareham, Claudia Langenberg, Robert A Sacott, and Jian'an Luan are supported by the MRC (MC_U106179471 and MC_UU_12015/1). The BRIGHT study was supported by the Medical Research Council of Great Britain (Grant Number G9521010D); and by the British Heart Foundation (Grant Number PG/02/128). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). We would also like to thank the Barts Genome Centre staff for their assistance with this project. The ASCOT study and the collection of the ASCOT DNA repository was supported by Pfizer, New York, NY, USA, Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. Genotyping of the Exome Chip in ASCOT-SC and ASCOT-UK was funded by the National Institutes of Health Research (NIHR). Anna F. Dominiczak was supported by the British Heart Foundation (Grant Numbers RG/07/005/23633, SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). Nilesh J. Samani is supported by the British Heart Foundation and is a Senior National Institute for Health Research Investigator. Panos Deloukas is supported by the British Heart Foundation (RG/14/5/30893), and NIHR, where his work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Centre which is funded by the National Institute for Health Research (NIHR). The LOLIPOP study is supported by the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre Imperial College Healthcare NHS Trust, the British Heart Foundation (SP/04/002), the Medical Research Council (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z, 090532 & 098381) the NIHR (RP-PG-0407-10371), the NIHR Official Development Assistance (ODA, award 16/136/68), the European Union FP7 (EpiMigrant, 279143) and H2020 programs (iHealth-T2D, 643774). We acknowledge support of the MRC-PHE Centre for Environment and Health, and the NIHR Health Protection Research Unit on Health Impact of Environmental Hazards. The work was carried out in part at the NIHR/Wellcome Trust Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the Imperial College Healthcare NHS Trust, the NHS, the NIHR or the Department of Health. We thank the participants and research staff who made the study possible. JC is supported by the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator (STaR) Award (NMRC/STaR/0028/2017). The research was supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility and ERC grant 323195; SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC to T.M. Frayling. Hanieh Yaghootkar is funded by Diabetes UK RD Lawrence fellowship (grant:17/0005594) Anna Dominiczak was funded by a BHF Centre of Research Excellence Award (RE/13/5/30177) GSCAN participating cohorts: The Collaborative Study on the Genetics of Alcoholism (COGA), Principal Investigators: B. Porjesz, V. Hesselbrock, H. Edenberg, L. Bierut. The study includes eleven different centers: University of Connecticut (V. Hesselbrock); Indiana University (H.J. Edenberg, J. Nurnberger Jr., T. Foroud); University of Iowa (S. Kuperman, J. Kramer); SUNY Downstate (B. Porjesz); Washington University in St. Louis (L. Bierut, J. Rice, K. Bucholz, A. Agrawal); University of California at San Diego (M. Schuckit); Rutgers University (J. Tischfield, A. Brooks); Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA (L. Almasy), Virginia Commonwealth University (D. Dick), Icahn School of Medicine at Mount Sinai (A. Goate), and Howard University (R. Taylor). Other COGA collaborators include: L. Bauer (University of Connecticut); J. McClintick, L. Wetherill, X. Xuei, Y. Liu, D. Lai, S. O'Connor, M. Plawecki, S. Lourens (Indiana University); G. Chan (University of Iowa; University of Connecticut); J. Meyers, D. Chorlian, C. Kamarajan, A. Pandey, J. Zhang (SUNY Downstate); J.-C. Wang, M. Kapoor, S. Bertelsen (Icahn School of Medicine at Mount Sinai); A. Anokhin, V. McCutcheon, S. Saccone (Washington University); J. Salvatore, F. Aliev, B. Cho (Virginia Commonwealth University); and Mark Kos (University of Texas Rio Grande Valley). A. Parsian and M. Reilly are the NIAAA Staff Collaborators. COGA investigators continue to be inspired by their memories of Henri Begleiter and Theodore Reich, founding PI and Co-PI of COGA, and also owe a debt of gratitude to other past organizers of COGA, including Ting-Kai Li, P. Michael Conneally, Raymond Crowe, and Wendy Reich, for their critical contributions. COGA investigators are very grateful to Dr. Bruno Buecher without whom this project would not have existed. The authors also thank all those at the GECCO Coordinating Center for helping bring together the data and people that made this project possible. ASTERISK, a GECCO sub-study, also thanks all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians and students. As part of the GECCO sub-studies, CPS-II authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Another GECCO sub-study, HPFS and NHS investigators would like to acknowledge Patrice Soule and Hardeep Ranu of the Dana Farber Harvard Cancer Center High-Throughput Polymorphism Core who assisted in the genotyping for NHS, HPFS under the supervision of Dr. Immaculata Devivo and Dr. David Hunter, Qin (Carolyn) Guo and Lixue Zhu who assisted in programming for NHS and HPFS. HPFS and NHS investigators also thank the participants and staff of the Nurses' Health Study and the Health Professionals Follow-Up Study, for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. PLCO, a substudy within GECCO, was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and additionally supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS1, CGEMS pancreatic cancer scan (PanScan)2, 3, and the Lung Cancer and Smoking study4. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. The authors thank Drs. Christine Berg and Philip Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff or the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Tom Riley and staff, Information Management Services, Inc., Ms. Barbara O'Brien and staff, Westat, Inc., and Drs. Bill Kopp and staff, SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible. We also thank all participants and staff of the André and France Desmarais Montreal Heart Institute's (MHI) Biobank. The genotyping of the MHI Biobank was done at the MHI Pharmacogenomic Centre and funded by the MHI Foundation. HRS is supported by the National Institute on Aging (NIA U01AG009740). The genotyping was funded separately by the National Institute on Aging (RC2 AG036495, RC4 AG039029). Our genotyping was conducted by the NIH Center for Inherited Disease Research (CIDR) at Johns Hopkins University. Genotyping quality control and final preparation of the data were performed by the University of Michigan School of Public Health. CHDExome+ participating cohorts: BRAVE: The BRAVE study genetic epidemiology working group is a collaboration between the Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, UK, the Centre for Control of Chronic Diseases, icddr,b, Dhaka, Bangladesh and the National Institute of Cardiovascular Diseases, Dhaka, Bangladesh. CCHS, CIHDS, and CGPS collaborators thank participants and staff of the Copenhagen City Heart Study, Copenhagen Ischemic Heart