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 x 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 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 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 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease / D. Harold, R. Sims, A. Gerrish, J..C. Lambert, M..M. Carrasquillo, R. Abraham, M..L. Hamshere, J..S. Pahwa, V. Moskvina, K. Dowzell, N. Jones, A. Stretton, C. Thomas, A. Richards, D. Ivanov, C. Widdowson, J. Chapman, S. Lovestone, J. Powell, P. Proitsi, M..K. Lupton, C. Brayne, D..C. Rubinsztein, M. Gill, B. Lawlor, A. Lynch, K..S. Brown, P..A. Passmore, D. Craig, B. Mcguinness, S. Todd, C. Holmes, D. Mann, A..D. Smith, H. Beaumont, D. Warden, G. Wilcock, S. Love, P..G. Kehoe, N..M. Hooper, E..R. Vardy, J. Hardy, S. Mead, N..C. Fox, M. Rossor, J. Collinge, W. Maier, F. Jessen, E. Rüther, B. Schürmann, R. Heun, H. Kölsch, H. van den Bussche, I. Heuser, J. Kornhuber, J. Wiltfang, M. Dichgans, L. Frölich, H. Hampel, J. Gallacher, M. Hüll, D. Rujescu, I. Giegling, A..M. Goate, J..S. Kauwe, C. Cruchaga, P. Nowotny, J..C. Morris, K. Mayo, K. Sleegers, K. Bettens, S. Engelborghs, P..P. De Deyn, C. Van Broeckhoven, G. Livingston, N..J. Bass, H. Gurling, A. Mcquillin, R. Gwilliam, P. Deloukas, A. Al Chalabi, C..E. Shaw, M. Tsolaki, A..B. Singleton, R. Guerreiro, T..W. Mühleisen, M..M. Nöthen, S. Moebus, K..H. Jöckel, N. Klopp, H..E. Wichmann, V..S. Pankratz, S..B. Sando, J..O. Aasly, M. Barcikowska, Z..K. Wszolek, D..W. Dickson, N..R. Graff Radford, R..C. Petersen, the Alzheimer's Disease Neuroimaging Initiative, C..M. van Duijn, M..M. Breteler, M..A. Ikram, A..L. Destefano, A..L. Fitzpatrick, O. Lopez, L..J. Launer, S. Seshadri, C. Charge, C. Berr, D. Campion, J. Epelbaum, J..F. Dartigues, C. Tzourio, A. Alpérovitch, M. Lathrop, C. Eadi1, T..M. Feulner, P. Friedrich, C. Riehle, M. Krawczak, S. Schreiber, M. Mayhaus, S. Nicolhaus, S. Wagenpfeil, S. Steinberg, H. Stefansson, K. Stefansson, J. Snædal, S. Björnsson, P..V. Jonsson, V. Chouraki, B. Genier Boley, M. Hiltunen, H. Soininen, O. Combarros, D. Zelenika, M. Delepine, M..J. Bullido, F. Pasquier, I. Mateo, A. Frank Garcia, E. Porcellini, O. Hanon, E. Coto, V. Alvarez, P. Bosco, G. Siciliano, M. Mancuso, F. Panza, V. Solfrizzi, B. Nacmias, S. Sorbi, P. Bossù, P. Piccardi, B. Arosio, G. Annoni, D. Seripa, A. Pilotto, E..A. Scarpini, D. Galimberti, A. Brice, D. Hannequin, F. Licastro, L. Jones, P..A. Holmans, T. Jonsson, M. Riemenschneider, K. Morgan, S..G. Younkin, M..J. Owen, M. O'Donovan, P. Amouyel, J. Williams. - In: NATURE GENETICS. - ISSN 1061-4036. - 43:5(2011), pp. 429-436. [10.1038/ng.803]
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
B. Arosio;G. Annoni;E..A. Scarpini;D. Galimberti;
2011
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 x 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 x 10(-17); including ADGC data, meta P = 5.0 x 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 x 10(-14); including ADGC data, meta P = 1.2 x 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 x 10(-4); including ADGC data, meta P = 8.6 x 10(-9)), CD33 (GERAD+, P = 2.2 x 10(-4); including ADGC data, meta P = 1.6 x 10(-9)) and EPHA1 (GERAD+, P = 3.4 x 10(-4); including ADGC data, meta P = 6.0 x 10(-10)).
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