Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
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DOI：
10.1038/s41588-019-0358-2
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发表时间：
2019-03-01
期刊：
影响因子：
30.8
通讯作者：
Pericak-Vance, Margaret A.
中科院分区：
文献类型：
--
作者：
Kunkle, Brian W.;Grenier-Boley, Benjamin;Pericak-Vance, Margaret A.
迟发性阿尔茨海默病(LOAD)是最常见的痴呆症，其风险部分由遗传因素决定。为了确定负荷风险基因座，我们对临床诊断的负荷(94,437人)进行了一项大型全基因组关联荟萃分析。我们确认了20个先前的负载风险基因座，并确定了5个新的全基因组基因座(IQCK、ACE、ADAM10、ADAMTS1和WWOX)，其中两个(ADAM10、ACE)在最近的一项以家族为单位的全基因组关联(GWAS)中被发现。人类白细胞抗原(人类白细胞抗原)区域的精细图谱证实，神经和免疫介导的疾病单倍型HLA-DR15是负荷的危险因素。通路分析涉及免疫、脂质代谢、tau结合蛋白和淀粉样前体蛋白(APP)代谢，表明影响APP和Aβ加工的基因变异不仅与早发性常染色体显性阿尔茨海默病有关，而且与负荷有关。对风险基因和途径的分析表明，稀有变异丰富(P=1.32×10(-7))，表明还有其他稀有变异有待识别。我们还确定了负荷与特征之间的重要遗传相关性，如家族史、痴呆症病史和教育程度。
Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A beta processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 x 10(-7)), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.