ABSTRACT NUMBER: ESOC2026A159 GENOME-WIDE ASSOCIATION STUDY OF INTRACRANIAL ANEURYSMS REVEALS 60 RISK LOCI AND MARKED SEX-SPECIFICITY

Abstract Background and aims Intracranial aneurysms (IA) are more common in women and are strongly influenced by genetic factors. Previous genome-wide association studies (GWAS) uncovered 22 genetic risk loci, yet the genetic mechanisms underlying IA, and their sex-specific contribution remains largely unknown. To elucidate the genetic underpinnings of IA, we conducted a new GWAS. Methods We performed a GWAS including 40,427 IA cases (ruptured and unruptured) and 2,898,910 controls from European and East-Asian ancestry. Comprehensive downstream analyses included pathway analysis, cell-type enrichment, Mendelian randomization, drug target identification and sex-specific genetic architecture analysis, aiming to characterize the biological mechanisms, identify modifiable risk factors, identify potential drug targets, and delineate sex-specific aspects of IA susceptibility. Results We uncovered 60 risk loci, including 39 novel loci, which we pinpointed to 68 risk genes (See figure). No loci were found on the X-chromosome. Sex-stratified analyses showed female-only GWASs yielded substantially more risk loci than equally sized male GWASs. Pathways related to developmental processes were identified, with several demonstrating sex-specificity. Vascular endothelial and smooth muscle cells showed significant and sex-specific enrichment. Furthermore, we provide genetic evidence for several drug classes with repurposing potential. Conclusions We nearly tripled the number of genetic risk loci for IAs to 60. Our findings provide insights into novel risk genes and pathways, cell-type contributions, and potential drug targets, and offer new perspectives on the sex-specific genetic architecture of IA, highlighting widespread genetic differences between men and women. Conflict of interest Qi Chang Lin: nothing to disclose. Dennis Maas: nothing to disclose. Mark Bakker: nothing to disclose. Ynte Ruigrok: nothing to disclose. Figure 1 - belongs to Results