Disease Study, and the Copenhagen General Population Study for their important contributions. EPIC-CVD: CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were principally supported by grants awarded to the University of Cambridge from the EU Framework Programme 7 (HEALTH-F2-2012-279233), the UK Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), and the European Research Council (268834). We thank all EPIC participants and staff for their contribution to the study, the laboratory teams at the Medical Research Council Epidemiology Unit for sample management and Cambridge Genomic Services for genotyping, Sarah Spackman for data management, and the team at the EPIC-CVD Coordinating Centre for study coordination and administration. MORGAM: The work by MORGAM collaborators has been sustained by the MORGAM Project's recent funding: European Union FP 7 projects ENGAGE (HEALTH-F4-2007-201413), CHANCES (HEALTH-F3-2010-242244) and BiomarCaRE (278913). This has supported central coordination, workshops and part of the activities of the The MORGAM Data Centre, at THL in Helsinki, Finland. MORGAM Participating Centres are funded by regional and national governments, research councils, charities, and other local sources. PROSPER: collaborators have received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° HEALTH-F2-2009-223004 PROMIS: The PROMIS collaborators are are thankful to all the study participants in Pakistan. Recruitment in PROMIS was funded through grants available to investigators at the Center for Non-Communicable Diseases, Pakistan (Danish Saleheen and Philippe Frossard) and investigators at the University of Cambridge, UK (Danish Saleheen and John Danesh). Field-work, genotyping, and standard clinical chemistry assays in PROMIS were principally supported by grants awarded to the University of Cambridge from the British Heart Foundation, UK Medical Research Council, Wellcome Trust, EU Framework 6-funded Bloodomics Integrated Project, Pfizer. We would like to acknowledge the contributions made by the following individuals who were involved in the field work and other administrative aspects of the study: Mohammad Zeeshan Ozair, Usman Ahmed, Abdul Hakeem, Hamza Khalid, Kamran Shahid, Fahad Shuja, Ali Kazmi, Mustafa Qadir Hameed, Naeem Khan, Sadiq Khan, Ayaz Ali, Madad Ali, Saeed Ahmed, Muhammad Waqar Khan, Muhammad Razaq Khan, Abdul Ghafoor, Mir Alam, Riazuddin, Muhammad Irshad Javed, Abdul Ghaffar, Tanveer Baig Mirza, Muhammad Shahid, Jabir Furqan, Muhammad Iqbal Abbasi, Tanveer Abbas, Rana Zulfiqar, Muhammad Wajid, Irfan Ali, Muhammad Ikhlaq, Danish Sheikh and Muhammad Imran. INTERVAL: Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Centre (www.cambridge-brc.org.uk). The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194), and NIHR Research Cambridge Biomedical Research Centre. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass. ; NIH [N01 AG 12100, U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, U01 HL084756, N01-AG-12100, U24AG051129]; NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); Mid-Atlantic Nutrition and Obesity Research Center of Maryland [P30 DK072488]; NIH/NIAMS [F32AR059469]; American Heart Association [10SDG2690004]; NHLBI [N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, HL080295, HL087652, HL105756, HL103612, HL120393, HL130114]; NINDS; NIA [AG-023629, AG-15928, AG-20098, AG-027058, 1R01AG032098-01A1]; National Center for Research Resources [UL1RR033176]; CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Disease grant [DK063491]; Southern California Diabetes Endocrinology Research Center; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 33CS30-139468, 33CS30-148401]; deCODE Genetics, ehf; Cancer Research United Kingdom; Medical Research Council; EU [LSHM-CT-2003-503041]; Wellcome Trust [WT098051, WT089062, WT098017]; Netherlands Organisation for Scientific Research (NWO); Erasmus MC; Centre for Medical Systems Biology (CMSB); European Community's Seventh Framework Programme (FP7), ENGAGE Consortium [HEALTH-F4-2007-201413]; Wellcome Trust; Support for Science Funding programme; CamStrad; Danish Council for Independent Research [DFF-1333-00124, DFF-1331-00730B]; US National Institute for Arthritis, Musculoskeletal and Skin Diseases; National Institute on Aging [U24AG051129, R01 AR 41398, R01AR057118]; FP7-PEOPLE-Marie Curie Career Integration Grants (CIG); National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix, Inc. [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; Genome Quebec; Genome Canada; Canadian Institutes of Health Research (CIHR); Swedish Research Council; Swedish Foundation for Strategic Research; ALF/LUA research grant in Gothenburg; Lundberg Foundation; Emil and Vera Cornell Foundation; Torsten and Ragnar Soderberg's Foundation; Petrus and Augusta Hedlunds Foundation; Vastra Gotaland Foundation; Goteborg Medical Society; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015G]; National Institutes of Aging; National Institutes of Health [HHSN268200782096C, R01 AG 041517, M01 RR-00750]; Intramural Research Program of the NIH, National Library of Medicine. Kora; Helmholtz Center Munich, German Research Center for Environmental Health; German Federal Ministry of Education and Research (BMBF); State of Bavaria; German National Genome Research Network [NGFN-2, NGFNPlus: 01GS0823]; Munich Center of Health Sciences (MC Health) as part of LMUinnovativ; British Heart Foundation; Kidney Research UK; National Institute for Health Research (NIHR) programme grant; Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; National Institute on Aging grants [R01AG17917, R01AG15819, R01AG24480]; Illinois Department of Public Health; Rush Clinical Translational Science Consortium; Arthritis Research UK; Chronic Disease Research Foundation; National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award; Israel Science Foundation [994/10]; NIA Intramural Research Program; Hjartavernd (the Icelandic Heart Association); German Federal Ministry of Education and Research (BMBF) [16SV5536K, 16SV5537, 16SV5538, 16SV5837, 01UW0808]; Max Planck Institute for Human Development (MPIB); Max Planck Institute for Molecular Genetics (MPIMG); Charite University Medicine; German Institute for Economic Research (DIW); University of Lubeck in Lubeck, Germany; Netherlands Organization for Health Research and Development (ZonMw) the Hague [6130.0031]; NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation, the Hague [KB-15-004-003]; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam; Healthway Health Promotion Foundation of Western Australia; Australasian Menopause Society; Australian National Health and Medical Research Council [254627, 303169, 572604]; National Health and Medical Research Council of Australia Career Development Fellowship; Karen Elise Jensen foundation; NIH from NHLBI [R01-HL-117078, R01-HL-087700, R01-HL-088215]; NIH from NIDDK [R01-DK-089256, R01-DK-075681]; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; Academy of Finland [251217, 136895, 141005, 139635, 129494, 269517]; Finnish foundation for