Large-scale association analysis identifies novel loci associated with waist-to-hip ratio and suggests underlying biological mechanisms. D. Shungin1,2,3, D. C. Croteau-Chonka5,6, A. E. Locke7, T. W. Winkler4, T. Ferreira8, R. Magi8,9, T. H. Pers10,11,12, A. E. Justice13, R. J. Strawbridge14, C. Fox15, K. E. North13, E. Speliotes16,17, I. Heid4,18, I. Barroso19,20, R. J. Loos22, L. A. Cupples15,23, P. W. Franks1,2, E. Ingelsson21, A. Morris8, K. L. Mohlke6, C. M. Lindgren8,17 on behalf of the Genetic Investigation of ANthropometric Traits (GIANT) Consortium 1) Department of Clinical Sciences, Skane University Hospital, Lund University, Malmo, Sweden; 2) Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden; 3) Department of Odontology, Umea University, Umea, Sweden; 4) Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany; 5) Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; 6) Department of Genetics, University of North Carolina, Chapel Hill, NC; 7) Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI; 8) Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; 9) Estonian Genome Center, University of Tartu, Estonia; 10) Division of Endocrinology, Children's Hospital Boston, Boston, MA; 11) Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; 12) Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark; 13) Department of Epidemiology and Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC; 14) Cardiovascular Genetics and Genomics Group, Karolinska Institutet, Stockholm Sweden; 15) National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, MA; 16) Department of Internal Medicine, Division of Gastroenterology, and Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI; 17) Broad Institute, Cambridge, MA; 18) Genetic Epidemiology, Helmholtz Zentrum Muenchen-German Research Center for Environmental Health, Neuherberg, Germany; 19) Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK; 20) University of Cambridge Metabolic Research Labs, Institute of Metabolic Science Addenbrooke's Hospital, Cambridge, UK; 21) Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; 22) Charles R. Bronfman Institute of Personalized Medicine, Child Health and Development Institute, Department of Preventive medicine, Mount Sinai School of Medicine, New York, NY; 23) Department of Biostatistics, Boston University School of Public Health, Boston, MA.

   To study the genetic and biological underpinnings of waist-to-hip ratio (WHR) adjusted for BMI, a measure of adipose tissue distribution associated with increased cardiometabolic risk independent from overall adiposity, we performed sex-combined and sex-stratified fixed effects meta-analyses in 210,087 individuals from 57 GWA studies and 40 studies genotyped on the Metabochip, discovering 35 novel and confirming 14 previously reported loci associated at P<510-8 To identify potential causal variants at these loci, we examined expression QTL data in multiple trait-relevant tissues and found that at 21 loci (12 novel and 9 reported) the WHR-associated SNP was either the strongest SNP associated in cis with significant (P<10-5) expression of the gene transcript, or that it explained a substantial proportion of the variance in gene transcript levels when conditional analysis was performed. Out of 21 loci, 15 SNPs (9 novel) were associated with expression levels in subcutaneous adipose tissue and 8 SNPs (4 novel) were associated with expression levels in omental adipose tissue To investigate whether the loci associated with WHR might also play pleiotropic roles for other cardiometabolic traits, we tested for enrichment of directionally-consistent associations among all 49 WHR loci with 22 cardiometabolic traits. We found significant enrichment for T2D, fasting insulin adjusted for BMI (FI), and fasting glucose (13, 27, and 9 SNPs with significant (P<6.510-4) effects). In unsupervised hierarchical clustering of standardized association statistics for the 49 loci across 22 traits, we identified a cluster of 30 SNPs associated with high-density lipoprotein cholesterol, FI, and triglycerides Finally, to broadly identify biologically relevant WHR genes and pathways, we used the Data-driven Enrichment-Prioritized Integration for Complex Traits method to analyze all SNPs with P<10-5 and identified at least one significantly prioritized gene (false-discovery rate [FDR] < 5%) at 49 WHR loci. Further, we identified 781 significant gene sets or pathways (FDR < 5%), the top ones being Decreased percent body fat and Abnormal skeleton morphology This effort from the GIANT consortium further elucidates the genetic architecture of fat distribution, provides biological data that may help identify the functional loci underlying the SNP associations and confirms epidemiological assumptions about the shared genetic underpinnings of related cardiometabolic traits.

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