Previous studies have implicated common and rare genetic variants as risk factors for late‐onset Alzheimer's disease (LOAD). Here, weighted burden analysis was applied to over 10,000 exome‐sequenced subjects from the Alzheimer's Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7, and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R, and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Because PIK3R1 variants are expected to impair PI3K/Akt/GSK‐3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models, suggesting that this pathway is protective against Alzheimer's disease.

中文翻译：

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对外显子组测序的迟发性阿尔茨海默病病例和对照的加权负荷分析为 PSEN1 的作用提供了进一步的证据，并表明 PI3K/Akt/GSK-3β 和 WNT 信号通路的参与


先前的研究表明，常见和罕见的遗传变异是迟发性阿尔茨海默病 (LOAD) 的危险因素。在这里，加权负担分析应用于阿尔茨海默病测序项目的 10,000 多名外显子组测序受试者。进行了分析，以调查预测在基因内具有功能作用的罕见变异是否在病例或对照中更常见。 TREM2、ABCA7 和 SORL1 获得了确认结果。为 PSEN1 (p = 0.0002) 提供了额外的支持，此前 PSEN1 仅与 LOAD 存在微弱关联。有提示性证据表明，PIK3R1、WNT7A、C1R 和 EXOC5 的功能变异可能会增加风险，而 TIAF1 和/或 NDRG2 的变异可能具有保护作用。总体而言，有强有力的证据 (p = 5 × 10−6) 表明酪氨酸磷酸酶基因的变异可降低发生 LOAD 的风险。由于 PIK3R1 变异预计会损害 PI3K/Akt/GSK-3β 信号传导，而酪氨酸磷酸酶基因的变异会增强它，因此这些发现与动物模型的结果一致，表明该途径可以预防阿尔茨海默病。