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Variants in MTNR1B influence fasting glucose levels

Abstract

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06–0.08) mmol/l in fasting glucose levels (P = 3.2 × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05–1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci.

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Figure 1: Regional plot of fasting glucose association results for the MTNR1B locus across ten MAGIC GWAS.
Figure 2: Association of rs10830963 with type 2 diabetes (T2D) in 13 case-control studies.

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Acknowledgements

The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. They would also like to acknowledge those who agreed to participate in these studies. Major funding for the work described in this paper comes from Academy of Finland (124243); the Administration of Lanusei, Ilbono, Arzana and Elini (Sardinia, Italy); American Diabetes Association (1-05-RA-140); the Center for Inherited Disease Research; Clinical Research Institute (HUCH); Diabetes UK; the European Bioinformatics Institute; the European Commission (contracts LSHM-CT-2006-037197, LSHM-CT-2003-503041, QLK6-CT-2002-02629, QLG2-CT-2002-01254, HEALTH-F4-2007-201413, LSHG-CT-2004-512066, QLRT-2001-01254, LSHG-CT-2004-518153); the Faculty of Biology and Medicine of Lausanne; Finnish Diabetes Research Foundation; Folkhalsan Research Foundation; Foundation of the NIH (GAIN initiative); German Federal Ministry of Education and Research; German Federal Ministry of Health and Social Security; German National Genome Research Network; GlaxoSmithKline; GSF-National Research Center for Environment and Health; LMUinnovativ; Ministry of Science and Research of the State North-Rhine Westphalia; Municipality of Rotterdam; US National Institutes of Health (HG-02651, HL-084729, HL-087679, HC-25195, N02-HL-6-4278, DK-078616, DK-080140, DK-065978, RR-163736, MH059160, DK069922, DA-021519, DK-062370, DK-072193, US National Human Genome Research Institute intramural project HG-000024; and the Intramural Program of the National Institute on Aging); the UK National Institute for Health Research (Oxford Biomedical Research Centre and Guys and St. Thomas' Biomedical Research Centre); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health, Welfare and Sports; Novartis; NWO (904-61-090, 904-61-193, 480-04-004, 400-05-717); NWOGenomics; NWOInvestments; Research Institute for Diseases in the Elderly (RIDE); Sigrid Juselius Foundation; Spinozapremie; Swedish Research Council (349-2006-237); UK Medical Research Council (G0500539, G0000649, G016121); UK National Health Services Research and Development; the Wellcome Trust (including intramural support for the Wellcome Trust Sanger Institute, GR069224, Strategic Awards 076113 and 083948, Biomedical Collections Grant GR072960); and ZonMw (10-000-1002). A full list of acknowledgments is provided in the Supplementary Note.

Author information

Authors and Affiliations

Authors

Contributions

Project management: DFS: R.N.B., A. Cao, F.S.C., K.L.M., J.T., D.S., M.U., E.L., L.C.G., M. Boehnke, G.R.A.; ENGAGE: P.E., A.H., J.H.S., H.-E.W., G. Willemsen, D.I.B., B.W.J.H.P., M.R.J., L.P., U.T., C.v.D., K. Stefansson, M.I.M.; FHS: J.D., J.B.M.; GEM: T.D.S., I.B., N.J.W.

Study design: DFS: R.S., V.L., R.N.B., T.A.B., A. Cao, F.S.C., K.L.M., L.J.S., J.T., D.S., M.U., E.L., M. Boehnke, R.M.W., G.R.A.; ENGAGE: L.P., A.H., U.T., C.v.D., K. Stefansson, M.I.M.; FHS: J.D., J.C.F., J.B.M.; GEM: C.L., N.S., R.J.F.L., J.S.B., M. Bochud, D.W., M.S., T.D.S., P.V., G. Waeber, V.M., I.B., N.J.W.

Genome-wide association sampling and genotyping: DFS: M.R.E., L.L.B., A. Cao, L. Crisponi, T.E.H., B.I., U.L., S.N., M.O., A.S., H.M.S., T.T., J.T., M.U., D.A., L.C.G.; ENGAGE: P.E., N.F., A.P., E.S., V.S., A.G.U., J.C.M.W., D.I.B., M.R.J., L.P., U.T., C.v.D., K. Stefansson, M.I.M.; FHS: C.S.F., L.A.C., J.D., J.B.M.; GEM: K.A., A. Cervino, P.D., M.I., O.T.M.

Statistical analysis and informatics: DFS: R.S., A.U.J., S. Sanna, W.-M.C., V.G., P.S., B.F.V., R.M.W.; ENGAGE: I.P., G.T., Y.A., J.-J.H., M. Kaakinen, L. Coin, E.J.C.d.G., A.D., C.H., A.K., M. Krestyaninova, C.M.L., J.R., V.S., E.Z., C.v.D.; FHS: A.K.M., J.D.; GEM: C.L., N.S., S.C.P., E.W., S.H., T.J., N.L., S. Sharp, K. Song, X.Y., J.H.Z.

Replication sampling and genotyping: A.S.F.D., A.H., T.I., M.L., A.D.M., C.N.A.P., W.R., J.S., H.E.W.

MAGIC management committee: I.P., C.L., J.C.F., R.S., N.S., G.T., R.J.F.L., A.U.J., Y.A., E.W., V.L., C.M.L., D.W., D.S., M.S., P.V., G. Waeber., L.C.G., V.M., U.T., M. Boehnke, I.B., J.D., R.M.W., M.I.M., N.J.W., J.B.M., G.R.A.

Writing team: I.P., C.L., J.C.F., R.S., N.S., G.T., M. Boehnke, I.B., C.v.D., J.D., R.M.W., K. Stefansson, M.I.M., N.J.W., J.B.M., G.R.A.

Corresponding authors

Correspondence to Mark I McCarthy, Nicholas J Wareham, James B Meigs or Gonçalo R Abecasis.

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Competing interests

Dawn Waterworth and Vincent Mooser are full-time employees of GlaxoSmithKline. Inês Barroso owns stock in GlaxoSmithKline and Incyte. Drs. Thorleifsson, Kong, Steinsthorsdottir, Thorsteinsdottir, and Stefansson are employees at deCODE genetics, and own stock or stock options in the company. Dr. Meigs currently has research grants from GlaxoSmithKline and Sanofi-Aventis, and serves on consultancy boards for GlaxoSmithKline, Sanofi-Aventis, Interleukin Genetics, Kalypsis, and Outcomes Sciences. Dr. Florez has received consulting honoraria from Merck and from Publicis Healthcare Communications, an advertising agency for Amylin Pharmaceuticals.

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Supplementary Note, Supplementary Methods, Supplementary Figure 1 and Supplementary Tables 1–6 (PDF 523 kb)

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Prokopenko, I., Langenberg, C., Florez, J. et al. Variants in MTNR1B influence fasting glucose levels. Nat Genet 41, 77–81 (2009). https://doi.org/10.1038/ng.290

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