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Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

Abstract

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).

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Figure 1: GERAD+ study design.
Figure 2: Schematic of the associated variants reported in reference to (a) ABCA7 and (b) chromosomal region chr11: 59.81Mb–60.1Mb harboring members of the MS4A gene cluster.
Figure 3

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Acknowledgements

For complete acknowledgments, please see the Supplementary Note. We thank the individuals and families who took part in this research and those who funded the groups who contributed to this study: Wellcome Trust; Medical Research Council (UK); Alzheimer's Research UK; the Welsh Assembly Government; Mercer's Institute for Research on Ageing; Alzheimer's Society; Ulster Garden Villages; Northern Ireland R&D Office; Royal College of Physicians; Dunhill Medical Trust; Bristol Research into Alzheimer's and Care of the Eldery; US National Institutes of Health, the Barnes Jewish Foundation; Charles and Joanne Knight Alzheimer's Research Initiative; University College London (UCL) Hospital/UCL Biomedical Centre; Lundbeck; German Federal Ministry of Education and Research Competence Network Dementia and Competence Network Degenerative Dementia; Alfried Krupp von Bohlen und Halbach-Stiftung; Intramural Research Program of the National Institute of Ageing Department of Health and Human Services; University of Antwerp, Fund for Scientific Research-Flanders; Foundation for Alzheimer Research; Methusalem Excellence grant; Federal Science Policy Office Interuniversity Attraction Poles program; Mayo AD Research Center; National Institute of Neurological Disorders and Stroke; Robert and Clarice Smith Postdoctoral Fellowship and AD Research Program; Palumbo Professorship in AD Research; Carl Edward and Susan Bass Bolch Gift; Institut Pasteur de Lille; Centre National de Génotypage; Fondation pour la Recherche Médicale Caisse; Nationale Maladie des Travailleurs Salariés, Direction Générale de la Sant; Institut de la Longévité; Agence Française de Sécurité Sanitaire des Produits de Santé; Aquitaine and Bourgogne Regional Councils; Fondation de France; French Ministry of Research/Institute national de la santé et de la recherché medicale; Eisai; Health Research Council of the Academy of Finland; Nordic Centre of Excellence in Neurodegeneration; Italian Ministry of Research; Carimonte Foundation; Italian Ministry of Health; Fondazione Monzino; Ministerio de Educación y Ciencia the Ministerio de Sanidad y Consumo; Fundación Ramón Areces; National Institute of Biomedical Imaging Bioengineering; Abbott; AstraZeneca, Bayer Schering Pharma; Bristol-Myers Squibb; Elan; Genentech; GE; GlaxoSmithKline; Innogenetics; Johnson and Johnson; Eli Lilly; Medpace; Merck; Novartis; Pfizer; Hoffman-La Roche; Schering-Plough; Synarc; Wyeth; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; US Food and Drug Administration; Foundation for the National Institutes of Health Northern California Institute for Research and Education; Dana Foundation; German National Genome Research Network; German Ministry for Education and Research; National Institute on Deafness and Other Communication Disorders; Hjartavernd; Althingi; National Heart Lung and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; Robert Dawson Evans Endowment; Netherlands Organisation of Scientific Research; Netherlands Genomics Initiative; Erasmus Medical Center; Netherlands organization for scientific research; Netherlands Organization for the Health Research and Development; the Research Institute for Diseases in the Elderly; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission and the Municipality of Rotterdam. G.W. was partly funded by the NIHR Biomedical Research Centre Programme, Oxford. The Leeds sample collection was funded by the Health Foundation.

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J. Williams directed this study, assisted by M.J.O. and M.O.D. and was also helped by P.H., R.S., A.G., R.A., L.J. and D. Harold. J. Williams, P.H. and D.H. took primary responsibility for drafting the manuscript, assisted by R.S., A.G., R.A., M.O.D. and M.J.O. All authors contributed to the sample collection, sample preparation, genotyping and/or conduct of the GWAS upon which this study is based. J. Williams, R.A., P.H., R.S., A.G., C.W., J. Chapman, K.D., N.J., A.S., C. Thomas, S. Lovestone, J.P., P. Proitsi, M.K.L., C. Brayne, D.C.R., M.G., B.L., A.L., K. Morgan, K.S.B., P.A.P., D. Craig, B.M., S.T., C.H., D.M., A.D.S., S. Love, P.G.K., J.H., S. Mead, N.C.F., M. Rossor, J. Collinge, W.M., F.J., B.S., E.R., R.H., H.K., H.v.d.B., I.H., J.K., J. Wiltfang, M. Dichgans, L.F., H.H., M. Hüll, J.G., A.M.G., D.R., I.G., J.S.K.K., C.C., P.N., J.C.M., K. Mayo, K. Sleegers, K.B., S.E., P.P.D., C.V.B., G.L., N.J.B., H.G., A.M., M.T., T.W.M., M.M.N., S. Moebus, K.-H.J., N.K. and H.-E.W. contributed to clinical sample collection, ascertainment, diagnosis and preparation of samples from the independent GERAD2 sample genotyped as part of this study. R.S., D. Harold, A.G., D.R. and I.G. were responsible for procedures related to genotyping the GERAD2 sample. V.C., B.G.-B., M. Hiltunen, O.C., D.Z., M. Delepine, M.J.B., F. Pasquier, I.M., A.F.-G., E.P., O.H., E. Coto, V.A., P. Bosco, G.S., M. Mancuso, F. Panza, B.N., S. Sorbi, P. Bossù, P. Piccardi, B.A., G.A., D.S., E.S., D.G., A.B., D. Hannequin, F.L., H. Soininen, J.-C.L. and P.A. were responsible for sample collection, sample preparation, genotyping and analysis of the EADI2 Sample. S.S., A.L.D., O.L. and L.J.L., as well as M.A.I., C.M.v.D. and M.M.B.B. contributed clinical and genotypic data to the CHARGE GWAS. J.-C.L. and P.A. contributed clinical and genotypic data. M.M.C. played a leading role, along with H.B., D.W., G.W., N.M.H., E.R.L.C.V., S.B.S., J.O.A., M.B., Z.K.W., D.W.D., N.R.G.R., R.C.P., K. Morgan and S.G.Y. in sample collection, sample preparation, genotyping and analysis of the Mayo2 sample. M. Riemenschneider, T.M.F., P.F., C.R., M.K., S. Schreiber, M. Mayhaus, S.N. and S.W. were responsible for sample collection, conduct and analysis of the AD-IG GWAS. S. Steinberg, T.J., H. Stefansson, K. Stefansson, J.S., S.B. and P.V.J were responsible for sample collection, conduct and analysis of the deCODE GWAS. D. Harold and P.H. completed statistical quality control and produced association statistics under the supervision of J. Williams and P.A.H. All authors discussed the results and approved the manuscript.

Corresponding authors

Correspondence to Michael J Owen or Julie Williams.

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The authors have applied for an International PCT (Patent Co-operation Treaty) patent filing (European Office).

Additional information

Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (see URLs). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. See URLs for a complete listing of the ADNI investigators.

Supplementary information

Supplementary Text and Figures

Supplementary Note and Supplementary Tables 1–5 (PDF 526 kb)

Supplementary Table 6

Results for SNPs at the CD2AP, EPHA1, ARID5B and CD33 loci. (XLS 93 kb)

Supplementary Table 7

Sample size tested for each SNP (XLS 75 kb)

Supplementary Table 8

Summary statistics for each dataset (XLS 285 kb)

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Hollingworth, P., Harold, D., Sims, R. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 43, 429–435 (2011). https://doi.org/10.1038/ng.803

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