Journal Article

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

Sando, Sigrid B, Combarros, Onofre, Engelborghs, Sebastiaan, Holmans, Peter A, Fox, Nick C, Aasly, Jan O, Morgan, Kevin, Heuser, Isabella, Bettens, Karolien, Rossor, Martin, Kornhuber, Johannes, Sims, Rebecca, Tzourio, Christophe, Pilotto, Alberto, Gurling, Hugh, Moskvina, Valentina, Collinge, John, Galimberti, Daniela, Heun, Reiner, Richards, Alex, Passmore, Peter A, Beaumont, Helen, Stefansson, Kari, Siciliano, Gabriele, Mead, Simon, Porcellini, Elisa, Coto, Eliecer, Lathrop, Mark, Dickson, Dennis W, Wilcock, Gordon, Björnsson, Sigurbjörn, Wiltfang, Jens, Mühleisen, Thomas W, O'Donovan, Michael, Solfrizzi, Vincenzo, Zelenika, Diana, Morris, John C, Maier, Wolfgang, Petersen, Ronald C, Moebus, Susanne, Shaw, Christopher E, Nöthen, Markus M, Thomas, Charlene, Gwilliam, Rhian, Bass, Nicholas J, Soininen, Hilkka, Dowzell, Kimberley, Scarpini, Elio, Mateo, Ignacio, Hampel, Harald, Campion, Dominique, Owen, Michael J, Carrasquillo, Minerva M, De Deyn, Peter P, Lopez, Oscar, Lupton, Michelle K, Goate, Alison M, Piccardi, Paola, Launer, Lenore J, Kölsch, Heike, Dichgans, Martin, Guerreiro, Rita, Mayhaus, Manuel, Hi

2011

Overview

Julie Williams, Michael Owen and colleagues report staged follow-up and meta-analyses of genome-wide association studies for Alzheimer's disease from the GERAD+ consortium. They identify common variants at ABCA7 and MS4A6A/MS4A4E associated with Alzheimer's disease and support for several additional susceptibility loci. 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 ).

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/727/2000 / 692/699/375/365/1283 / Adaptor Proteins, Signal Transducing - genetics / Adult and adolescent clinical studies / Aged / Aged, 80 and over / Agriculture / Alzheimer Disease - genetics / Alzheimer's disease / Animal Genetics and Genomics / Antigens, CD - genetics / Antigens, Differentiation, Myelomonocytic - genetics / ATP-Binding Cassette Transporters - genetics / Biological and medical sciences / Biomedical and Life Sciences / Biomedical research / Biomedicine / Cancer Research / Case-Control Studies / Cytoskeletal Proteins - genetics / Databases, Genetic / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease susceptibility / Drug therapy / Female / Fundamental and applied biological sciences. Psychology / Gene Function / Genes / Genetic aspects / Genetic Predisposition to Disease / Genetic Variation / Genetics of eukaryotes. Biological and molecular evolution / Genome-Wide Association Study / Genomes / Health aspects / Human Genetics / Humans / letter / Male / Medical imaging / Medical sciences / Membrane Proteins - genetics / Multigene Family / Neurology / Organic mental disorders. Neuropsychology / Polymorphism, Single Nucleotide / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Receptor, EphA1 - genetics / Risk factors / Sialic Acid Binding Ig-like Lectin 3 / Single nucleotide polymorphisms