Progranulin genetic variant rs5848 displays ancestry-specific associations with Alzheimer's disease.

BACKGROUND: Progranulin is a molecular modifier of Alzheimer’s disease (AD). However, its cis-regulatory region remains under-characterized. Association studies of genetic variants in this region with AD have obtained conflicting results across different human populations. METHODS: We define the cis-regulatory region of the progranulin gene (GRN). Querying the genetically admixed Alzheimer’s Disease Sequencing Project whole-genome sequencing dataset (n = 9,416 cases; 13,603 controls), we conduct ancestry-specific analyses of AD association with GRN genetic variants. RESULTS: We report predicted impacts of genetic variation on transcription factor binding for 150 unique transcription factors across the GRN cis-regulatory region. We identify 99 common variants (MAF > 0.005) in one or more superpopulations (African, Admixed American, East Asian, European, and South Asian). The common GRN variant rs5848 is significantly associated with AD only in East Asian ancestry. CONCLUSIONS: Ancestry-specific effects may contribute to discordant findings in the literature. European-centric results in AD might not be generalizable to other populations.