Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

Abstract

Variation in body fat distribution contributes to the metabolic sequelae of obesity. The genetic determinants of body fat distribution are poorly understood. The goal of this study was to gain new insights into the underlying genetics of body fat distribution by conducting sample-size-weighted fixed-effects genome-wide association meta-analyses in up to 9,594 women and 8,738 men of European, African, Hispanic and Chinese ancestry, with and without sex stratification, for six traits associated with ectopic fat (hereinafter referred to as ectopic-fat traits). In total, we identified seven new loci associated with ectopic-fat traits (ATXN1, UBE2E2, EBF1, RREB1, GSDMB, GRAMD3 and ENSA; P < 5 × 10−8; false discovery rate < 1%). Functional analysis of these genes showed that loss of function of either Atxn1 or Ube2e2 in primary mouse adipose progenitor cells impaired adipocyte differentiation, suggesting physiological roles for ATXN1 and UBE2E2 in adipogenesis. Future studies are necessary to further explore the mechanisms by which these genes affect adipocyte biology and how their perturbations contribute to systemic metabolic disease.

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Figure 1: Functional characterization of Atxn1, Ebf1, Rreb1 and Ube2e2.

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Acknowledgements

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 US Department of Health and Human Services. Please see the Supplementary Note for acknowledgments and funding sources.

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X.G., A.H.K., J.K., L.J.L., M.O., P.A.P., I.B.B., D.W.B., S.A.C., J.D., V.G., T.B.H., C.D.L., L. Lind, Y.L., J.I.R., B.T. and M.A. contributed to the study design; Yi Zhang, L.J.L., M.O., P.A.P., J.G.T., I.B.B., D.W.B., J.J.C., S.A.C., V.G., T.B.H., L. Lind, B.D.M., T.H.M., J.I.R., A.R.S., H.V., J.G.W. and M.A. contributed to study management; A.H.K., J.K., M.K.W., D.W.B., S.A.C., V.G., L. Lind, B.D.M., T.H.M., A.R.S., B.T. and H.V. recruited subjects; A.Y.C., X.D., V.A.F., Yang Zhang, M.F.F., C.-T.L., O.W., A.C.C., Q.D., X.G., N.L.H.-C., X.L., L. Lu, J.R.O., A.P., A.V.S., Yi Zhang, A.H.K., M.O., P.A.P., J.G.T., M.K.W., L.F.B., I.B.B., D.W.B., J.J.C., S.A.C., J.D., N.F., S.L.R.K., C.D.L., Y.L., B.D.M., J.I.R., A.R.S., B.T., H.W., M.A., C.M.L., W.G., L.A.C., M.L.S. and C.S.F. interpreted results; A.Y.C., Yang Zhang, M.F.F., X.G., J.W.K., Yi Zhang, A.H.K., M.K.W., I.B.B., C.M.L., M.L.S. and C.S.F. drafted the manuscript; A.Y.C., X.D., V.A.F., M.F.F., C.-T.L., O.W., A.C.C., X.G., N.L.H.-C., J.W.K., X.L., L. Lu, A.M., J.R.O., A.P., Yi Zhang, G.H., A.H.K., J.K., M.N., M.O., P.A.P., J.G.T., L.F.B., J.B., I.B.B., D.W.B., J.J.C., S.A.C., J.D., N.F., E.I., S.L.R.K., C.D.L., L. Lind, Y.L., B.D.M., A.P.M., T.H.M., J.I.R., A.R.S., B.T., H.V., H.W., M.A., C.M.L., W.G., L.A.C., M.L.S. and C.S.F. performed critical review; A.Y.C., X.D., V.A.F., A.D., Yang Zhang, M.F.F., A.C.C., Q.D., T.D.D., J.D.E., X.G., N.L.H.-C., T.K., J.W.K., L.A.L., X.L., K.L., L. Lu, A.M., J.R.O., A.P., J.M.P., A.V.S., J.Y., L.F.B., J.D., C.D.L., Y.L., B.D.M., A.P.M., C.M.L. contributed to statistical methods and analysis; Yi Zhang, G.H., M.O., D.W.B., S.A.C., E.I., S.L.R.K., Y.L., A.P.M., J.I.R., A.R.S., B.T. and C.M.L. performed genotyping; A.Y.C., X.D., V.A.F., M.F.F., C.-T.L., A.C.C., J.D.E., A.D.J., T.K., A.V.S. and Yi Zhang contributed to bioinformatics; Yang Zhang, O.W., R.L., N.F., W.G. and M.L.S. worked on data collection; and Yang Zhang and M.L.S. contributed to animal work and functional data.

Corresponding authors

Correspondence to Audrey Y Chu or Matthew L Steinhauser or Caroline S Fox.

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Competing interests

C.S.F. and A.Y.C. are currently employed by Merck Research Laboratories.

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Chu, A., Deng, X., Fisher, V. et al. Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation. Nat Genet 49, 125–130 (2017). https://doi.org/10.1038/ng.3738

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