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

Abstract

Importance: 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. Design: We perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. Setting: We perform a meta-analysis across 24 published GWAS of rIA. Participants: Our cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). Main Outcome and Measure: Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. Results: 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 (r)IA. 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. Single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery identified high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. Patients with a Mendelian disease caused by FGD6 mutations (Aarskog-Scott syndrome) have been diagnosed with rIA, among other features, providing direct causal evidence for FGD6 in rIA pathogenesis. Conclusions and Relevance: We identify and characterize a previously unknown risk loci for rIA containing FGD6. Variable expressivity of FDG6 causes a range of clinical features from Mendelian disease to sporadic rIA. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA.