Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

The genetic mechanisms regulating intracranial aneurysm (IA) formation and rupture are largely unknown. To identify germline-genetic risk factors for IA, we perform a multinational genome-wide association study (GWAS) of individuals from the United Kingdom, Finland, and Japan.To identify a shared, multinational genetic basis of IA.Using GWAS summary statistics from UK Biobank, FinnGen, and Biobank Japan, we perform a meta-analysis of IA, containing ruptured and unruptured IA cases. Logistic regression was used to identify IA-associated single-nucleotide polymorphisms. Effect size was calculated using the coefficient r , estimating the contribution of the single-nucleotide polymorphism to the genetic variance of the trait. Genome-wide significance was set at 5.0 × 10 -8 . Expression quantitative trait loci mapping and functional genomics approaches were used to infer mechanistic consequences of implicated variants.Our cohort contained 155 154 individuals (3132 IA cases and 152 022 controls). We identified 4 genetic loci reaching genome-wide: rs73392700 ( SIRT3 , effect size = 0.28, P = 4.3 × 10 -12 ), rs58721068 ( EDNRA , effect size = -0.20, P = 4.8 × 10 -12 ), rs4977574 ( AL359922.1 , effect size = 0.18, P = 7.9 × 10 -12 ), and rs11105337 ( ATP2B1 , effect size = -0.15, P = 3.4 × 10 -8 ). Expression quantitative trait loci mapping suggests that rs73392700 has a large effect size on SIRT3 gene expression in arterial and muscle, but not neurological, tissues. Functional genomics analysis suggests that rs73392700 causes decreased SIRT3 gene expression.We perform a multinational GWAS of IA and identify 4 genetic risk loci, including 2 novel IA risk loci ( SIRT3 and AL359922.1 ). Identification of high-risk genetic loci across ancestries will enable population-genetic screening approaches to identify patients with IA.