Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease

Denise Harold, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Marian L. Hamshere, Jaspreet Singh Pahwa, Valentina Moskvina, Kimberley Dowzell, Amy Williams, Nicola Jones, Charlene Thomas, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol Brayne, David C. RubinszteinMichael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, John Hardy, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Reinhard Heun, Hendrik Van Den Bussche, Isabella Heuser, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Harald Hampel, Michael Hüll, Dan Rujescu, Alison M. Goate, John S.K. Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Kristel Sleegers, Karolien Bettens, Sebastiaan Engelborghs, Christine Van Broeckhoven, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew McQuillin, Rhian Gwilliam, Panagiotis 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, Minerva M. Carrasquillo, V. Shane Pankratz, Peter A. Holmans, Michael O'Donovan, Michael J. Owen, Julie Williams

Research output: Contribution to journalArticle

1828 Scopus citations

Abstract

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 × 10 157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 × 10 9) and 5′ to the PICALM gene (rs3851179, P = 1.9 × 10 8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 × 10 10, odds ratio = 0.86; rs3851179, P = 1.3 × 10 9, odds ratio = 0.86).

Original languageEnglish (US)
Pages (from-to)1088-1093
Number of pages6
JournalNature Genetics
Volume41
Issue number10
DOIs
StatePublished - Oct 1 2009

ASJC Scopus subject areas

  • Genetics

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    Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., Jones, N., Thomas, C., Stretton, A., Morgan, A. R., Lovestone, S., Powell, J., Proitsi, P., Lupton, M. K., Brayne, C., ... Williams, J. (2009). Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genetics, 41(10), 1088-1093. https://doi.org/10.1038/ng.440