Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

BackgroundThe genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the [~]50% mortality rate of rIA, approaches to identify patients at high-risk will inform screening, diagnostic, and preventative measures. ObjectiveOur goal was to identify and characterize the genetic basis of rIA. MethodsWe perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. We perform a meta-analysis across 24 published GWAS of rIA. Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. ResultsOur cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). We identify 5 independent genetic loci reaching genome-wide significance (p<5.0x10-8) for rIA including rs12310399 (FGD6, OR=1.16), which to our knowledge, has not been implicated in prior GWAS of rIA. We then quantified gene-level mutation-burden across [~]20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Expression quantitative trait loci (eQTL) mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Next, we utilized publicly available single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery and identify high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. These data suggest how alterations in FGD6 may confer risk to rIA. ConclusionWe identify and characterize a previously unknown risk loci for rIA containing FGD6. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA. FundingNo funding sources were used for the material presented herein.