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. 2009 Oct;41(10):1088-93.
doi: 10.1038/ng.440. Epub 2009 Sep 6.

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

Denise Harold  1 , 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 Rubinsztein, Michael 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, Peter P De Deyn, 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, Steven G Younkin, Peter A Holmans, Michael O'Donovan, Michael J Owen, Julie Williams
Affiliations

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

Denise Harold et al. Nat Genet. 2009 Oct.

Erratum in

  • Nat Genet. 2009 Oct;41(10):1156
  • Nat Genet. 2013 Jun;45(6):712. Haun, Reinhard [added]

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 x 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 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 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 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

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Figures

Figure 1
Figure 1
Scatterplot of chromosomal position (x-axis) against −log 10 GWAS P-value (y-axis). The y-axis scale has been limited to 9.25 (p = 5.6×10−10), although highly significant association was observed with SNPs in the vicinity of the APOE locus (e.g. rs2075650 with p = 1.8×10−157). The threshold for genome-wide significance (p ≤ 9.4×10−8) is indicated by the red horizontal line. 761 SNPs with p ≤ 1×10−3 lie above the blue horizontal line and are listed in Supplementary Table 2. The plot was produced using Haploview v4.0.
See this image and copyright information in PMC

Comment in

  • Alzheimer's disease beyond APOE.
    van Es MA, van den Berg LH. van Es MA, et al. Nat Genet. 2009 Oct;41(10):1047-8. doi: 10.1038/ng1009-1047. Nat Genet. 2009. PMID: 19786950 No abstract available.

References

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    1. Beecham GW, et al. Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet. 2009;84:35–43. - PMC - PubMed
    1. Bertram L, et al. Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet. 2008;83:623–32. - PMC - PubMed
    1. Carrasquillo MM, et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat Genet. 2009;41:192–8. - PMC - PubMed

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