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Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

Abstract

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D–CHD analysis identified eight variants—two of which are coding—where T2D and CHD associations appear to colocalize, including a new joint T2D–CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

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Figure 1: A circular Manhattan plot summarizing the association results for the T2D scan.

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Acknowledgements

D.S. has received support from NHLBI, NINDS, Pfizer, Regeneron Pharmaceuticals, Genentech, and Eli Lilly. Genotyping in PROMIS was funded by the Wellcome Trust, UK, and Pfizer. Biomarker assays in PROMIS have been funded through grants awarded by the NIH (RC2HL101834 and RC1TW008485) and Fogarty International (RC1TW008485). The RACE study has been funded by NINDS (R21NS064908), Fogarty International (R21NS064908), and the Center for Non-Communicable Diseases (Karachi, Pakistan). B.F.V. was supported by funding from the American Heart Association (13SDG14330006), the W.W. Smith Charitable Trust (H1201), and the NIH/NIDDK (R01DK101478). J.D. is a British Heart Foundation Professor, European Research Council Senior Investigator, and NIHR Senior Investigator. V.S. was supported by the Finnish Foundation for Cardiovascular Research. S. Ripatti was supported by the Academy of Finland (251217 and 255847), the Center of Excellence in Complex Disease Genetics, the European Union's Seventh Framework Programme projects ENGAGE (201413) and BioSHaRE (261433), the Finnish Foundation for Cardiovascular Research, Biocentrum Helsinki, and the Sigrid Juselius Foundation. The Mount Sinai IPM Biobank Program is supported by the Andrea and Charles Bronfman Philanthropies. S. Anand is supported by grants from the Canada Research Chair in Ethnic Diversity and CVD and from the Heart and Stroke Michael G. DeGroote Chair in Population Health, McMaster University. Data contributed by Biobank Japan were partly supported by a grant from the Leading Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank the participants and staff of the Copenhagen Ischemic Heart Disease Study and the Copenhagen General Population Study for their important contributions. The CHD Exome+ Consortium was funded by the UK Medical Research Council (G0800270), the British Heart Foundation (SP/09/002), the UK NIHR Cambridge Biomedical Research Centre, the European Research Council (268834), the European Commission's Framework Programme 7 (HEALTH-F2-2012-279233), Merck, and Pfizer. PROSPER has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004.

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A.R., B.F.V., B.G.N., D.J.R., D.S., D.S.A., J.I.R., M.R., O.M., P.F., R.C., R.J.F.L., S. Anand, S.E., S.M., S. Ripatti, T.-D.W., W.H.-H.S., and W. Zhao conceived of and designed the experiments. A.I., A.M., A.R., A.S.B., B.F.V., B.G.N., B.R.S., C.A.H., D.J.R., D.K.S., D.S., D.S.A., E.P.B., E.S.T., E.T., F.M., F.-u.-R.M., G.P., I.-T.L., I.H.Q., J.-J.L., J.C.C., J.I.R., J.M.M.H., J.S.K., J.W.J., J.Z.K., K.-W.L., K.D.T., K.M., K.T., M.B., N.M., M.O.-M., N.A., N.H.M., S.N.H.R., N.Q., N. Sattar, O.M., P.C., P.F., P.S., R.-H.C., R.C., R.F.-S., R.J.F.L., S. Abbas, S. Anand, S.E., S.J., S.M., S.N.H.R., S. Ralhan, S. Ripatti, S.Z.R., T.-D.W., T.-u.S., T.K., T.L.A., T.S., T.Y., U.M., W.H.-H.S., W.I., W. Zhang, W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., Y.Y.T., and Z.Y. performed the experiments. A.R., A.S.B., B.F.V., C.A.H., D.S., E.D.A., E.P.B., E.T., I.-T.L., J.-J.L., J.-M.J.J., J.C.C., J.D., J.M.M.H., J.S.K., J.W.J., J.Z.K., K.-W.L., K.D.T., M.B., M.I., M.O.-M., M.R., N.K.M., N. Sattar, N. Shah, O.M., P.C., P.F., P.R.K., P.S., R.-H.C., R.C., R.F.-S., R.J.F.L., R.S., R.Y., S. Anand, S. Asma, S.D., S.F.N., S.M., S. Ralhan, T.-D.W., N.M., T.L.A., T.Q., T.S., T.Y., U.M., V.S., W.-J.L., W.H.-H.S., W. Zhang, W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., and Y.Y.T. performed statistical analyses. A.I., A.R., A.S., A.S.B., A.T.-H., B.F.V., B.R.S., C.-C.H., C.A.H., D.K.S., D.S., E.D.A., E.P.B., E.S.T., E.T., F.M., G.P., I.-T.L., J.-J.L., J.-M.J.J., J.C.C., J.D., J.I.R., J.S.K., J.Z.K., K.-W.L., K.D.T., K.T., M.I., M.O.-M., M.R., N.H.M., N.Q., N. Sattar, N. Shah, O.M., P.C., P.R.K., P.S., R.-H.C., R.F.-S., R.J.F.L., R.S., R.Y., S. Abbas, S. Asma, S.D., S.J., S. Ralhan, T.K., T.L.A., T.Q., T.S., T.Y., U.M., V.S., W.-J.L., W. Zhao, X.G., Y.-D.I.C., Y.-J.H., Y.L., Y.Y.T., and Z.Y. analyzed the data. A.M., A.S., A.T.-H., B.F.V., B.G.N., D.J.R., D.S., F.u.R.M., G.P., I.H.Q., J.-M.J.J., J.D., J.W.J., N.M., K.M., M.B., M.R., N.A., P.R.K., R.S., S.E., S.N.H.R., S. Ripatti, S.Z.R., T.-u.-S., V.S., W.I., and W. Zhao contributed-reagents, materials, and/or analysis tools. A.R., A.S.B., B.F.V., D.J.R., D.K.S., D.S., E.T., G.P., J.-J.L., J.D., J.I.R., J.M.M.H., M.R., N. Sattar, V.S., and W. Zhao wrote the manuscript. D.S. and B.F.V. led the writing group. W. Zhao, A.R., E.T., B.F.V., and D.S. were equal contributors. B.F.V. and D.S. jointly supervised all aspects of the work.

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Correspondence to Benjamin F Voight or Danish Saleheen.

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The authors declare competing financial interests from their affiliations with Pfizer, Regeneron Pharmaceuticals, Genenetech, and Eli Lilly.

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Zhao, W., Rasheed, A., Tikkanen, E. et al. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet 49, 1450–1457 (2017). https://doi.org/10.1038/ng.3943

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