ABSTRACT NUMBER: ESOC2026A2182 SHARED GENETIC ARCHITECTURE OF CERVICAL ARTERY DISSECTION AND INTRACRANIAL ANEURYSM ACROSS NON-SYNDROMIC ARTERIOPATHIES

Abstract Background and aims Dissections and aneurysms frequently occur in individuals without vascular risk factors and can involve multiple arterial territories in the absence of recognized connective tissue disorders. This pattern suggests shared biological susceptibility across anatomically distinct arteriopathies, potentially driven by common genetic mechanisms. Methods We investigated the shared genetic architecture of five arteriopathies: cervical artery dissection (CeAD), intracranial aneurysm (IA), spontaneous coronary artery dissection (SCAD), aortic aneurysm (AA), and fibromuscular dysplasia (FMD), using multi-trait analysis of genome-wide association studies (MTAG) across all traits, followed by cross-platform proteome and transcriptome-wide Mendelian randomization (MR) to prioritize candidate causal loci (Figure 1). Results We identified positive genetic correlations for CeAD with SCAD and AA, and for IA with SCAD and AA (Figure 2). MTAG identified 71 lead variants, with CDKN2B shared across all traits (Figure 3). Four novel loci were prioritized for CeAD (CDKN2B, SNX13, TGFB3, KCNE2), one for IA (FGF5), three for SCAD (ANP32E, CDKN2B, EDNRA), four for FMD (ECM1, SLC22A5, EDNRA, ATF1), and two for AA. Several loci demonstrated strong cross-trait colocalisation, including PHACTR1 and LRP1. Proteome-wide MR identified 67 proteins associated with at least one trait, including ECM1 and SHISA5 for CeAD and FGF5 for IA, with 46 supported by colocalisation. Transcriptome-wide MR identified vascular tissue–specific associations across all traits, including PHACTR1 and LRP1 for CeAD. Enrichment analyses implicated vascular development, smooth muscle function, and vessel wall integrity pathways. Conclusions These findings support shared genetic architecture across five arteriopathies, implicating pathways in vascular structure and integrity and prioritizing targets for mechanistic and translational follow-up. Conflict of interest Stephen Brennan: nothing to disclose. Alexander Tinworth: nothing to disclose. Iyas Daghlas: nothing to disclose. Quentin Le Grand: nothing to disclose. Stephanie Debette: nothing to disclose. Peter Kelly: nothing to disclose. John McCabe: nothing to disclose. Figure 1 - belongs to Methods Figure 2 - belongs to Results Figure 3 - belongs to Conclusions