Cardiovascular Research; Sigrid Juselius Foundation; Yrjo Jahnsson Foundation; Finnish Diabetes Research Society; Samfundet Folkhalsann; Novo Nordisk Foundation; Liv och Halsa; Finska Lakaresallskapet; Signe and Ane Gyllenberg Foundation; University of Helsinki; European Science Foundation (EUROSTRESS); Ministry of Education; Ahokas Foundation; Emil Aaltonen Foundation; Juho Vainio Foundation; Centers for Disease Control and Prevention/Association of Schools of Public Health [S043, S1734, S3486]; NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant [5-P60-AR30701]; NIAMS Multidisciplinary Clinical Research Center grant [5 P60 AR49465-03]; Research Program - Korea Centers for Disease Control and Prevention [2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00]; Helmholtz Center Munich; German Research Center for Environmental Health; British Heart Foundation Grant [SP/04/002]; Academy of Finland; Finnish Diabetes Research Foundation; Finnish Cardiovascular Research Foundation; Strategic Research Funding from the University of Eastern Finland, Kuopio; EVO grant from the Kuopio University Hospital [5263]; Swedish Research Council [2006-3832, K2009-53X-14691-07-3, K2010-77PK-21362-01-2, 2008-2202, 2005-8214]; Greta and Johan Kock Foundation; A. Pahlsson Foundation; A. Osterlund Foundation; Malmo University Hospital Research Foundation; Research and Development Council of Region Skane, Sweden; Swedish Medical Society; National Institutes of Health; National Institute on Aging (NIA); National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Center for Advancing Translational Sciences (NCATS); NIH Roadmap for Medical Research [U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, UL1 TR000128]; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [RC2ARO58973]; FAS [2007-2125]; Chief Scientist Office of the Scottish Government [CZB/4/276, CZB/4/710]; Royal Society; MRC Human Genetics Unit; Arthritis Research UK [17539]; European Union framework program 6 EUROSPAN project [LSHG-CT-2006-018947]; ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden; European Union Grant [QLG1-CT-2001-01252]; AstraZeneca; SHIP, part of the Community Medicine Research Network of the University of Greifswald, Germany; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network "Greifswald Approach to Individualized Medicine (GANI_MED)" - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare, Erlangen, Germany; National Institute on Aging (NIA) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576]; Wallenberg foundation; Medical Research Council (UK); Republic of Croatia Ministry of Science, Education and Sports [108-1080315-0302]; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; US National Institutes of Health grants [1-ZIA-HG000024, U01DK062370, R00DK099240]; American Diabetes Association Pathway to Stop Diabetes Grant [1-14-INI-07]; Academy of Finland Grants [271961, 272741, 258753]; Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA; National Heart Lung and Blood Institute of the National Institutes of Health [HL57453]; [HHSN268201200036C] ; This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10−8) or suggestively genome wide (p < 2.3 × 10−6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass. ; We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in development and support of this manuscript. CHARGE members include the Netherland's Rotterdam Study (RS), Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), the NHLBI's Atherosclerosis Risk in Communities (ARIC) Study, and Iceland's Age, Gene/Environment Susceptibility (AGES) Reykjavik Study. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik): has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Old Order Amish (OOA): this work was supported by NIH research grants U01 HL72515, U01 GM074518, R01 HL088119, R01 AR046838, and U01 HL084756. Partial funding was also provided by the Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488).). L.M.Y.-A. was supported by F32AR059469 from NIH/NIAMS. M.F. was supported by American Heart Association grant 10SDG2690004. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts N01-HC- 85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, N01-HC-85239, and by HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756, HL103612, HL120393, and HL130114 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping at Cedars-Sinai Medical Center was supported in part by the National Center for Research Resources, grant UL1RR033176, and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124; in addition to the National Institute of Diabetes and Digestive and Kidney Disease grant DK063491 to the Southern California Diabetes Endocrinology Research Center. CoLaus: The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). We thank Vincent Mooser and Gérard Waeber, Co-PIs of the CoLaus study. Special thanks to Yolande Barreau, Mathieu Firmann, Vladimir Mayor, Anne-Lise Bastian, Binasa Ramic, Martine Moranville, Martine Baumer, Marcy Sagette, Jeanne Ecoffey, and Sylvie Mermoud for data collection. Data analysis was supervised by Sven Bergmann and Jacques S. Beckmann. The computations for this paper were performed in part at the Vital-IT Center for high-performance computing of the Swiss Institute of Bioinformatics. deCODE Study: The study was funded by deCODE Genetics, ehf. We thank all the participants of this study, the staff of deCODE Genetics core facilities and recruitment center and the densitometry clinic at the University Hospital for their important contributions to this work. The EPIC Study: The EPIC Obesity study is funded by Cancer Research United Kingdom and the Medical Research Council. I.B. acknowledges support from EU FP6 funding (contract no. LSHM-CT-2003-503041) and by the Wellcome Trust (WT098051). Erasmus Rucphen Family (ERF) Study: The study was supported by grants from The Netherlands Organisation for Scientific Research (NWO), Erasmus MC, the Centre for Medical Systems Biology (CMSB), and the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE Consortium, grant agreement HEALTH-F4-2007-201413. We are grateful to all general practitioners for their contributions, to Petra Veraart for her help in genealogy, Jeannette Vergeer for the supervision of the laboratory work and Peter Snijders for his help in data collection. Fenland: The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. We are grateful to all the volunteers for their time and help, and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team and the Field Epidemiology team of the MRC Epidemiology Unit for recruitment and clinical testing. Tuomas O. Kilpeläinen was supported by the Danish Council for Independent Research (DFF—1333-00124 and Sapere Aude program grant DFF—1331-00730B). Framingham Osteoporosis Study (FOS)/Framingham Heart Study (FHS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR 41398 and U24AG051129; D.P.K. and R01AR057118; D.K. D.K. was also supported by FP7-PEOPLE-2012-Marie Curie Career Integration Grants (CIG)). