University of Washington, Seattle, Washington, USA.
Veterans Administration Puget Sound Health Care, Seattle, Washington, USA.
Dement Geriatr Cogn Disord. 2018;45(1-2):1-17. doi: 10.1159/000485503. Epub 2018 Feb 27.
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.
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.
背景/目的：阿尔茨海默病测序项目（ADSP）旨在鉴定影响阿尔茨海默病（AD）的新基因。以前，已知导致除 AD 以外的痴呆症的基因中的变异与 AD 风险相关。我们描述了 ADSP 中痴呆症基因中的变异与临床上诊断的 AD 之间共同分离和关联的证据。
我们总结了痴呆症基因中已知致病性变异的特征，描述了 ClinVar 中注释为“致病性”的变异以及在 ADSP 家族中观察到的新候选变异的共同分离，并在 ADSP 病例对照研究中测试了痴呆症基因中的罕见变异之间的关联。参与者接受了 AD 的临床评估，他们代表欧洲、加勒比西班牙裔和孤立的荷兰人群。
结果/结论：痴呆症基因中的致病性变异主要是罕见且保守的编码变化。观察到 ARSA、CSF1R 和 GRN 中的致病性变异，并且在 ADSP 家族中提名了 GRN 和 CHMP2B 的候选变异。一项独立的病例对照研究提供了证据表明 TREM2、APOE、ARSA、CSF1R、PSEN1 和 MAPT 中的变异与 AD 的风险相关。导致痴呆症的基因中的变异可能会影响 ADSP 中一小部分病例的 AD 临床诊断。
