John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.
Nat Genet. 2019 Mar;51(3):414-430. doi: 10.1038/s41588-019-0358-2. Epub 2019 Feb 28.
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 Aβ 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 × 10), 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.
迟发性阿尔茨海默病（LOAD）风险，最常见的痴呆症，部分由遗传驱动。为了确定LOAD 的风险基因座，我们对临床诊断的LOAD（94437 人）进行了大规模的全基因组关联荟萃分析。我们确认了 20 个先前的LOAD 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 2 个（ADAM10、ACE）是在最近的全基因组关联（GWAS）-通过亲属代理的阿尔茨海默病或痴呆症中确定的。人类白细胞抗原（HLA）区域的精细映射证实了神经和免疫介导疾病 HLA-DR15 单倍型是LOAD 的危险因素。途径分析表明，免疫、脂质代谢、tau 结合蛋白和淀粉样前体蛋白（APP）代谢与遗传变异有关，这些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LOAD 有关。风险基因和途径的分析显示稀有变异的富集（P=1.32×10），表明还有其他稀有变异有待确定。我们还确定了LOAD 与痴呆家族史和教育等特征之间的重要遗传相关性。
