A Genetic Risk Factor for Intracranial Aneurysm Rupture

Abdullah Hashmi, MD

April 27, 2022

The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

  • The study identified five independent genetic loci with genome-wide significance for intracranial aneurysm rupture (rIA). Among these, a novel locus, FGD6, was identified that had not been previously implicated in rIA biology.

  • Gene burden analysis and functional characterization indicated that genetic variation in the FGD6 locus contributes to rIA risk with decreased expression in arterial tissue.

  • Single-cell RNA sequencing analysis of endothelial and perivascular cells showed FGD6 expression in neurovascular cells where alterations in FGD6 altered cell identity and function.

Why This Matters

  • The study used functional genomics to uncover genetic determinants of risk for rIA. A strong genetic component is thought to be involved in intracranial aneurysm (IA). The results from the study have uncovered previously unknown genetic loci to aid in disease prevention, diagnosis, and treatment.

  • This study used unbiased genome-wide approaches to understand genetic determinants of IA pathophysiology and rupture risk.

  • The study identified and characterized a previously unknown risk locus for rIA.

Study Design

  • The Cerebrovascular Disease Knowledge Portal was used to obtain a cohort of 84,353 individuals from 24 published genome-wide association studies (GWASs). Of these, 7843 had rIA, and 76,510 were control patients. Participants were of European or East Asian descent.

  • The study used functional genomics and gene-burden analysis and analyzed data for single-nucleotide polymorphisms (SNPs) to characterize genetic risk factors.

Key Results

  • The GWAS analysis identified five independent genetic loci of significance for rIA. These included CDKN2B, EDNRA, RBBP8, RP1, and FDG6. Among these, the FGD6 locus had not been previously implicated as a risk factor.

  • Gene-level mutational burden was determined using SNP analysis. It revealed that FGD6 was associated with 21 SNPs and reached transcriptome-wide importance.

  • Quantitative trait loci expression mapping revealed that rs12310399 causes decreased FGD6 expression in arterial tissue.

  • Single-cell RNA sequencing of normal human cerebrovascular cells identified high expression of FGD6 in 1 of 3 arterial lineages. FGD6 has been shown to play a role in regulating angiogenesis and actin cytoskeleton rearrangement.

Limitations

  • It was not possible to include rare variants in the array-based GWASs.

Disclosures

  • The study received no commercial funding.

  • The authors have disclosed no relevant financial relationships.

This is a summary of a preprint research study, "Integrative Genomics Analysis Implicates Decreased FGD6 Expression Underlying Risk of Intracranial Aneurysm Rupture," written by researchers at Department of Neuroscience, the University of Alabama–Birmingham, and the Department of Medical Bioinformatics, Vanderbilt University Medical Center, Nashville, Tennessee, published on medRxiv and provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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