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR). Gothenburg Osteoporosis and Obesity Determinants Study (GOOD): The study was funded by the Swedish Research Council, the Swedish Foundation for Strategic Research, The ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Emil and Vera Cornell Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, and the Göteborg Medical Society. We would like to thank Dr Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015G for access to their grid resources. We also thank Karol Estrada, Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands for advice regarding the grid resources. Health Aging and Body Composition Study (Health ABC): This study was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Indiana: We thank the individuals who participated in this study, as well as the study coordinators, without whom this work would not have been possible. This work was supported by National Institutes of Health grants R01 AG 041517 and M01 RR-00750. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Kora (KORA F3 and KORA F4): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. The London Life Sciences Population (LOLIPOP): The study was funded by the British Heart Foundation, Wellcome Trust, the Medical Research Council, and Kidney Research UK. The study also receives support from a National Institute for Health Research (NIHR) programme grant. Rotterdam Study (RSI, RSII & RSIII): The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project no. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, PhD, for the creation and analysis of imputed data. The Rotterdam Study is funded by 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 Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. We thank Dr Karol Estrada, Dr Fernando Rivadeneira, Dr Tobias A. Knoch, Anis Abuseiris, and Rob de Graaf (Erasmus MC Rotterdam, The Netherlands) for their help in creating GRIMP, and we thank BigGRID, MediGRID, and Services@MediGRID/D-Grid (funded by the German Bundesministerium fuer Forschung und Technology; grants 01 AK 803 A-H, 01 IG 07015G) for access to their grid computing resources. Rush Memory and Aging Project (MAP): The Memory and Aging Project was supported by National Institute on Aging grants R01AG17917, R01AG15819, and R01AG24480, the Illinois Department of Public Health, the Rush Clinical Translational Science Consortium, and a gift from Ms Marsha Dowd. TwinsUK (TUK): The study was funded by the Wellcome Trust, Arthritis Research UK, and the Chronic Disease Research Foundation. The study also received support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. We thank the staff and volunteers of the TwinsUK study. The study was also supported by Israel Science Foundation, grant number 994/10. Age, Gene/Environment Susceptibility Reykjavik Study (AGES-Reykjavik) has been funded by NIH contract N01-AG-12100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN: 00-063) and the Data Protection Authority. The researchers are indebted to the participants for their willingness to participate in the study. Berlin Aging Study II (BASE-II) was supported by the German Federal Ministry of Education and Research (BMBF (grants #16SV5536K, #16SV5537, #16SV5538, and #16SV5837; previously #01UW0808)). Additional contributions (e.g., financial, equipment, logistics, personnel) are made from each of the other participating sites, i.e., the Max Planck Institute for Human Development (MPIB), Max Planck Institute for Molecular Genetics (MPIMG), Charite University Medicine, German Institute for Economic Research (DIW), all located in Berlin, Germany, and University of Lübeck in Lübeck, Germany. B-vitamins in the prevention of osteoporotic fractures (B-PROOF): B-PROOF is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw, grant 6130.0031), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; VU University Medical Center, Amsterdam; Erasmus Medical Center, Rotterdam. All organizations are based in the Netherlands. We thank Dr Tobias A. Knoch, Anis Abuseiris, Karol Estrada, and Rob de Graaf as well as their institutions the Erasmus Grid Office, Erasmus MC Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology (grants #01 AK 803 A-H and #01 IG 07015G) for access to their gird resources. Further, we gratefully thank all participants. Calcium Intake Fracture Outcome Study (CAIFOS): This study was funded by Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grants (254627, 303169, and 572604). We are grateful to the participants of the CAIFOS Study. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship. Danish Osteoporosis Study (DOPS): The study was supported by Karen Elise Jensen foundation. Family Heart Study (FamHS): The study was supported by NIH grants R01-HL-117078, R01-HL-087700, and R01-HL-088215 from NHLBI; and R01-DK-089256 and R01-DK-075681 from NIDDK. GenMets (Health 2000): S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680), Academy of Finland (251217), the Finnish foundation for Cardiovascular Research and the Sigrid Juselius Foundation. S.M. was supported by grants #136895 and #141005, V.S. by grants #139635 and 129494, and M.P. by grant #269517 from the Academy of Finland and a grant from the Finnish Foundation for Cardiovascular Research. M.P. was supported by the Yrjö Jahnsson Foundation. Helsinki Birth Cohort Study (HBCS): We thank all study participants as well as everybody involved in the HBCS. HBCS has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Samfundet Folkhälsann, Novo Nordisk Foundation, Liv och Hälsa, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, European Science Foundation (EUROSTRESS), Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation, Juho Vainio Foundation, and Wellcome Trust (grant number WT089062). Johnston County Study: The Johnston County Osteoarthritis Project is supported in part by cooperative agreements S043, S1734, and S3486 from the Centers for Disease Control and Prevention/Association of Schools of Public Health; the NIAMS Multipurpose Arthritis and Musculoskeletal Disease Center grant 5-P60-AR30701; and the NIAMS Multidisciplinary Clinical Research Center grant 5 P60 AR49465-03. Genotyping services were provided by Algynomics company. Korean Genome Epidemiology Study (KoGES): Korean Genome Epidemiology Study (KoGES): This work was supported by the Research Program funded by the Korea Centers for Disease Control and Prevention (found 2001-347-6111-221, 2002-347-6111-221, 2009-E71007-00, 2010-E71004-00). Kora F3 and Kora F4: The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. LOLIP-REP-IA610: The study was supported by the Wellcome Trust. We thank the participants and research teams involved in LOLIPOP. LOLIP-REP-IA_I: The study was supported by the British Heart Foundation Grant SP/04/002. LOLIP-REP-IA_P: The study was supported by the British Heart Foundation Grant SP/04/002. METSIM: The study was supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and the EVO grant 5263 from the Kuopio University Hospital. MrOS Sweden: Financial support was received from the Swedish Research Council (2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar Söderberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Västra Götaland Foundation, the Göteborg Medical Society, and the Novo Nordisk foundation. Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. MrOS US: The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the MrOS ancillary study "GWAS in MrOS and SOF" under the grant number RC2ARO58973. Osteoporosis Prospective Risk Assessment study (OPRA): This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Orkney Complex Disease Study (ORCADES): ORCADES was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), the Royal Society, the MRC Human Genetics Unit, Arthritis Research UK (17539) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. We acknowledge the invaluable contributions of Lorraine Anderson and the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. PEAK 25: This work was supported by grants from the Swedish Research Council (K2009-53X-14691-07-3, K2010-77PK-21362-01-2), FAS (grant 2007-2125), Greta and Johan Kock Foundation, A. Påhlsson Foundation, A. Osterlund Foundation, Malmö University Hospital Research Foundation, Research and Development Council of Region Skåne, Sweden, the Swedish Medical Society. We are thankful to all the women who kindly participated in the study and to the staff at the Clinical and Molecular Osteoporosis Research Unit for helping in recruitment of study individuals. Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS): The study was supported by grants from the Swedish research council (projects 2008-2202 and 2005-8214) and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC): The RISC study is supported by European Union Grant QLG1-CT-2001-01252 and AstraZeneca. We thank Merck Research Labs for conducting DNA genotyping on RISC samples.Rotterdam III: Rotterdam Study (RS): See discovery. SHIP and SHIP TREND: This work was supported by SHIP, which is part of the Community Medicine Research Network of the University of Greifswald, Germany, by the Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania and the network "Greifswald Approach to Individualized Medicine (GANI_MED)" funded by the Federal Ministry of Education and Research (03IS2061A). Genome-wide data have been supported by the Federal Ministry of Education and Research (03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the "Center of Knowledge Interchange" program of the Siemens. A.G. and the Cache´ Campus program of the InterSystems GmbH. The SHIP authors are grateful to the contribution of Florian Ernst, Anja Wiechert, and Astrid Petersmann in generating the SNP data and to Mario Stanke for the opportunity to use his Server Cluster for SNP Imputation. Data analyses were further supported by the German Research Foundation (DFG Vo 955/10-1) and the Federal Ministry of Nutrition, Agriculture and Consumer's Safety. SOF: The Study of Osteoporotic Fractures (SOF) is supported by National Institutes of Health funding. The National Institute on Aging (NIA) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided funding for the SOF ancillary study "GWAS in MrOS and SOF" under the grant number RC2ARO58973. Uppsala Longitudinal Study of Adult Men (ULSAM): The study was funded by grants from the Swedish research council (projects 2008-2202 and 2005-8214), the Wallenberg foundation, and ALF/LUA research grants from Uppsala university hospital, Uppsala, Sweden. Andrew P. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science, grant number WT098017. CROATIA-VIS (VIS): The CROATIA-Vis study was funded by grants from the Medical Research Council (UK) and Republic of Croatia Ministry of Science, Education and Sports research grants to I.R. (108-1080315-0302). We acknowledge the staff of several institutions in Croatia that supported the field work, including but not limited to The University of Split and Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb and Croatian Institute for Public Health. The SNP genotyping for the CROATIA-Vis cohort was performed in the core genotyping laboratory of the Wellcome Trust Clinical Research Facility at the Western General Hospital, Edinburgh, Scotland. Women's Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. We thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf. FUSION: This research was supported in part by US National Institutes of Health grants 1-ZIA-HG000024 (to F.S.C.), U01DK062370 (to M.B.), R00DK099240 (to S.C.J.P.), the American Diabetes Association Pathway to Stop Diabetes Grant 1-14-INI-07 (to S.C.J.P.), and Academy of Finland Grants 271961 and 272741 (to M.L.) and 258753 (to H.A.K.). We thank all the subjects for participation and the study personnel for excellent technical assistance. The Pima Indian Study: This study was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, USA. Studies of a Targeted Risk Reduction Intervention with Defined Exercise (STRRIDE): This study was supported by the National Heart Lung and Blood Institute of the National Institutes of Health, HL57453 (WEK). Gene expression in old and young muscle biopsies: S.M. and T.G. were supported in part by NIH U24AG051129. ; Peer Reviewed

Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery. ; The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (102318; 104781, 120315, 123885, 129619, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 250207, 258753, 41071, 77299, 124243, 1114194, 24300796); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la Recherche; Agency for Health Care Policy Research (HS06516); Age UK Research into Ageing Fund; Åke Wiberg Foundation; ALF/LUA Research Grant in Gothenburg; ALFEDIAM; ALK-Abello´ A/S (Hørsholm, Denmark); American Heart Association (13POST16500011, 10SDG269004); Ardix Medical; Arthritis Research UK; Association Diabète Risque Vasculaire; AstraZeneca; Australian Associated Brewers; Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498); Avera Research Institute; Bayer Diagnostics; Becton Dickinson; Biobanking and Biomolecular Resources Research Infrastructure (BBMRI –NL, 184.021.007); Biocentrum Helsinki; Boston Obesity Nutrition Research Center (DK46200); British Heart Foundation (RG/10/12/28456, SP/04/002); Canada Foundation for Innovation; Canadian Institutes of Health Research (FRN-CCT-83028); Cancer Research UK; Cardionics; Center for Medical Systems Biology; Center of Excellence in Complex Disease Genetics and SALVECenter of Excellence in Genomics (EXCEGEN); Chief Scientist Office of the Scottish Government; City of Kuopio; Cohortes Santé TGIR; Contrat de Projets État-Région; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF–1333-00124, DFF–1331-007308); Danish Diabetes Academy; Danish Medical Research Council; Department of Psychology and Education of the VU University Amsterdam; Diabetes Hilfs- und Forschungsfonds Deutschland; Dutch Brain Foundation; Dutch Ministry of Justice; Emil Aaltonen Foundation; Erasmus Medical Center; Erasmus University; Estonian Government (IUT20-60, IUT24-6); Estonian Ministry of Education and Research (3.2.0304.11-0312); European Commission (230374, 284167, 323195, 692145, FP7 EurHEALTHAgeing-277849, FP7 BBMRI-LPC 313010, nr 