Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium


Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10−6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.

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A full list of acknowledgments appears in Supplementary Table 6. We acknowledge the essential role of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium for encouraging CHARGE studies to participate in this effort and for the contributions of CHARGE members to the analyses conducted for this research. Dr. Caren Smith is supported by NHLBI K08 HL112845.

Authors contributions

D.I.C., T.T., and A.Y.C. conceived and designed the study. A.E.J., M.G., C.P., G.V.D., R.N.L., M.K.W., S.M., J.S.N., M.K., T.S.A., N.P., D.K.H., C.B., T.H., M.O., A.C.F.-W., D.O.M.-K., L.P., C.E.P., P.S.V., T.V., O.L., S.K., L.M.R., T.L., J.H.Z., M.F.F., J.L., N.M.M., J.A.S., T.H., N.E., M.A.N., T.R., J.H., D.G.H., C.-A.S., A.M., R.L.-G., M.-C.V., C.A.W., F.J.A.R., J.S., I.P.K., F.D., P.M.R., M.K., D.S.S., C.L., W.Z., A.A., P.K., M.G., D.C.R., Q.Q., L.F., U.E., J.B., A.H., Z.P., V.M., N.J.W., S.L.R.K., O.P., A.J., J.E.C., M.C.Z., J.S.V., N.G.F., J.M.O., J.C.L., H.R., A.G.U., O.T.R., J.C.K.-d.J., J.D., J.I.R., K.W.N., R.A.S., M.A.P., M.P., L.A.C., S.T.T., T.I.A.S., V.K., Y.L., Y.S., L.Q., S.B., S.S.R., R.M., A.T., W.H.O., O.H.F., T.P., J.C.F., P.D., L.-P.L., contributed to data collection. J.M., H.S.D., D.I.C., T.T., and A.Y.C. performed quality control and meta-analyses. J.M., A.E.J., C.S., S.X.L. performed additional analyses including look-up in the NH.G.R.I.-E.B.I. G.W.A.S. Catalog, fine-mapping analyses, colocalization analyses for Expression Quantitative Trait loci and Human Atlas of long non-coding R.N.A., L.D. score regression analyses and Mendelian randomization. J.M., H.S.D., S.X.L., A.E.J., M.G., C.P., C.E.S., G.V.D., D.I.C., T.T., and A.Y.C. wrote the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Toshiko Tanaka.

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MANs’ participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA, as a possible conflict of interest. Dr. Nalls also consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others. AYC is currently employed by Merck Research Laboratories.

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