Intracranial aneurysm risk genes newly identified through GWAS reveal an anti-atherosclerotic phenotype
International Aneurysm Genetics Consortium, Murat Gunel, Katsuhito Yasuno
Introduction: Intracranial aneurysm (IA), and subsequent aSAH are multifactorial disorders. Besides environmental risk factors, genetic variations are associated with IA. To date, genome-wide association (GWA) studies of IA have identified common variants in seven genetic loci to be associated with IA risk, revealing novel risk genes, such as SOX17 and EDNRA.
Objective: We hypothesized that further discoveries of IA risk genes through GWA studies would promote our mechanistic understanding of the molecular basis of IA.
Methods: We conducted largest to date multi-ancestry genome-wide association meta-analysis of saccular intracranial aneurysm (IA) with independent replication, using a total of 7,267 IA cases and 22,994 controls, across 8.7 million variants throughout the autosomal genome. We tested heterogeneous genetic architectures associated with known risk factors, like smoking. We identified colocalized loci between IA and other traits and performed colocalization analysis of the trait-associated variants with cis-expression quantitative trait loci (cis-eQTL).
Results: We report a total of 44 IA risk loci, which represents a near-exhaustive list of common IA risk variants. These include eight novel as well as seven previously identified IA loci and 29 others, identified by two-trait colocalization. Surprisingly, the effect directions of some of the IA risk loci were opposite to that of atherosclerosis risk, implying an “anti-atherosclerotic” molecular mechanism.
Conclusions: We discovered a novel anti-atherosclerotic (anti-migratory, anti-proliferative and anti-inflammatory) phenotype of vascular smooth muscle and endothelial cells, which confer significant risk for IA formation. These findings for the first time define an intermediate aneurysmal vascular cell phenotype with a unique genomic pattern, which can now serve as the basis of future biologic studies to define novel treatments for IA.