602633, HEALTH-F2-2008-201865-GEFOS, HEALTH-F4-2007-201413, FP6 LSHM-CT-2004-005272, FP5 QLG2-CT-2002-01254, FP6 LSHG-CT-2006-01947, FP7 HEALTH-F4-2007-201413, FP7 279143, FP7 201668, FP7 305739, FP6 LSHG-CT-2006-018947, HEALTH-F4-2007-201413, QLG1-CT-2001-01252); European Regional Development Fund; European Science Foundation (EuroSTRESS project FP-006, ESF, EU/QLRT-2001-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012, 03IS2061A); Federal State of Mecklenburg - West Pomerania; Fédération Française de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Food Standards Agency; Fondation de France; Fonds Santé; Genetic Association Information Network of the Foundation for the National Institutes of Health; German Diabetes Association; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); German Research Council (SFB-1052, SPP 1629 TO 718/2-1); GlaxoSmithKline; Göran Gustafssons Foundation; Göteborg Medical Society; Health and Safety Executive; Heart Foundation of Northern Sweden; Icelandic Heart Association; Icelandic Parliament; Imperial College Healthcare NHS Trust; INSERM, Réseaux en Santé Publique, Interactions entre les déterminants de la santé; Interreg IV Oberrhein Program (A28); Italian Ministry of Economy and Finance; Italian Ministry of Health (ICS110.1/RF97.71); John D and Catherine T MacArthur Foundation; Juho Vainio Foundation; King's College London; Kjell och Märta Beijers Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); Leiden University Medical Center; Lilly; LMUinnovativ; Lundbeck Foundation; Lundberg Foundation; Medical Research Council of Canada; MEKOS Laboratories (Denmark); Merck Santé; Mid-Atlantic Nutrition Obesity Research Center (P30 DK72488); Ministère de l'Économie, de l'Innovation et des Exportations; Ministry for Health, Welfare and Sports of the Netherlands; Ministry of Cultural Affairs of the Federal State of Mecklenburg-West Pomerania; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science of the Netherlands; MRC Human Genetics Unit; MRC-GlaxoSmithKline Pilot Programme Grant (G0701863); Municipality of Rotterdam; Netherlands Bioinformatics Centre (2008.024); Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Genomics Initiative; Netherlands Organisation for Health Research and Development (904-61-090, 985-10-002, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192); Netherlands Organisation for Health Research and Development (2010/31471/ZONMW); Netherlands Organisation for Scientific Research (10-000-1002, GB-MW 940-38-011, 100-001-004, 60-60600-97-118, 261-98-710, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MaGW 452-04-314, GB-MaGW 452-06-004, 175.010.2003.005, 175.010.2005.011, 481-08-013, 480-05-003, 911-03-012); Neuroscience Campus Amsterdam; NHS Foundation Trust; Novartis Pharmaceuticals; Novo Nordisk; Office National Interprofessionel des Vins; Paavo Nurmi Foundation; Påhlssons Foundation; Päivikki and Sakari Sohlberg Foundation; Pierre Fabre; Republic of Croatia Ministry of Science, Education and Sport (108-1080315-0302); Research Centre for Prevention and Health, the Capital Region for Denmark; Research Institute for Diseases in the Elderly (014-93-015, RIDE2); Roche; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Executive Health Department (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Société Francophone du Diabète; State of Bavaria; Stroke Association; Swedish Diabetes Association; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20140543); Swedish Research Council (2015-03657); Swedish Medical Research Council (K2007-66X-20270-01-3, 2011-2354); Swedish Society for Medical Research; Swiss National Science Foundation (33CSCO-122661, 33CS30-139468, 33CS30-148401); Tampere Tuberculosis Foundation; The Marcus Borgström Foundation; The Royal Society; The Wellcome Trust (084723/Z/08/Z, 088869/B/09/Z); Timber Merchant Vilhelm Bangs Foundation; Topcon; Torsten and Ragnar Söderberg's Foundation; UK Department of Health; UK Diabetes Association; UK Medical Research Council (MC_U106179471, G0500539, G0600705, G0601966, G0700931, G1002319, K013351, MC_UU_12019/1); UK National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre; UK National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; UK National Institute for Health Research (RP-PG-0407-10371); Umeå University Career Development Award; United States – Israel Binational Science Foundation Grant (2011036); University Hospital Oulu (75617); University Medical Center Groningen; University of Tartu (SP1GVARENG); National Institutes of Health (AG13196, CA047988, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSC271201100004C, HHSN268200900041C, HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, HHSN268201500001I, HL36310, HG002651, HL034594, HL054457, HL054481, HL071981, HL084729, HL119443, HL126024, N01-AG12100, N01-AG12109, N01-HC25195, N01-HC55015, N01-HC55016, N01-HC55018, N01-HC55019, N01-HC55020, N01-HC55021, N01-HC55022, N01-HD95159, N01-HD95160, N01-HD95161, N01-HD95162, N01-HD95163, N01-HD95164, N01-HD95165, N01-HD95166, N01-HD95167, N01-HD95168, N01-HD95169, N01-HG65403, N02-HL64278, R01-HD057194, R01-HL087641, R01-HL59367, R01HL-086694, R01-HL088451, R24-HD050924, U01-HG-004402, HHSN268200625226C, UL1-RR025005, UL1-RR025005, UL1-TR-001079, UL1-TR-00040, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, DA12854, MH081802, MH66206, R01-D004215701A, R01-DK075787, R01-DK089256, R01-DK8925601, R01-HL088451, R01-HL117078, R01-DK062370, R01-DK072193, DK091718, DK100383, DK078616, 1Z01-HG000024, HL087660, HL100245, R01DK089256, 2T32HL007055-36, U01-HL072515-06, U01-HL84756, NIA-U01AG009740, RC2-AG036495, RC4-AG039029, R03 AG046389, 263-MA-410953, 263-MD-9164, 263-MD-821336, U01-HG004802, R37CA54281, R01CA63, P01CA33619, U01-CA136792, U01-CA98758, RC2-MH089951, MH085520, R01-D0042157-01A, MH081802, 1RC2-MH089951, 1RC2-MH089995, 1RL1MH08326801, U01-HG007376, 5R01-HL08767902, 5R01MH63706:02, HG004790, N01-WH22110, U01-HG007033, UM1CA182913, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221); USDA National Institute of Food and Agriculture (2007-35205-17883); Västra Götaland Foundation; Velux Foundation; Veterans Affairs (1 IK2 BX001823); Vleugels Foundation; VU University's Institute for Health and Care Research (EMGO+, HEALTH-F4-2007-201413) and Neuroscience Campus Amsterdam; Wellcome Trust (090532, 091551, 098051, 098381); Wissenschaftsoffensive TMO; and Yrjö Jahnsson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer Reviewed

