Gene‐Based Analysis with Functional Annotation in 2680 South Asians from the LASI‐DAD Study

Abstract

AbstractBackgroundThe prevalence of dementia among South Asians across India is as high as 10% in those 55 years and older, yet little is known about the risk dementia factors in this population. To date, most known genetic risk loci of Alzheimer’s disease (AD) were identified from studies conducted in European Ancestry (EA) participants. The full mutational spectrum and the functional relevance of those loci in South Asians remains unknown. Analyzing DNA sequence data poses challenges due to the large number of rare variants tested, with most variants likely not associated with dementia. These challenges can be addressed with an annotation‐informed gene‐based analysis.MethodUsing 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 known to be associated with AD in EA. We investigated associations with the Hindi Mental State Examination (HMSE) score, 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).ResultIn the missense/LoF analysis, when controlling for age, sex, state/territory, and the first 10 principal components, 16 genes were nominally associated with at least one cognitive outcome (p<0.05). Three genes (APOE, PICALM, TSPOAP1) were significant after multiple testing correction (FDR q<0.1). In the brain‐specific promoter/enhancer analysis, 21 genes were nominally significant, but none were significant at FDR q<0.1. Results remained similar after adding annotation weights. The most strongly associated variants in each gene were rs429358 (APOE), rs779406084 (PICALM), and rs9913145 (TSPOAP1). rs779406084 is a missense mutation that is more prevalent in this Indian sample (MAF = 0.075%) compared to EA (MAF = 0.0015%).ConclusionSome genes associated with AD in EA are also associated with cognitive outcomes in South Asians in India. Analyzing sequence data in South Asians provides opportunities to identify potential novel causal variants that are enriched in this population.