Multi-trait and Gene-Based Analyses Identify Genetic Variants Associated with Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of acute myocardial infarction (MI) that predominantly affects young women. As an under-recognized cause of MI, large genome-wide association studies (GWAS) remain challenging. We aimed to leverage SCAD shared genetic basis with related vascular diseases to uncover genetically determined biological mechanisms.

Summary statistics for SCAD GWAS (1,917 cases, 9,293 controls) was harmonised with seven related vascular traits: fibromuscular dysplasia, intracranial aneurysm, cervical artery dissection, migraine, coronary artery disease, abdominal aortic aneurysm, and thoracic aortic aneurysm/dissection. We applied Multi-Trait Analysis of GWAS (MTAG). We integrated coronary-artery regulatory annotations, cis-eQTL mapping, and colocalization to prioritize candidate genes. Gene-based testing (LDAK-GBAT) was applied to SCAD dataset.

MTAG identified 40 independent SCAD loci, including 24 that were novel. Candidate variants were enriched in open chromatin from coronary smooth muscle cells and fibroblasts and in vascular regulatory regions. LDAK-GBAT identified 46 significant genes, including 12 outside MTAG loci. Integrated functional annotation prioritized 56 genes linked to arterial integrity, vasoactive tone, haemostasis, and coagulation. Extracellular matrix organization was confirmed as a key pathway, with additional enrichment in bone mineralization and TGF-β related terms.

Integrating multi-trait GWAS, gene-based testing, epigenetic and transcriptomic data substantially expanded the SCAD genetic landscape. Our findings implicate key arterial-wall pathways beyond extracellular matrix organization, and point at relevant biological mechanisms in non-atherosclerotic dissection. These findings nominate tractable targets for experimental follow-up and support future efforts toward SCAD risk stratification in women.