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape. ; Funding: Funding for this study was provided by the Aarne Koskelo Foundation; the Aase and Ejner Danielsens Foundation; the Academy of Finland (40758, 41071, 77299, 102318, 104781, 117787, 117844, 118590, 120315, 121584, 123885, 124243, 124282, 126925, 129269, 129293, 129378, 130326, 134309, 134791, 136895, 139635, 211497, 263836, 263924, 1114194, 24300796); the Agency for Health Care Policy Research (HS06516); the Agency for Science, Technology and Research of Singapore (A*STAR); the Ahokas Foundation; the ALF/LUA research grant in Gothenburg; the ALK-Abello A/S (Horsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories Denmark; the Althingi (the Icelandic Parliament); the American Heart Association (AHA; 13POST16500011); the ANR ("Agence Nationale de la 359 Recherche"); the Ark (NHMRC Enabling Facility); the Arthritis Research UK (19542, 18030); the AstraZeneca; the Augustinus Foundation; the Australian National Health and Medical Research Council (NHMRC; 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506); the Australian Research Council (ARC; DP0770096 and DP1093502); the Becket Foundation; the bi-national BMBF/ANR funded project CARDomics (01KU0908A); the Biobanking and Biomolecular Resources Research Infrastructure (BBMRINL; 184.021.007, CP 32); the Biocentrum Helsinki; the Boehringer Ingelheim Foundation; the British Heart Foundation (RG/10/12/28456, SP/04/ 002); the Canadian Institutes for Health Reseaerch (FRCN-CCT-83028); the Cancer Research UK (C490/A10124, C490/A10119); the Center for Medical Systems Biology (CMSB; NWO Genomics); the Centers for Disease Control and Prevention and Association of Schools of Public Health (1734, S043, S3486); the Centre of Excellence Baden-Wurttemberg Metabolic Disorders; the Chief Scientist Office of the Scottish Government; the Clinical Research Facility at Guys & St Thomas NHS Foundation Trust; the Contrat de Projets Etat-Region (CPER); the Croatian Science Council (Grant no. 8875); the CVON (GENIUS); the Danish Agency for Science, Technology and Innovation; the Danish Centre for Health Technology Assessment, Novo Nordisk Inc.; the Danish Council for Independent Research (DFF 1333-00124); the Danish Diabetes Association; Danish Heart Foundation; the Danish Medical Research Council; the Danish Ministry of Internal Affairs and Health; the Danish National Research Foundation; the Danish Pharmaceutical Association; Danish Pharmacists Fund; the Danish Research Council; the Deutsche Forschungsgemeinschaft; the Diabetes Hilfs-und Forschungsfonds Deutschland (DHFD); the Dr. Robert Pfleger-Stiftung; the Dresden University of Technology Funding Grant, Med Drive; the Dutch Brain Foundation; the Dutch Diabetes Research Foundation; the Dutch Economic Structure Enhancing Fund (FES); the Dutch Kidney Foundation; the Dutch Ministry for Health, Welfare and Sports; the Dutch Ministry of Economic Affairs; the Dutch Ministry of Education, Culture and Science; the Egmont Foundation; the Else Kraner-Fresenius Stiftung (2012_A147, P48/08//A11/08); the Emil Aaltonen Foundation; the Erasmus Medical Center and Erasmus University, Rotterdam; the Estonian Ministry of Science and Education (SF0180142s08); the European Commission (223004, 2004310, DGXII, FP6-EUROSPAN, FP6-EXGENESIS, FP6-LSHG-CT2006-018947, FP6-LSHG-CT-2006-01947, FP6-LSHM- CT-2004-503485, FP6-LSHM-CT-2006037593, FP6-LSHM-CT-2007-037273, FP7-201379, FP7-201668, FP7-279143, FP7-305739, FP7313010, FP7-ENGAGE-HEALTH-F4-2007-201413, FP7-EurHEALTHAgeing-277849, FP7-HEALTH-F42007-201550, HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F2-2008-201865-GEFOS, HEALTH-F7305507 HOMAGE, LSHM-CT-2006-037593, QLG1CT-2001-01252, QLG1-CT-2002-00896, QLG2-CT2002-01254); the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive TMO; the European Regional Development Fund to the Centre of Excellence in Genomics (EXCEGEN; 3.2.0304.11-0312); the European Research Council (ERC; 2011-StG-280559-SEPI, 2011-294713-EPLORE, 230374); the European Science Foundation (ESF; EU/QLRT-2001-01254); the EuroSTRESS project FP-006; the Finlands Slottery Machine Association; the Finnish Centre for Pensions (ETK); the Finnish Cultural Foundation; the Finnish Diabetes Association; the Finnish Diabetes Research Foundation; the Finnish Foundation for Cardiovascular Research; the Finnish Foundation for Pediatric Research; the Finnish Funding Agency for Technology and Innovation (40058/07); the Finnish Medical Society; the Finnish Ministry of Education and Culture (627; 2004-2011); the Finnish Ministry of Health and Social Affairs (5254); the Finnish National Public Health Institute (current National Institute for Health and Welfare); the Finnish Special Governmental Subsidy for Health Sciences; the Finska Lakaresallskapet, Signe and Ane Gyllenberg Foundation; the Flemish League against Cancer, ITEA2 (project Care4Me); the Folkhalsan Research Foundation; the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen; the Foundation for Life and Health in Finland; the Foundation for Strategic Research (SSF) and the Stockholm County Council (560283); the G. Ph. Verhagen Foundation; the Gene-diet Interactions in Obesity' project (GENDINOB); the Genetic Association Information Network (GAIN); the GENEVA Coordinating Center (U01 HG 004446); the GenomEUtwin (EU/QLRT2001-01254; QLG2-CT-2002-01254); the German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); the German Diabetes Association; the German Ministry of Cultural Affairs; the German Federal Ministry of Education and Research (BMBF; 03IS2061A, 03ZIK012, 01ZZ9603, 01ZZ0103, 01ZZ0403); the German National Genome Research Network (NGFN-2 and NGFN-plus); the German Research Council (SFB1052 "Obesity mechanisms"); the Great Wine Estates of the Margaret River region of Western Australia; the Greek General Secretary of Research and Technology research grant (PENED 2003); the Gyllenberg Foundation; the Health Care Centers in Vasa, Narpes and Korsholm; the Health Fund of the Danish Health Insurance Societies; the Helmholtz Zentrum Munchen-German Research Center for Environmental Health; the Helsinki University Central Hospital special government funds (EVO #TYH7215, #TKK2012005, #TYH2012209); the Hjartavernd (the Icelandic Heart Association); the Ib Henriksen Foundation; the Illinois Department of Public Health, and the Translational Genomics Research Institute; the INTERREG IV Oberrhein Program (Project A28); the Interuniversity Cardiology Institute of the Netherlands (ICIN; 09.001); the Italian Ministry of Health "targeted project" (ICS110.1/RF97.71); the Italian National Centre of Research InterOmics PB05_ SP3; the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health; the Johns Hopkins University Center for Inherited Disease Research (CIDR); the Joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania; the Juho Vainio Foundation; the Juselius Foundation (Helsinki, Finland); the Juvenile Diabetes Research Foundation International (JDRF); the KfH Stiftung Praventivmedizin e. V.; the Knut and Alice Wallenberg Foundation; the Kuopio University Hospital; the Leenaards Foundation; the Leiden University Medical Center; the Liv och Halsa; the Local Government Pensions Institution (KEVA); the Lokaal Gezondheids Overleg (LOGO) Leuven and Hageland; the LudwigMaximilians- Universitat, as part of LMUinnovativ; the Lundberg Foundation; the March of Dimes Birth Defects Foundation; the Medical Research Council (G0601966; G0700931; G0000934; G0500539; G0600705; G1002319; G0701863; PrevMetSyn/SALVE; MC_ U106179471; MC_ UU_ 12019/1); the MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE); the MRC Centre for Obesity and Related Metabolic Diseases; the MRC Human Genetics Unit; the Medical Research Council of Canada; the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488); the Ministry of the Flemish Community, Brussels, Belgium (G. 0881.13 and G. 0880. 