Supplementary Material for: Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer’s Disease Sequencing Project

Background/Aims: The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer’s disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as “pathogenic” in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

研究背景与目的：阿尔茨海默病测序项目（Alzheimer’s Disease Sequencing Project, ADSP）旨在筛选影响阿尔茨海默病（Alzheimer’s disease, AD）发病的全新基因。此前已有研究表明，除阿尔茨海默病外其他痴呆症相关致病基因的变异，与阿尔茨海默病的发病风险存在关联。本研究基于ADSP数据，阐述痴呆症相关基因变异与临床确诊阿尔茨海默病之间的共分离现象及关联证据。

研究方法：本研究首先梳理了已知痴呆症相关致病基因的变异特征；其次分析了临床变异数据库（ClinVar）注释为“致病”的变异，以及在ADSP家系中观测到的新候选变异的共分离情况；最后针对ADSP病例-对照研究中的痴呆症相关基因罕见变异开展关联分析。所有研究参与者均接受了阿尔茨海默病临床评估，其种族背景涵盖欧洲人群、加勒比西班牙裔人群以及孤立荷兰人群。

研究结果与结论：痴呆症相关致病基因的变异多为罕见且保守的编码区变异。在ADSP家系中观测到ARSA、CSF1R及GRN基因的致病变异，并筛选出GRN与CHMP2B基因的候选变异。一项独立病例-对照研究证实，TREM2、APOE、ARSA、CSF1R、PSEN1及MAPT基因的变异与阿尔茨海默病发病风险存在关联。在ADSP队列中，少数病例的临床确诊阿尔茨海默病可能受到致痴呆相关基因变异的影响。