Abstract

Contemporary genetic methods have not yet solved the ‘missing heritability’ problem of complex diseases such as Alzheimer’s disease (AD). The impact of rare or less common variation on human complex diseases and traits remains to date barely investigated. In this study rare population variants detected using whole-exome sequencing were employed to examine how molecular pathways are prioritized in four groups: Alzheimer’s disease (AD) patients, Frontotemporal dementia (FTD) patients, young and healthy individuals and centenarians. The set of prioritized genes in AD patients associated with Semaphorin interactions pathways, contrasting with the results of the other groups. We identified rare pathogenic, likely pathogenic and variants of unknown significance in these prioritized genes in AD patients. The results of this study offer evidence that semaphorin pathways play a role in AD genetic etiology.

摘要

现代遗传方法尚未解决阿尔茨海默病 (AD) 等复杂疾病的“遗传性缺失”问题。罕见或不太常见的变异对人类复杂疾病和性状的影响迄今为止仍鲜有研究。在这项研究中，使用全外显子组测序检测到的罕见人群变异被用来检查分子通路如何在四组中优先排序：阿尔茨海默病 (AD) 患者、额颞叶痴呆 (FTD) 患者、年轻健康的个体和百岁老人。AD患者中与Semaphorin相互作用相关的一组优先基因路径，与其他组的结果形成对比。我们在 AD 患者的这些优先基因中发现了罕见的致病性、可能致病性和意义未知的变异。这项研究的结果提供了信号蛋白通路在 AD 遗传病因学中发挥作用的证据。