Abu-Amara Hasan, Zhao Wei, Li Zheng, Leung Yuk Yee, Schellenberg Gerard D, Wang Li-San, Moorjani Priya, Dey A B, Dey Sharmistha, Zhou Xiang, Gross Alden L, Lee Jinkook, Kardia Sharon L R, Smith Jennifer A
University of Michigan.
University of Pennsylvania.
Res Sq. 2024 Aug 10:rs.3.rs-4712660. doi: 10.21203/rs.3.rs-4712660/v1.
The prevalence of dementia among South Asians across India is approximately 7.4% in those 60 years and older, yet little is known about genetic risk factors for dementia in this population. Most known risk loci for Alzheimer's disease (AD) have been identified from studies conducted in European Ancestry (EA) but are unknown in South Asians. 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 of 84 genes previously associated with AD in EA. We investigated associations with the Hindi Mental State Examination (HMSE) score and factor scores for general cognitive function and five cognitive domains. For each gene, we examined missense/loss-of-function (LoF) variants and brain-specific promoter/enhancer variants, 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). In the missense/LoF analysis without annotation weights and controlling for age, sex, state/territory, and genetic ancestry, three genes had an association 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 more prevalent in LASI-DAD than in EA (minor allele frequency=0.075% vs. 0.0015%); the other two are common variants. No genes in the brain-specific promoter/enhancer analysis met criteria for significance. Results with and without annotation weights were similar. 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 identification of potential novel causal variants enriched in South Asians.
在印度，60岁及以上的南亚人中痴呆症患病率约为7.4%，但对于该人群中痴呆症的遗传风险因素知之甚少。大多数已知的阿尔茨海默病（AD）风险基因座是从欧洲血统（EA）人群的研究中确定的，在南亚人中尚不清楚。利用来自印度纵向衰老研究痴呆诊断评估（LASI-DAD）的2680名参与者的全基因组序列数据，我们对先前在EA人群中与AD相关的84个基因进行了基于基因的分析。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。对于每个基因，我们分别检查了错义/功能丧失（LoF）变异以及脑特异性启动子/增强子变异，在使用注释信息进行关联的变异集检验（STAAR）中，分别纳入和不纳入额外的注释权重（例如有害性、保守性评分）。在不考虑注释权重并控制年龄、性别、邦/地区和遗传血统的错义/LoF分析中，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（ ）。rs779406084是一种罕见的错义突变，在LASI-DAD中比在EA人群中更普遍（次要等位基因频率=0.075%对0.0015%）；其他两个是常见变异。在脑特异性启动子/增强子分析中，没有基因达到显著标准。有无注释权重的结果相似。一些先前在EA人群中与AD相关的基因中的错义/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。
