中文摘要

阿尔茨海默病（AD）是痴呆症的主要原因，其遗传度估计约为70%。AD的遗传因子主要通过全基因组关联研究进行评估，这些研究没有发现罕见变异带来的风险，科学家比较了16036名AD病患和16522名对照（共32558名个体）的外显子组测序数据中罕见破坏性变体的基因负荷。除了TREM2、SORL1和ABCA7中的变异外，他们观察到ATP8B4和ABCA1中罕见的、预测的损伤性变异与AD风险以及ADAM10中的提示性信号显著相关。此外，RIN3、CLU、ZCWPW1和ACE中的罕见变异负载突出了这些基因作为各自AD全基因组关联研究基因座的潜在驱动因素。与AD风险影响最强相关的变异，特别是功能丧失变异，在早发AD病例中丰富。他们的结果为AD中淀粉样β前体蛋白加工、淀粉样β聚集、脂质代谢和小胶质细胞功能的主要作用提供了新的证据。

英文摘要

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants2. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 inpiduals-16,036 AD cases and 16,522 controls. Next to variants in TREM2, SORL1 and ABCA7, we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10. Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.