Integrative Genomics Analysis Implicates Decreased FGD6 Expression Underlying Risk of Intracranial Aneurysm Rupture

BACKGROUND: The 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. OBJECTIVE: To identify and characterize the genetic basis of rIA. METHODS: We perform a genome-wide association study (GWAS) using 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, gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. RESULTS: Our cohort contains 84 353 individuals (7843 rIA cases and 76 510 controls). We identify 5 independent genetic loci reaching genome-wide significance ( P < 5.0 × 10 −8 ) for rIA including rs12310399 ( FGD6 , odds ratio = 1.16), which has been implicated in prior GWAS of IA. We then quantified gene-level mutation burden across ∼20 000 genes, and only FGD6 (containing 21 rIA-associated single nucleotide polymorphisms) reached transcriptome-wide significance. Expression quantitative trait loci mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Next, we used 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. CONCLUSION: We identify and characterize a known risk loci for IA, but not 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.