Genome-wide association study of brain arteriolosclerosis

Abstract

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 (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 = $1.8\times {10}^{-7}$; rs2603462, p = $4\times {10}^{-7}$) 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.

Keywords: SVD; VCID; aging; arteriosclerosis; dementia; neuropathology.

Figure 1.

Overall study design. First, quality control (QC) was performed on all neuropathological and genotype data sets used (see Methods). GWAS were performed across three stages. In Stage 1, GWAS was performed on NACC participants (n = 3382). In Stage 2, all variants with p <  $1\times {10}^{-5}$ (k = 14) were analyzed separately in ROSMAP (n = 1187), and then NACC and ROSMAP participant data were merged for mega-analysis (n = 4569). In Stage 3, top variants from Stage 2 mega-analysis with p <  $1\times {10}^{-6}$ (k = 2) were analyzed in two replication cohorts, ADNI (n = 47) and ACT (n = 512), and then NACC, ROSMAP, ADNI, and ACT data were merged for mega-analysis. Downstream functional analyses, consisting of colocalization and gene-based analyses, were then performed on Stage 3 mega-analysis results. Mediation analyses for HTN and DM were also performed using a subset of NACC participants with clinical data available (n = 1726).

Figure 2.

Stage 2 mega-analysis results. (a) Manhattan plot of Stage 2 GWAS mega-analysis of NACC and ROSMAP. The horizontal dashed line in each plot is the suggestive threshold (p <  $1\times {10}^{-5}$ ) while the solid line is the threshold for genome-wide significance (p <  $5\times {10}^{-8}$ ). (b & c) Regional plots of rs2603462 and rs7902929 +/− 1000 kb, respectively.