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Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

Abstract

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

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Figure 1: Manhattan plot of stage 1 for genome-wide association with Alzheimer's disease (17,008 cases and 37,154 controls).
Figure 2

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Acknowledgements

This work was made possible by the generous participation of the control subjects, the patients and their families. iSelect chips were funded by the French National Foundation on Alzheimer's Disease and Related Disorders. Data management involved the Centre National de Génotypage and was supported by the Institut Pasteur de Lille, INSERM, FRC (Fondation pour la Recherche sur le Cerveau) and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease). The French National Foundation on Alzheimer's Disease and Related Disorders and the Alzheimer's Association (Chicago, Illinois) grant supported in-person meetings and communication for IGAP, and the Alzheimer's Association (Chicago, Illinois) grant provided some funds to each consortium for analyses.

GERAD was supported by the Wellcome Trust, the MRC, Alzheimer's Research UK (ARUK) and the Welsh government. ADGC and CHARGE were supported by the US National Institutes of Health, National Institute on Aging (NIH-NIA), including grants U01 AG032984 and R01 AG033193 (additional US National Institutes of Health grant numbers are listed in the Supplementary Note). CHARGE was also supported by Erasmus Medical Center and Erasmus University.

Complete acknowledgments are detailed in the Supplementary Note.

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Study concept and design: J.-C.L., C.A.I.-V., D. Harold, A.C.N., A.L.D., J.C.B., A.V.S., M.A.I., H. Schmidt, A.L.F., V.G., O.L.L., D.W.T., D. Blacker, T.H.M., T.B.H., J.I.R., W.A.K., M. Boada, R. Schmidt, R.M., A.H., B.M.P., J.L.H., P.A.H., M.L., M.A.P.-V., L.J.L., L.A.F., C.M.v.D., V.M., S. Seshadri, J.W., G.D.S. and P.A. Acquisition of data: J.-C.L., C.A.I.-V., D. Harold, C. Bellenguez, R. Sims, G.J., B.G.-B., G.R., N.J., V.C., C. Thomas, D.Z., Y.K., A.G., H. Schmidt, M.L.D., M.-T.B., S.-H.C., P.H., V.G., C. Baldwin, C.C., C. Berr, O.L.L., P.L.D.J., D.E., L. Letenneur, G.E., K.S., A.M.G., N.F., M.J.H., M.I.K., E.B.L., A.J.M., C.D., S.T., S. Love, E.R., P.S.G.-H., L.Y., M.M.C., D. Beekly, F.Z., O.V., S.G.Y., W.G., M.J.O., K.M.F., P.V.J., M.C.O., L.B.C., D.A.B., T.B.H., R.F.A.G.d.B., T.J.M., J.I.R., K.M., T.M.F., W.A.K., J.F.P., M.A.N., K.R., J.S.K.K., E.B., M.R., M. Boada, L.-S.W., J.-F.D., C. Tzourio, M.M.N., B.M.P., L.J., J.L.H., M.L., L.J.L., L.A.F., A.H., C.M.v.D., S. Seshadri, J.W., G.D.S. and P.A. Sample contribution: A. Ruiz, F. Pasquier, A. Ramirez, O.H., J.D.B., D. Campion, P.K.C., C. Baldwin, T.B., C.C., D. Craig, V.D., J.A.J., S. Lovestone, F.J.M., D.C.R., K.S., A.M.G., N.F., M.G., K. Brown, M.I.K., L.K., P.B.-G., B.M., R.G., A.J.M., D.W., E.R., J.G., P.S.G.-H., J.C., A.L., A. Bayer, M.T., P. Bossù, G.S., P. Proitsi, J.C., S. Sorbi, F.S.-G., N.C.F., J.H., M.C.D.N., P. Bosco, R.C., C. Brayne, D.G., M. Mancuso, F.M., S. Moebus, P.M., M.D.Z., W.M., H. Hampel, A.P., M. Bullido, F. Panza, P.C., B.N., M. Mayhaus, L. Lannfelt, H. Hakonarson, S.P., M.M.C., M.I., V.A., S.G.Y., E.C., C. Razquin, P. Pastor, I.M., O.C., H. Soininen, S. Mead, D.A.B., L.F., C.H., P. Passmore, T.J.M., K. Bettens, A. Brice, D. Hannequin, K.R., M.R., M.H., D.R., C.G. and C.V.B. Data analysis: C.A.I.-V., D. Harold, A.C.N., R. Sims, C. Bellenguez, G.J., A.L.D., J.C.B., G.W.B., B.G.-B., G.R., T.A.T.-W., N.J., A.V.S., V.C., M.A.I., D.Z., Y.K., B.N.V., C.-F.L., A.G., B.K., C. Reitz, J.R.G., O.V., W.A.K., K.L.L., K.L.H.-N., E.R.M., L.-S.W., B.M.P., M.L., V.M. and J.W. Statistical analysis and interpretation: J.-C.L., C.A.I.-V., D. Harold, A.C.N., C. Bellenguez, G.J., A.L.D., J.C.B., G.W.B., T.A.T.-W., A.V.S., V.C., M.A.I., B.N.V., Y.K., C.-F.L., B.K., C. Reitz, A.L.F., N.A., J.R.G., R.F.A.G.d.B., W.A.K., K.L.L., E.R.M., L.-S.W., B.M.P., L.J., J.L.H., P.A.H., M.A.P.-V., L.J.L., L.A.F., C.M.v.D., V.M., S. Seshadri, J.W., G.D.S. and P.A. Drafting of the manuscript: J.-C.L., C.A.I.-V., D. Harold, A.C.N., C. Bellenguez, A.L.D., J.C.B., A.V.S., R.M., B.M.P., J.L.H., M.A.P.-V., L.J.L., L.A.F., C.M.v.D., C.V.B., S. Seshadri, J.W., G.D.S. and P.A.

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Correspondence to Julie Williams or Philippe Amouyel.

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Full lists of members and affiliations appear in the Supplementary Note

Full lists of members and affiliations appear in the Supplementary Note

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Lambert, JC., Ibrahim-Verbaas, C., Harold, D. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45, 1452–1458 (2013). https://doi.org/10.1038/ng.2802

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