Group Name

On behalf of the International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group

Background And Aims

There is currently no clinically relevant risk model for intracranial aneurysms (IA), and phenotypic heterogeneity makes assessing risk of rupture of an IA difficult. Recently, we performed the largest genome-wide association study (GWAS) of IA and subarachnoid hemorrhage (SAH) and explained over half of the genetic contribution to IA. How this genetic risk precisely relates to aneurysm characteristics and rupture risk is still unclear.

Methods

We constructed a genetic risk score (GRS) for IA, by using GWAS summary statistics for IA and its risk factors: a metaGRS. The metaGRS was trained using UK Biobank genotype data and IA status.

In the largest cohort of patients with an IA and with detailed phenotypic information (N=5,560), we associated the metaGRS with aneurysm location, multiplicity, family history, rupture, location, age- and size at rupture. Associations were tested by linear regression, using sex and cohort as covariates.

Results

Persons with an IA that ruptured at a younger age had an increased genetic risk (P=1.82e-8), while persons with an aneurysm at the internal carotid artery had a lower genetic risk (P=0.0041). A nominally significantly higher genetic risk was found in persons with multiple aneurysms versus one aneurysm (P=0.010). All of these effects were independent of smoking and hypertension status.

Conclusions

We found a strong link between genetic risk of IA and IA characteristics. Understanding what drives phenotypic heterogeneity, and using genetic risk scores to identify persons at risk, could have a substantial impact on monitoring IA and preventing SAH.

Trial Registration Number

Not applicable