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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Abstract

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1,2,3,4,5,6,7,8,9,10,11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 × 10−14), CDC123-CAMK1D (P = 1.2 × 10−10), TSPAN8-LGR5 (P = 1.1 × 10−9), THADA (P = 1.1 × 10−9), ADAMTS9 (P = 1.2 × 10−8) and NOTCH2 (P = 4.1 × 10−8) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

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Figure 1: Regional plots of six confirmed associations.

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Acknowledgements

UK: Collection of the UK type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The GWA genotyping was supported by the Wellcome Trust (076113), and the replication genotyping was supported by the European Commission (EURODIA LSHG-CT-2004- 518153), MRC (Project Grant G0601261), Wellcome Trust, Peninsula Medical School and Diabetes UK. E.Z. is a Wellcome Trust Research Career Development Fellow. We acknowledge the contribution of M. Sampson and our team of research nurses. We acknowledge the efforts of J. Collier, P. Robinson, S. Asquith and others at KBiosciences for their rapid and accurate large-scale genotyping.

DGI: We thank the study participants who made this research possible. We thank colleagues in the Broad Genetic Analysis and Biological Samples Platforms for their expertise and contributions to genotyping, data and sample management, and analysis. The initial GWAS genotyping was supported by Novartis (to D.A.); support for additional analysis and genotyping in this report was provided by funding from the Broad Institute of Harvard and MIT, by the Richard and Susan Smith Family Foundation/American Diabetes Association Pinnacle Program Project Award (to D.A.), and by a Freedom to Discovery award of the Foundation of Bristol Myers Squibb (to D.A.). P.I.W.dB., M.J.D. and D.A. acknowledge support from US National Institutes of Health/National Heart, Lung, and Blood Institute grant (U01 HG004171). D.A. was a Burroughs Wellcome Fund Clinical Scholar in Translational Research and is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. L.G., T.T., B.I. and M.R.T. and the Botnia Study are principally supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd; work in Malmö, Sweden was also funded by a Linné grant from the Swedish Research Council (349-2006-237). We thank the Botnia and Skara research teams for clinical contributions, and colleagues at MGH, Harvard, Broad, Novartis and Lund for helpful discussions throughout the course of this work.

FUSION: We thank the Finnish citizens who generously participated in this study and R.Welch for bioinformatics support. Support for this research was provided by US National Institutes of Health grants DK062370 (M.B.), DK072193 (K.L.M.), HL084729 (G.R.A.), HG002651 (G.R.A.) and U54 DA021519; National Human Genome Research Institute intramural project number 1 Z01 HG000024 (F.S.C.); and a postdoctoral fellowship award from the American Diabetes Association (C.J.W.). Genome-wide genotyping was performed by the Johns Hopkins University Genetic Resources Core Facility (GRCF) SNP Center at the Center for Inherited Disease Research (CIDR) with support from CIDR NIH Contract Number N01-HG-65403 and the GRCF SNP Center.

deCODE: We thank the Icelandic study participants whose contribution made this work possible. We also thank the nurses at Noatun (deCODE's sample recruitment center) and personnel at the deCODE core facilities.

KORA study: We thank C. Gieger and G. Fischer for expert data handling. The MONICA/KORA Augsburg studies were financed by the GSF-National Research Center for Environment and Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN). Our research was also supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies.

Danish study: This work was supported by the European Union (EUGENE2, grant no. LSHM-CT-2004-512013), Lundbeck Foundation centre of Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care and The Danish Medical Research Council.

HUNT: The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between The HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), The National Institute of Public Health, The National Screening Service of Norway and The Nord-Trøndelag County Council.

NHS: The Nurses' Health Study is funded by National Cancer Institute grant CA87969. L.Q. is supported by an American Heart Association Scientist Development Grant. F.B.H. is supported by NIH grants DK58845 and U01 HG004399.

GEM Consortium: We thank all study participants. The work on the Cambridgeshire case-control, Ely, ADDITION and EPIC-Norfolk studies was funded by support from the Wellcome Trust and MRC. The Norfolk Diabetes study is funded by the MRC with support from NHS Research & Development and the Wellcome Trust. We are grateful to S. Griffin, MRC Epidemiology Unit, for assistance with the ADDITION study and M. Sampson and E. Young for help with the Norfolk Diabetes Study. We thank S. Bumpstead, W.E. Bottomley and A. Chaney for rapid and accurate genotyping and J. Ghori for assay design and informatics support. We are grateful to P. Deloukas for overall genotyping support. F.P. and I.B. are funded by the Wellcome Trust.

METSIM: The METSIM study has received grant support from the Academy of Finland (no. 124243).

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Contributions

Writing team and project management: L.J.S., E.Z., R.S., B.F.V., D.A., M.B. & M.I.M. Study design: R.S., B.F.V., E.Z., L.J.S., T.E.H., F.B.H., J.J.R., H.C., K.S., O.P., T.I., K.H., M.L., A.T.H., I.B., N.J.W., F.S.C., L.G., D.A., M.I.M. & M.B. Analysis: K.S.E., R.M.F., H.L., C.M.L., J.R.B.P., I.P., N.W.R., N.J.T., M.N.W., J.L.M. & E.Z. (UK), P.S.C., C.-J.D., W.L.D., T. Hu, A.U.J., Y.L., H.M.S., C.J.W., G.R.A. & L.J.S. (FUSION), R.S., B.F.V., P.I.W.dB., F.G.K., P.A. & M.J.D. (DGI), U.T. & A.K. (deCODE), N.G., G.A., T.H. & O.P. (Danish), K.M. (HUNT), L. Qi (NHS), C.L. (GEM Consortium), M.L. (Metsim). Clinical samples and genotyping: WTCCC, A.S.F.D., T.M.F., C.J.G., G.A.H., K.R.O., C.N.A.P., B.S., M.W., A.D.M., A.T.H. & M.I.M. (UK), L.L.B., P.D., M.R.E., K.K., M.A.M., N.N., M.R., A.J.S., R.N.B., K.L.M., J.T., A.F.M., L. Qin & R.M.W. (FUSION), K.A., K.B.B., N.P.B., L. Gianniny, C.G., B.I., V.L., P.N., M.S., T.T. & L. Groop (DGI), V.S., G.T. & K.S. (deCODE), H.G., C.H., C.M. & T.I. (KORA), G.A., N.G., T.H., T.J., T.L., A.S., K.B.-J. & O.P. (Danish), K.M., E.P., C.P. & K.H. (HUNT), F.B.H. (NHS), F.P., I.B. & N.J.W. (GEM Consortium), J.K. (METSIM).

Corresponding authors

Correspondence to Mark I McCarthy, Michael Boehnke or David Altshuler.

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Competing interests

G.T., V.S., A.K., K.S. and U.T. are employees at deCODE genetics, and own stock or stock options in the company. J.J.R., T.E.H. and H.C. are employees and shareholders of Novartis Institute of Biomedical Research, Inc. O.P. K.B.-J., G.A., N.G. and T.H. are employees of the Steno Diabetes Center, a hospital providing health service for the public health care system but owned by Novo Nordisk A/S, Bagsværd, Denmark. O.P., K.B.-J., N.G. and T.H. hold equity in Novo Nordisk A/S. I.B. holds equity in GlaxoSmithKline and Incyte.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Figures 1–4, Supplementary Tables 1–4 and 6–10 , Supplementary Note (PDF 1512 kb)

Supplementary Table 5

Details of stage 1, 2, 3 and meta-analysis results for the set of SNPs followed-up after stage 1 meta-analysis (XLS 70 kb)

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Zeggini, E., Scott, L., Saxena, R. et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40, 638–645 (2008). https://doi.org/10.1038/ng.120

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