163 Integrative Genomics Analysis Implicates Decreased FGD6 Expression Underlying Risk of Intracranial Aneurysm Rupture. (April 2023)

• Record Type: Journal Article
• Authors: Hale, Andrew T.; He, Jing; Jones, Jesse
• Is Part Of: Neurosurgery. Volume 69(2023)Supplement 1
• Page Start: 44
• Page End: 45
• Publication Date: 2023-04
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1227/neu.0000000000002375_163
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract : INTRODUCTION: The genetic determinants of intracranial aneurysm rupture (rIA) are largely unknown. To identify and characterize genetic risk factors for rIA, we perform a genome-wide association study (GWAS) containing 84, 353 individuals (7, 843 rIA cases and 76, 510 controls). We then use functional genomics approaches to delineate the mechanistic consequences of rIA risk loci. METHODS: We perform a meta-analysis across 24 published GWAS of rIA. Logistic regression was used to identify rIA-associated single nucleotide polymorphisms (SNPs). Gene-burden, expression quantitative trait loci (eQTL) mapping, and analysis of publicly-available single-cell RNA sequencing (scRNA-seq) data from normal human brain endothelial and perivascular cells was used to delineate cell-lineage expression of rIA-associated genes. RESULTS: We identify 5 independent genetic loci reaching genome-wide significance (p < 5.0 x 10 -8 ) for rIA: rs73392700 (CDKN2B, OR = 1.12), rs6841581 (EDNRA, OR = 0.77), rs11661542 (RBBP8, OR=0.84), rs62516550 (RP1, OR = 1.20), and rs12310399 (FGD6, OR = 1.16). FGD6, 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. Functional eQTL mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. scRNA-seq identified high expression of FGD6 in 1 of 3 arterial lineages, but absent in perivascular cells, identifying the likely cell-lineage underlying FGD6-mediated rIA risk. CONCLUSIONS: We perform the largest genetic study of rIA to date. We 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 enabling early treatment and improved patient outcomes.