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

P Hollingworth, D Harold, R Sims, A Gerrish, JC Lambert, MM Carrasquillo, R Abraham, ML Hamshere, JS Pahwa, V Moskvina, K Dowzell, N Jones, A Stretton, C Thomas, A Richards, D Ivanov, C Widdowson, J Chapman, S Lovestone, J PowellP Proitsi, MK Lupton, C Brayne, DC Rubinsztein, M Gill, B Lawlor, A Lynch, KS Brown, PA Passmore, D Craig, B McGuinness, S Todd, C Holmes, D Mann, AD Smith, H Beaumont, D Warden, G Wilcock, S Love, PG Kehoe, NM Hooper, ERLC Vardy, J Hardy, S Mead, NC Fox, M Rossor, J Collinge, W Maier, F Jessen, E Ruther, B Schurmann, R Heun, H Kolsch, H van den Bussche, I Heuser, J Kornhuber, J Wiltfang, M Dichgans, L Frolich, H Hampel, J Gallacher, M Hull, D Rujescu, I Giegling, AM Goate, JSK Kauwe, C Cruchaga, P Nowotny, JC Morris, K Mayo, K (Kristel) Sleegers, K Bettens, S Engelborghs, PP de Deyn, C van Broeckhoven, G Livingston, NJ Bass, H Gurling, A McQuillin, R Gwilliam, P Deloukas, A Al-Chalabi, CE Shaw, M Tsolaki, AB Singleton, R Guerreiro, TW Muhleisen, MM Nothen, S Moebus, KH Jockel, N Klopp, HE Wichmann, VS Pankratz, SB Sando, JO Aasly, M Barcikowska, ZK Wszolek, DW Dickson, NR Graff-Radford, RC Petersen, Cornelia Duijn, Monique Breteler, Arfan Ikram, AL DeStefano, AL Fitzpatrick, O Lopez, LJ (Lenore) Launer, S Seshadri, C Berr, D Campion, J Epelbaum, JF Dartigues, C Tzourio, A Alperovitch, M Lathrop, TM Feulner, P Friedrich, C Riehle, M Krawczak, S Schreiber, M Mayhaus, S Nicolhaus, S Wagenpfeil, S Steinberg, H Stefansson, K Stefansson, J Snaedal, S Bjornsson, PV Jonsson, V Chouraki, B Genier-Boley, M Hiltunen, H Soininen, O Combarros, D Zelenika, M Delepine, MJ 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 Bossu, P Piccardi, B Arosio, G Annoni, D Seripa, A Pilotto, E Scarpini, D Galimberti, A Brice, D Hannequin, F Licastro, L Jones, PA Holmans, T Jonsson, M Riemenschneider, K Morgan, SG Younkin, MJ Owen, M O'Donovan, P Amouyel, J Williams

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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)).
Original languageUndefined/Unknown
Pages (from-to)429-435
Number of pages7
JournalNature Genetics
Volume43
Issue number5
DOIs
Publication statusPublished - 2011

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