Genome-wide association and colocalization analyses identify target genes for brain arteriolosclerosis.

Abstract

Brain arteriolosclerosis (B-ASC) is a small-vessel cerebrovascular pathologic change involving sclerotic thickening of arterioles in the brain. B-ASC pathology is common in aged autopsy cohorts, is associated with worse cognitive functioning, and is also associated with other neuropathologies. The genetics of dementia and other pathologic changes have been studied extensively, but to date no in-depth study has been conducted on genetic risk of autopsy-proven B-ASC. We performed the first genome-wide association study (GWAS) focusing on B-ASC using multiple cohorts. We then followed up on identified risk variants with functional analysis to investigate potential biological mechanisms. Individual GWAS and mega-analyses were conducted using data from participants in the National Alzheimer's Coordinating Center (NACC) (N = 3318) and the Religious Orders Study and Memory and Aging Project (ROSMAP) (N=1190). In total, 4,577,283 variants (MAF > 5%) were present in both datasets and passed quality control. Variants identified in GWAS were then checked for quantitative trait loci (QTL) associations in the Genotype Tissue Expression (GTEx) project. Colocalization analysis was then performed on identified QTL in brain and vascular tissues. Variants most highly associated with B-ASC were also examined for association with neuroimaging correlates of B-ASC in the Alzheimer's Disease Neuroimaging Initiative. One intergenic locus on Chromosome 6 was significantly associated with B-ASC in NACC (P = 1.4e-08) and colocalized with ELOVL4 gene expression in the brain. Other loci in both cohorts achieved less stringent thresholds of association and colocalized with multiple QTL in GTEx. One intergenic locus on Chromosome 10 near SORCS3 was suggestively associated with B-ASC in NACC and was replicated in ROSMAP. Genetic loci associated with B-ASC pathology were identified using multiple cohorts. Most loci associated with B-ASC in one cohort were not associated in the other. Multiple identified risk loci colocalized with gene expression or splicing QTL, providing evidence for potential biological mechanisms through which variants may influence disease risk. Due to the relatively small sample sizes and heterogeneity between the cohorts used, additional studies are merited to better characterize genetic risk of B-ASC.