13); the MIUR-CNR Italian Flagship Project; the Montreal Heart Institute Foundation; the Munich Center of Health Sciences (MC Health); the Municipal Health Care Center and Hospital in Jakobstad; the Narpes Health Care Foundation; the National Alliance for Research on Schizophrenia and Depression (NARSAD); the National Cancer Institute (CA047988); the National Center for Advancing Translational Sciences (UL1TR000124); the National Center for Research Resources (U54RR020278); the National Heart, Lung and Blood Institute (NHLBI, 1RL1MH083268-01, 5R01HL087679-02, HHSN268200800007C, HHSN268201200036C, HL043851, HL080467, HL087647, HL36310, HL45670, N01HC25195, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N02HL64278, R01HL086694, R01HL087641, R01HL087652, R01HL087676, R01HL59367, R01HL103612, R01HL105756, R01HL120393, U01HL080295); the National Human Genome Research Institute (NHGRI, U01HG004402); the National Institute for Health and Welfare (THL); the National Institute for Health Research (NIHR, RP-PG-0407-10371); the National Institute of Allergy and Infectious Diseases (NIAID); the National Institute of Child Health and Human Development (NICHD); the National Institute of Diabetes and Digestive and Kidney Disease (NIDDKDRC, 1R01DK8925601, DK063491, R01DK089256, P30 DK072488); the National Institute of Food and Agriculture (2007-35205-17883); the National Institute of Neurological Disorders and Stroke (NINDS); the National Institute on Aging (NIA; 263-MA-410953, 263-MD-821336, 263-MD-9164, AG023629, AG13196, NO1AG12109, P30AG10161, R01AG15819, R01AG17917, R01AG023629, R01AG30146); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (5-P60-AR30701, 5-P60-AR49465-03); the National Institutes of Health (NIH; 1R01DK8925601, 1RC2MH089951, 1RC2MH089995, 1Z01HG000024, 2T32 HL 00705536, 5R01DK075681, 5R01MH63706: 02, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, AG028555, AG08724, AG04563, AG10175, AG08861, DA12854, DK046200, DK091718, F32AR059469, HG002651, HHSN268200625226C, HHSN268200782096C, HL084729, MH081802, N01AG12100, N01HG65403, R01AG011101, R01AG030146, R01D0042157-01A, R01DK062370, R01DK072193, R01DK093757, R01DK075787, R01DK075787, R01HL71981, R01MH59565, R01MH59566, R01MH59571, R01MH59586, R01MH59587, R01MH59588, R01MH60870, R01MH60879, R01MH61675, R01MH67257, R01MH81800, R01NS45012, U01066134, U01CA098233, U01DK062418, U01GM074518, U01HG004423, U01HG004436, U01HG004438, U01HL072515-06, U01HL105198, U01HL84756, U01MH79469, U01MH79470, U01NS069208-01, UL1RR025005); the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; the NIHR Cambridge Biomedical research Centre; the Netherlands Heart Foundation (2001 D 032); the Netherlands Organisation for Scientific Research (NWO; Geestkracht program grant 10-000-1002; 050-060-810; 100-001-004; 175.010.2003.005; 175.010.2005.011; 175.010.2007. 006; 261-98-710; 40-0056-98-9032; 400-05-717; 452-04-314; 452-06-004; 480-01-006; 480-04-004; 480-05-003; 480-07-001; 481-08-013; 60-60600-97-118; 904-61-090; 904-61-193; 911-03012; 985-10-002; Addiction-31160008; GB-MW 94038- 011; SPI 56-464-14192); the Netherlands Organization for the Health Research and Development (ZonMw; 91111025); the Nordic Center of Excellence in Disease Genetics; the Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET (070014); the Northern Netherlands Collaboration of Provinces (SNN); the Novo Nordisk Foundation; the Office of Research and Development, Medical Research Service, and the Baltimore Geriatrics Research, Education, and Clinical Center of the Department of Veterans Affairs; the Ollqvist Foundation; the Paavo Nurmi Foundation; the Pahlssons Foundation; the Paivikki and Sakari Sohlberg Foundation; the Perklen Foundation; the Republic of Croatia Ministry of Science, Education and Sports research (108-1080315-0302); the Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Foundation of Copenhagen County; the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the Reynold's Foundation; the Rotterdam Oncologic Thoracic Study Group, Erasmus Trust Fund, Foundation against Cancer; the Royal Swedish Academy of Science; the Russian Foundation for Basic Research (NWO-RFBR 047.017.043); the Rutgers University Cell and DNA Repository cooperative agreement (NIMH U24 MH068457-06); the Samfundet Folkhalsan; the Sigrid Juselius Foundation; the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (9M048, 9N035); the Social Ministry of the Federal State of Mecklenburg-West Pomerania; the Societe Francophone du 358 Diabste (SFD); the South Tyrolean Sparkasse Foundation; the Stichting Nationale Computerfaciliteiten (National Computing Facilities Foundation, NCF); the Strategic Cardiovascular Programme of Karolinska Institutet and the Stockholm County Council (560183); the Susan G. Komen Breast Cancer Foundation; the Swedish Cancer Society; the Swedish Cultural Foundation in Finland; the Swedish Diabetes Association; the Swedish Diabetes Foundation (grant no. 2013-024); the Swedish Foundation for Strategic Research (SSF; ICA08-0047); the Swedish HeartLung Foundation (20120197); the Swedish Medical Research Council (K2007-66X-20270-01-3, 20121397); the Swedish Ministry for Higher Education; the Swedish Research Council (8691, M-2005-1112, 2009-2298); the Swedish Society for Medical Research; the Swiss National Science Foundation (31003A-143914, 3200B0105993, 3200B0-118308, 33CSCO-122661, 33CS30-139468, 33CS30148401); SystemsX. ch (51RTP0_151019); the Tampere Tuberculosis Foundation; the TEKES (70103/06, 40058/07); the The Paul Michael Donovan Charitable Foundation; the Torsten and Ragnar Sderberg Foundation; the Umea Medical Research Foundation; the United Kingdom NIHR Cambridge Biomedical Research Centre; the Universities and Research of the Autonomous Province of Bolzano, South Tyrol; the University Hospital of Regensburg (ReForM A, ReForM C); the University Hospital Oulu, Biocenter, University of Oulu, Finland (75617); the University Medical Center Groningen; the University of Groningen; the University of Maryland General Clinical Research Center (M01RR16500, AG000219); the University of Tartu (SP1GVARENG); the University of Tromso, Norwegian Research Council (185764); the Vasterbottens Intervention Programme; the Velux Foundation; the VU University Institute for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam (NCA); the Wellcome Trust (064890, 068545/Z/02, 076113/B/04/Z, 077016/Z/05/Z, 079895, 084723/Z/08/Z, 086596/Z/ 08/Z, 088869/B/09/Z, 089062, 090532, 098017, 098051, 098381); the Western Australian DNA Bank (NHMRC Enabling Facility); the Yrjo Jahnsson Foundation (56358); and the Zorg Onderzoek Nederland-Medische Wetenschappen, KWF Kankerbestrijding, Stichting Centraal Fonds Reserves van voormalig Vrijwillige Ziekenfondsverzekeringen. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. More details of acknowledgements can be found in S2 Text.