Dissecting the Genetic Architecture of Intracranial Aneurysms

Area of Science:

• Genetics
• Cardiovascular Research
• Neuroscience

Background:

• Intracranial aneurysm (IA) genetic risk is linked to smoking and hypertension.
• The relationship of IA to other cardiovascular conditions and its genetic basis in cerebrovascular cells is not well understood.

Purpose of the Study:

• To identify novel genetic risk loci for intracranial aneurysms (IA).
• To investigate the genetic correlation of IA with other cardiovascular diseases.
• To determine the specific cerebrovascular cell types and gene programs involved in IA pathogenesis.

Main Methods:

• Genome-wide association study (GWAS) in the Million Veteran Program and Finnish cohort.
• Meta-analysis of GWAS data including over 1.5 million individuals.
• Integration of IA genetic data with cerebrovascular single-nuclear RNA sequencing.
• Construction and validation of a polygenic risk score for IA.

Main Results:

• Identified 5 novel IA susceptibility loci, bringing the total to 22.
• Found significant genetic correlation between IA, coronary artery disease, and abdominal aortic aneurysm.
• Associated IA genetic risk with pericytes and smooth muscle cells in the cerebrovasculature.
• Validated a polygenic risk score significantly predicting IA across European, African, and Hispanic ancestries.

Conclusions:

• Discovered 5 new loci associated with intracranial aneurysms (IA).
• Highlighted the role of cerebrovascular cell types involved in matrix production.
• Validated a polygenic risk score for predicting IA, independent of smoking and blood pressure.
• Suggests matrix production deficits may be a key driver of IA pathogenesis.