Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
Bibliographical noteFunding Information:
The authors declare the following competing interests: A.S.B. holds interest in AstraZeneca, Biogen, Bioverativ, Merck, Novartis and Pfizer. A.S.C. and C.S.F. are current employees of Merck. Authors affiliated with deCODE (V.St., G.T., U.T. and K.S.) are employed by deCODE Genetics/Amgen, Inc. H.D.W. has the following financial and non-financial competing interests to declare: research grants: Sanofi Aventis; Eli Lilly; NIH; Omthera Pharmaceuticals, Pfizer, Elsai Inc. AstraZeneca; DalCor and Services; lecture fees: Sanofi Aventis; advisory boards: Acetelion, Sirtex, CSL Boehring. J.D. has received grants from AstraZeneca, Biogen, Merck, Novartis and Pfizer. L.M.Y.A. and R.A.S. are employee stock holders of GlaxoSmithKline. M.P.D. received honoraria and holds minor equity in Dalcor. V.S. has participated in a conference trip sponsored by Novo Nordisk.
This work was primarily supported through funding from the National Institute of Health (NIH): 1K99HL130580, R01-DK089256, 2R01HD057194, U01HG007416, R01DK101855, T32 HL007055, KL2TR001109; and the American Heart Association (AHA): 13POST16500011 and 13GRNT16490017. Co-author Y. Jia recently passed away while this work was in process. This study was completed as part of the Genetic Investigation of ANtropometric Traits (GIANT) Consortium. This research has been conducted using the UK Biobank resource. A full list of acknowledgements is provided in the Supplementary Data 18.
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