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

2011; Nature Portfolio; Volume: 43; Issue: 5 Linguagem: Inglês

10.1038/ng.803

1546-1718

Paul Hollingworth, Denise Harold, Rebecca Sims, Amy Gerrish, Jean‐Charles Lambert, Minerva M. Carrasquillo, Richard Abraham, Marian L. Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Nicola Jones, Alexandra Stretton, Charlene Thomas, Alex Richards, Dobril Ivanov, Caroline S. Widdowson, Jade Chapman, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kristelle Brown, Peter Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A. David Smith, Helen Beaumont, Donald Warden, Gordon Wilcock, Seth Love, Patrick G. Kehoe, Nigel M. Hooper, Emma Vardy, John Hardy, Simon Mead, Nick C. Fox, Martin N. Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Eckart Rüther, Britta Schürmann, Reiner Heun, Heike Kölsch, Hendrik van den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, John Gallacher, Michael Hüll, Dan Rujescu, Ina Giegling, Alison Goate, John Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin H. Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Peter Paul De Deyn, Christine Van Broeckhoven, Gill Livingston, Nicholas Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panos Deloukas, Ammar Al‐Chalabi, Christopher E. Shaw, Magda Tsolaki, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl‐Heinz Jöckel, Norman Klopp, H‐Erich Wichmann, V. Shane Pankratz, Sigrid Botne Sando, Jan Aasly, Maria Barcikowska, Zbigniew K. Wszołek, Dennis W. Dickson, Neill R. Graff‐Radford, Ronald C. Petersen, Cornelia M. van Duijn, Monique M.B. Breteler, M. Arfan Ikram, Anita L. DeStefano, Annette L. Fitzpatrick, Lorna M. Lopez, Lenore J. Launer, Sudha Seshadri, Claudine Berr, Dominique Campion, Jacques Epelbaum, Jean‐François Dartigues, Christophe Tzourio, Annick Alpérovitch, Mark Lathrop, Thomas Feulner, Patricia F. Friedrich, Caterina Riehle, Michael Krawczak, Stefan Schreiber, Manuel Mayhaus, S Nicolhaus, Stefan Wagenpfeil, Stacy Steinberg, Hreinn Stefánsson, Kāri Stefánsson, Jón Snædal, Sigurbjörn Björnsson, Pálmi V. Jónsson, Vincent Chouraki, Benjamin Genier-Boley, Mikko Hiltunen, Hilkka Soininen, Onofre Combarros, Diana Zélénika, Marc Delépine, María J. Bullido, Florence Pasquier, Ignacio Mateo, Ana Frank, Elisa Porcellini, Olivier Hanon, Eliécer Coto, Victoria Álvarez, Paolo Bosco, Gabriele Siciliano, Michelangelo Mancuso, Francesco Panza, Vincenzo Solfrizzi, Benedetta Nacmias, Sandro Sorbi, Paola Bossù, Paola Piccardi, Beatrice Arosio, Giorgio Annoni, Davide Seripa, Alberto Pilotto, Elio Scarpini, Daniela Galimberti, Alexis Brice, Didier Hannequin, Federico Licastro, Lesley Jones, Peter Holmans, Thorlákur Jónsson, Markus J. Riemenschneider, Kevin Morgan, Steven G. Younkin, Michael J. Owen, Michael O’Donovan, Philippe Amouyel, Julie Williams,

Cholesterol and Lipid Metabolism

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).