Abu-Amara Hasan, Zhao Wei, Li Zheng, Leung Yuk Yee, Schellenberg Gerard D, Wang Li-San, Moorjani Priya, Dey Aparajit B, Dey Sharmistha, Zhou Xiang, Gross Alden L, Lee Jinkook, Kardia Sharon L R, Smith Jennifer A
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48104, USA.
Genes (Basel). 2025 May 27;16(6):640. doi: 10.3390/genes16060640.
The prevalence of dementia among South Asians across India is high among those who are 65 years and older, yet little is known about genetic risk factors for dementia in this population. Using whole-genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD), we performed a gene-based analysis on the missense/loss-of-function (LoF) and brain-specific promoter/enhancer variants of 84 genes, previously associated with AD in European Ancestry (EA). These analyses were performed separately, both with and without incorporating additional annotation weights (e.g., deleteriousness, conservation scores), using the variant-Set Test for Association using Annotation infoRmation (STAAR). We investigated associations with the Hindi Mental State Examination (HMSE) score and factor scores for general cognitive function and five cognitive domains. In the missense/LoF analysis, without annotation weights and controlling for age, sex, state/territory, and genetic ancestry, three genes were associated with at least one measure of cognitive function (FDR q < 0.1). was associated with four measures of cognitive function, was associated with HMSE score, and was associated with executive function. The most strongly associated variants in each gene were rs429358 ( ε4), rs779406084 (), and rs9913145 (). Rs779406084 is a rare missense mutation that is enriched in LASI-DAD compared to EA (minor allele frequency = 0.075% vs. 0.0015%). Missense/LoF variants in some genes previously associated with AD in EA are associated with measures of cognitive function in South Asians from India. Analyzing genome sequence data allows the identification of potential novel causal variants enriched in South Asians.
在印度，65岁及以上的南亚人群中痴呆症患病率较高，但对于该人群中痴呆症的遗传风险因素却知之甚少。利用来自印度纵向衰老研究痴呆症诊断评估（LASI-DAD）的2680名参与者的全基因组序列数据，我们对84个基因的错义/功能丧失（LoF）和脑特异性启动子/增强子变异进行了基于基因的分析，这些基因先前在欧洲血统（EA）人群中与阿尔茨海默病（AD）相关。这些分析分别在纳入和不纳入额外注释权重（如有害性、保守性评分）的情况下进行，使用基于注释信息的关联变异集检验（STAAR）。我们研究了与印地语精神状态检查（HMSE）评分以及一般认知功能和五个认知领域的因子评分之间的关联。在错义/LoF分析中，在不考虑注释权重并控制年龄、性别、邦/地区和遗传血统的情况下，有三个基因与至少一种认知功能指标相关（FDR q<0.1）。 与四种认知功能指标相关， 与HMSE评分相关， 与执行功能相关。每个基因中关联最强的变异分别是rs429358（ε4）、rs779406084（ ）和rs9913145（ ）。与EA相比，rs779406084是一种罕见的错义突变，在LASI-DAD中更为富集（次要等位基因频率=0.075%对0.0015%）。先前在EA中与AD相关的一些基因中的错义/LoF变异与来自印度的南亚人的认知功能指标相关。分析基因组序列数据有助于识别在南亚人群中富集的潜在新型因果变异。
