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

P Hollingworth, R Sims, A Gerrish, D Harold, R Abraham, ML Hamshere, JS Pahwa, V Moskvina, K Dowzell, N Jones, A Stretton, A Richards, D Ivanov, C Widdowson, J Chapman, S Lovestone, J Powell, P Proitsi, MK Lupton, C BrayneDC Rubinsztein, M Gill, B Lawlor, A Lynch, K Morgan, KS Brown, PA Passmore, D Craig, B McGuiness, S Todd, C Holmes, D Mann, AD Smith, S Love, PG Kehoe, J Hardy, S Mead, N Fox, M Rossor, J Collinge, W Maier, F Jessen, B Schürmann, H van den Bussche, I Heuser, J Kornhuber, J Wiltfang, M Dichgans, L Frölich, H Hampel, M Hüll, J Gallacher, D Rujescu, I Giegling, AM Goate, JSK Kauwe, C Cruchaga, P Nowotny, JC Morris, K Mayo, K Sleegers, K Bettens, S Engelborghs, PP De Deyn, C Van Broeckhoven, G Livingston, NJ Bass, H Gurling, A McQuillin, A Gwilliam, P Deloukas, A Al-Chalabi, CE Shaw, M Tsolaki, AB Singleton, R Guerreiro, TW Mühleisen, MM Nöthen, S Moebus, KH Jöckel, N Klopp, HE Wichmann, MM Carrasquillo, V Shane Pankratz, SG Younkin, Initiative The Alzheimer's Disease Neuroimaging, L Jones, PA Holmans, M O'Donovan, MJ Owen, J Williams

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1308 Citations (Scopus)

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)).
Translated title of the contributionCommon variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
Original languageEnglish
Pages (from-to)429 - 435
Number of pages7
JournalNature Genetics
Volume43 (5)
Issue number5
DOIs
Publication statusPublished - May 2012

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