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Younkin Steven G, Berr Claudine, Gudnason Vilmundur, Rujescu Dan, Dickson Dennis W, Dartigues Jean-François, DeStefano Anita L, Ortega-Cubero Sara, Hakonarson Hakon, Campion Dominique, Boada Merce, Kauwe John Keoni, Farrer Lindsay A, Van Broeckhoven Christine, Ikram M Arfan, Jones Lesley, Haines Jonathan L, Tzourio Christophe, Launer Lenore J, Escott-Price Valentina, Mayeux Richard, Deleuze Jean-François, Amin Najaf, Holmans Peter A, Pericak-Vance Margaret A, Amouyel Philippe, van Duijn Cornelia M, Ramirez Alfredo, Wang Li-San, Lambert Jean-Charles, Seshadri Sudha, Williams Julie, Schellenberg Gerard D
Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Nat Genet. 2017 Sep;49(9):1373-1384. doi: 10.1038/ng.3916. Epub 2017 Jul 17.
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10, odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10, OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10, OR = 1.67, MAF = 0.0143, MAF = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
在一项针对85133名受试者的三阶段病例对照研究中，我们鉴定出了与阿尔茨海默病相关的罕见编码变异。在第一阶段，我们使用全外显子微阵列对34174个样本进行了基因分型。在第二阶段，我们使用从头基因分型和推断基因型，在35962个独立样本中测试了相关变异（P < 1×10）。在第三阶段，我们使用另外14997个样本，通过推断基因型来测试第二阶段最显著的关联（P < 5×10）。我们观察到三个新的全基因组显著非同义变异与阿尔茨海默病相关：PLCG2中的一个保护性变异（rs72824905：p.Pro522Arg，P = 5.38×10，优势比（OR） = 0.68，次要等位基因频率（MAF） = 0.0059，MAF = 0.0093），ABI3中的一个风险变异（rs616338：p.Ser209Phe，P = 4.56×10，OR = 1.43，MAF = 0.011，MAF = 0.008），以及TREM2中的一个新的全基因组显著变异（rs143332484：p.Arg62His，P = 1.55×10，OR = 1.67，MAF = 0.0143，MAF = 0.0089），TREM2是阿尔茨海默病一个已知的易感基因。这些蛋白质改变发生在小胶质细胞中高表达的基因上，并突出了一个免疫相关的蛋白质-蛋白质相互作用网络，该网络富含先前在阿尔茨海默病中鉴定出的风险基因。这些遗传学发现提供了额外的证据，表明小胶质细胞介导的固有免疫反应直接促成了阿尔茨海默病的发展。
