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Common variants near MC4R are associated with fat mass, weight and risk of obesity


To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10−6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10−15) and 5,988 children aged 7–11 (0.13 Z-score units; P = 1.5 × 10−8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10−11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10−4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

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Figure 1: Regional plot of chromosome 18q21 (55,700–56,400 kb), showing the association signals for obesity for the meta-analysis of all 16,876 samples with genome-wide association scans.
Figure 2
Figure 3: Effects of rs17782313 on regulation of weight in early life.
Figure 4: Association between the combined rs17782313 and FTO genotypes and BMI in adults (EPIC-Norfolk, n = 15,622) and children (ALSPAC age 7 years, n = 5,779).

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We acknowledge support of the UK Medical Research Council, the Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, the European Commission, the Academy of Finland, the British Heart Foundation, the National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline and the German National Genome Research Net. Personal support was provided by NIDDK (E.K.S., H.N.L., J.N.H., F.S.C.), the Wellcome Trust (A.T.H., E.Z.), Diabetes UK (R.M.F.), the Throne-Holst Foundation (C.M.L.), the Vandervell Foundation (M.N.W.), American Diabetes Association (C.J.W.), Unilever Corporate Research (S.L.) and the British Heart foundation (N.J.S).

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Authors and Affiliations




Writing team: R.J.F.L., C.M.L., S.L., M.I.M., N.J.W., I.B.

Project management: R.J.F.L., C.M.L., P.D., M.I.M., N.J.W., I.B.

Genome-wide association sampling, genotyping and analysis: R.J.F.L., C.M.L., S.L., E.W., J.H.Z., I.P., M.I., A.P.A., J.S.B., S.B., S.A.B., M. Bochud, M. Brown, J.M.C., D.M.E., J.G., R.G., D.H., A.S.H., A.T.H., S.E.H., T.J., J.D.M.J., A.K., K.-T.K., R.L., M.M., J.M., W.L.M., R.M., P.B.M., A.C.N., K.K.O., K.P., S.P., S.M.R., M.S.S., M.A.S., K.S., N.S., N.J.T., C.W., D.M.W., M.N.W., The Wellcome Trust Case Control Consortium, X.Y., E.Z., D.P.S., W.H.O., M.J.C., N.J.S., T.M.F., P.V., G.W., V.M., P.D., M.I.M., N.J.W., I.B., A.J.B.

Replication samples, genotyping and analysis in adults: R.J.F.L., C.M.L., S.L., R.M.F., A.P.A., A.B., S.C., C.C., G.D.S., I.D., C.D., A.S.F.D., P.E., D.M.E., P.F., C.J.G., A.T.H., M.-R.J., J.D.M.J., F.K., D.M., A.D.M., M.J.N., K.K.O., S.O., K.R.O., C.N.A.P., A.P., A.R.N., S.M.R., M.S.S., M.A.S., H.E.S., N.J.T., M.N.W., V.L.W., E.Z., W.H.O., T.M.F., M.I.M., N.J.W., I.B.

GIANT Consortium samples, genotyping and analysis: S.I.B., K.B.J., S.J.C., R.B.H., I.M.H., C.L., C.G., T.I., T.M., H.-E.W., L.Q., P K., S.E.H., D.J.H., F.B.H, E.K.S., H.N.L., B.F.V., M.R., L.G., J.N.H., M.U., P.S., S.S., G.R.A., G.A., R.N., D.S., C.J.W., A.U. J., J.T., F.S.C., M. Boehnke., K.L.M., FUSION, DGI, PLCO, NHS, SardiNIA.

Replication samples, analysis and genotyping in children: R.M.F., S.C., G.D.S., I.D., C.D., I.S.F., P.F., A.T.H., J.H., A.H., D.M., A.R.N., K.K.O., S.O., S.M.R., A.S., N.J.T., J.H.T., V.L.W., T.M.F., C.I.G.V.

Statistical analysis and informatics: R.J.F.L., C.M.L., S.L., J.H.Z., I.P., R.M.F., S.D., E.T.D., K.S.E., B.H., S.E.H., T.J., J.M., R.M., S.P., J.C.R., N.W.R., A.S., S.A.T., N.J.T., E.Z., M.I.M., N.J.W., I.B.

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Correspondence to Mark I McCarthy, Nicholas J Wareham or Inês Barroso.

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Competing interests

Vincent Mooser, Dawn Waterworth and Kijoung Song are full-time employees of GlaxoSmithKline.

Peter Vollenweider and Gérard Waeber received financial support from GlaxoSmithKline to build the CoLaus study.

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A full list of authors is provided in the Supplementary Note.

A full list of authors is provided at the end of the reference list.

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Supplementary Note, Supplementary Tables 1–7 and Supplementary Figures 1–5 (PDF 1490 kb)

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Loos, R., Lindgren, C., Li, S. et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40, 768–775 (2008).

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