The genetic component of Alzheimer’s disease (AD) has been mainly assessed using Genome Wide Association Studies (GWAS), which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals —16,036 AD cases and 16,522 controls— in a two-stage analysis. Next to known genes 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. Next to these genes, the rare variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential driver genes in AD-GWAS loci. Rare damaging variants in these genes, and in particular loss-of-function variants, have a large effect on AD-risk, and they are enriched in early onset AD cases. The newly identified AD-associated genes provide additional evidence for a major role for APP-processing, Aβ-aggregation, lipid metabolism and microglial function in AD.

中文翻译：

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外显子组测序将 ATP8B4 和 ABCA1 中罕见的破坏性变异鉴定为阿尔茨海默病的新风险因素

阿尔茨海默病 (AD) 的遗传成分主要使用全基因组关联研究 (GWAS) 进行评估，该研究没有捕捉到罕见变异所带来的风险。在这里，我们在两阶段分析中比较了来自 32,558 名个体（16,036 名 AD 病例和 16,522 名对照）的外显子组测序数据中罕见破坏性变异的基因负担。在已知基因TREM2、SORL1和ABCA7 旁边，我们观察到ATP8B4和ABCA1中罕见的、预测的破坏性变异与 AD 风险之间存在显着关联，并且在ADAM10中具有暗示性信号。除了这些基因，RIN3、CLU、ZCWPW1和ACE中的罕见变异负荷强调这些基因是 AD-GWAS 基因座中的潜在驱动基因。这些基因中罕见的破坏性变异，特别是功能丧失变异，对 AD 风险有很大影响，并且它们在早期发病的 AD 病例中富集。新发现的 AD 相关基因为 AD 中 APP 加工、Aβ 聚集、脂质代谢和小胶质细胞功能的主要作用提供了额外的证据。