全基因组关联研究确定了与阿尔茨海默病相关的CLU和PICALM基因变体。
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
作者信息
Harold Denise, Abraham Richard, Hollingworth Paul, Sims Rebecca, Gerrish Amy, Hamshere Marian L, Pahwa Jaspreet Singh, Moskvina Valentina, Dowzell Kimberley, Williams Amy, Jones Nicola, Thomas Charlene, Stretton Alexandra, Morgan Angharad R, Lovestone Simon, Powell John, Proitsi Petroula, Lupton Michelle K, Brayne Carol, Rubinsztein David C, Gill Michael, Lawlor Brian, Lynch Aoibhinn, Morgan Kevin, Brown Kristelle S, Passmore Peter A, Craig David, McGuinness Bernadette, Todd Stephen, Holmes Clive, Mann David, Smith A David, Love Seth, Kehoe Patrick G, Hardy John, Mead Simon, Fox Nick, Rossor Martin, Collinge John, Maier Wolfgang, Jessen Frank, Schürmann Britta, Heun Reinhard, van den Bussche Hendrik, Heuser Isabella, Kornhuber Johannes, Wiltfang Jens, Dichgans Martin, Frölich Lutz, Hampel Harald, Hüll Michael, Rujescu Dan, Goate Alison M, Kauwe John S K, Cruchaga Carlos, Nowotny Petra, Morris John C, Mayo Kevin, Sleegers Kristel, Bettens Karolien, Engelborghs Sebastiaan, De Deyn Peter P, Van Broeckhoven Christine, Livingston Gill, Bass Nicholas J, Gurling Hugh, McQuillin Andrew, Gwilliam Rhian, Deloukas Panagiotis, Al-Chalabi Ammar, Shaw Christopher E, Tsolaki Magda, Singleton Andrew B, Guerreiro Rita, Mühleisen Thomas W, Nöthen Markus M, Moebus Susanne, Jöckel Karl-Heinz, Klopp Norman, Wichmann H-Erich, Carrasquillo Minerva M, Pankratz V Shane, Younkin Steven G, Holmans Peter A, O'Donovan Michael, Owen Michael J, Williams Julie
机构信息
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, UK.
出版信息
Nat Genet. 2009 Oct;41(10):1088-93. doi: 10.1038/ng.440. Epub 2009 Sep 6.
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).
我们开展了一项针对阿尔茨海默病（AD）的两阶段全基因组关联研究（GWAS），涉及超过16,000名个体，这是迄今为止规模最大的AD GWAS。在第一阶段（3,941例病例和7,848例对照），我们重复验证了与载脂蛋白E（APOE）基因座已确立的关联（最显著的单核苷酸多态性，rs2075650，P = 1.8×10⁻¹⁵⁷），并观察到在两个先前未与该疾病关联的基因座上，单核苷酸多态性与全基因组存在显著关联：在CLU（也称为APOJ）基因处（rs11136000，P = 1.4×10⁻⁹）以及PICALM基因5'端（rs3851179，P = 1.9×10⁻⁸）。这些关联在第二阶段（2,023例病例和2,340例对照）得到了重复验证，从而为在合并数据集中与阿尔茨海默病的关联提供了有力证据（rs11136000，P = 8.5×10⁻¹⁰，比值比 = 0.86；rs3851179，P = 1.3×10⁻⁹，比值比 = 0.86）。
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