Abstract 69: Trans-eQTL Analysis of Blood After Ischemic Stroke Reveals X-Linked SNP-Gene Relationships

Abstract

Objective: Single nucleotide polymorphism (SNP) is one of the most common types of genetic variation and likely has a contributing role in ischemic stroke (IS). The influence of SNPs on changes of gene expression in blood after IS remains largely unknown. Thus, we evaluated the association of genetic variants with changes in mRNA expression levels (i.e. expression quantitative trait loci;eQTL) in blood after IS. Methods: RNA and DNA were isolated from blood samples collected from 137 IS patients and 138 vascular risk factor controls (VRFC). Gene expression of protein-coding transcripts was quantified by Affymetrix HTA 2.0 microarrays and SNP variants assessed by Axiom Biobank Genotyping microarrays. A linear model with a genotype (SNP)х diagnosis (IS or VRFC) interaction was fit for each SNP-gene pair to identify novel IS diagnosis-dependent eQTL. Results: Our trans- eQTL interaction analysis found 70 significant SNP-gene pairs (FDR<0.01). Our observations indicated that 24 mRNAs were associated with significant genotype х diagnosis interaction. Among these genes, two X-linked genes ANOS1 and POF1B were found. Expression of ANOS1 was significantly associated with SNPs rs148791848 and rs149957475. The SNP, rs950391, was significantly associated with expression of POF1B, a gene previously shown as sexually dimorphic in stroke. Interestingly, some of the eQTL SNPs affected multiple genes in trans that are known to be altered after IS. For example, X-linked SNP rs950391, altered expression of ABCA6, CLNK, EML6, POF1B, and WNT16. Conclusions: To our knowledge, this is the first whole-genome study to examine the effect of genotype х diagnosis on gene expression of blood after IS. Some SNP-gene pairs are X-linked and may account for aspects of sexual dimorphism in stroke. Our findings facilitate better understanding of trans effects of genetic variation on gene expression in stroke.