Abstract P42: Genetic Variants Associated With Vasospasm Following Aneurysmal Subarachnoid Hemorrhage

Abstract

Background: Cerebral vasospasm is a major contributor to poor clinical outcomes in intracranial aneurysm (IA) patients and is involved in delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Little is known about the genetic factors associated with vasospasm pathogenesis. We performed a genome-wide association study (GWAS) to investigate association of common genetic variants with risk of vasospasm in IA patients with SAH. Methods: Our Caucasian cohort of 190 aSAH patients (121 with vasospasm diagnosed by angiography) were genotyped using UK Biobank Axiom Arrays. Genotypes were called using the Best Practices Workflow in the Axiom Analysis Suite v4.0.3.3. All samples had >97% call rate, one sample was removed due to sex mismatch, and a total of 634,781 single nucleotide polymorphisms (SNPs) with >0.01 minor allele frequency were analyzed for association with vasospasm in the final cohort of 189 cases (66.7% female, mean age 54.8 years). Logistic regression analysis was performed using an additive model adjusting for age at onset of symptoms and sex. Genome-wide significance was based on Bonferroni correction for multiple testing (P< 7.9x10 -8 ). Results: No SNPs were significantly associated with vasospasm at the genome-wide level. However, eleven SNPs were nominally associated with vasospasm (P<10E-5) including the most significant SNP mapping to an intron of GLIS3 (P=9.74E-06, OR=3.94, 95% CI: 2.15-7.22), three intronic SNPs mapping to ACVR1 , and additional SNPs mapping to introns in FSTL3 , TMEM242 , DCLK1 , one SNP upstream of RAC2 and two SNPs downstream of TEX29 and TGFBR3 , and one missense SNP mapping to MYO18B. Interestingly, two of these genes ( ACVR1 and TGFBR3 ) are in the transforming growth factor-beta (TGF-beta) signaling pathway, previously implicated in SAH pathogenesis. Conclusions: We performed a GWAS of vasospasm following aSAH. Our study suggests that common SNPs may contribute to vasospasm susceptibility following aSAH and suggests a potential role for TGF-beta signaling pathway genes in vasospasm. These findings warrant further replication in additional independent studies including other DCI outcomes.