Shade, Lincoln M. P.Katsumata, YurikoHohman, Timothy J.Nho, KwangsikSaykin, Andrew J.Mukherjee, ShubhabrataBoehme, Kevin L.Kauwe, John S. K.Farrer, Lindsay A.Schellenberg, Gerard D.Haines, Jonathan L.Mayeux, Richard P.Schneider, Julie A.Nelson, Peter T.Fardo, David W.2023-10-302023-10-302022Shade LM, Katsumata Y, Hohman TJ, et al. Genome-wide association study of brain arteriolosclerosis. J Cereb Blood Flow Metab. 2022;42(8):1437-1450. doi:10.1177/0271678X211066299https://hdl.handle.net/1805/36756Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p =  1.8×10−7 ; rs2603462, p =  4×10−7 ) were significant in the ADNI cohort (rs7902929, p =  0.012 ; rs2603462, p = 0.012 ). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.en-USPublisher PolicyArteriosclerosisNeuropathologyDementiaAgingArticle