BackgroundLate-onset Alzheimer’s disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population.MethodsTo identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk.ResultsVia step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10− 5, odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses.ConclusionsOur work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development.

中文翻译：

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SHARPIN 的一种罕见功能性变异减弱了炎症反应并与晚发性阿尔茨海默病的风险增加有关

背景迟发性阿尔茨海默病 (LOAD) 是最常见的痴呆形式，由多种环境和遗传因素之间复杂的相互作用引起。尽管最近在 LOAD 的遗传分析方面取得了进展，但该疾病一半以上的遗传性仍不清楚。尽管对白种人的遗传研究发现 LOAD 的罕见风险变异具有较大的影响，但这些变异在日本人群中几乎检测不到。 方法为了鉴定可能解释日本人 LOAD 部分遗传结构的罕见变异，我们进行了全外显子组测序分析202 个 LOAD 个体没有 APOE ε4 风险等位基因，这是 LOAD 易感性的主要遗传因素。我们还对变体进行了体外功能分析，以揭示与 LOAD 风险相关的可能功能。结果通过逐步选择全外显子组变异，我们发现了七个候选风险变异。然后，我们在一个由 4563 名病例和 16,459 名对照组成的大型日本队列中进行了病例对照关联研究。我们最终在 SHARPIN 中发现了一个罕见的非同义变体 rs572750141 (NM_030974.3:p.Gly186Arg)，它可能与 LOAD 的风险增加有关（校正 P = 8.05 × 10− 5，优势比 = 6.1）。SHARPIN 中的氨基酸变化导致变异蛋白的异常细胞定位并减弱了 NF-κB 的激活，NF-κB 是炎症和免疫反应的中心介质。结论我们的工作确定了一种罕见的功能性 SHARPIN 变异是以前未知的 LOAD 遗传风险因素.