Genome-wide association study of brain arteriolosclerosis.

  • Shade LM, Katsumata Y, Hohman TJ, Nho K, Saykin AJ, Mukherjee S, Boehme KL, Kauwe JS, Farrer LA, Schellenberg GD, Haines JL, Mayeux RP, Schneider JA, Nelson PT, Fardo DW. Genome-wide association study of brain arteriolosclerosis. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2022 Aug;42(42). 1437-1450. PMID: 35156446 [PubMed] PMCID: PMC9274864


Brain 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 ( = 3382) and Stage 2 mega-analysis ( = 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,  = ; rs2603462,  = ) were significant in the ADNI cohort (rs7902929,  = ; rs2603462, ). The rs2603462 lead variant colocalized with expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near and . We thus identified putative loci associated with B-ASC risk, but additional replication is needed.