Abstract 11949: Disease-Specific and Comorbidity-Related Polygenic Risk in Spontaneous Coronary Artery Dissection

Abstract

Introduction: Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome that typically affects younger women (24-52 years). Several comorbidities have now been reported, including migraine, fibromuscular dysplasia (FMD), connective tissue disorders, anxiety, and depression. Associations between SCAD and other conditions, such as autoimmune disorders, have been reported but remain contentious. SCAD is known to have a genetic element: both common and rare variants have been associated with the disease and familial clustering has been identified. However, the genetic etiology is not well resolved although common variants have been identified between SCAD, FMD, and migraine. Aims: We sought to determine if there is a polygenic disease burden of common genetic variation in a cohort of sporadic SCAD cases, and shared genetics between SCAD and reported comorbidities via the application of polygenic risk scores (PRSs) for these comorbidities. Methods: A cohort of 173 sporadic European SCAD cases and 1314 European controls were genotyped (88 cases, 1127 healthy elderly controls and 76 non-SCAD cardiomyopathy-diseased patients by whole genome sequencing; 85 cases and 111 controls by Axiom UK Biobank and PMDA array, respectively). Differences in genetic risk was assessed for cases and controls using established PRS, specific to either SCAD or conditions reported to be comorbid. Results: SCAD cases showed significantly higher SCAD-PRS than did controls (WGS p = 1.372e-09; array p = 5.264e-05). In contrast, there were no differences in SCAD-PRS between non-SCAD patients and controls (WGS only: p-value = 0.291) and non-SCAD patients also had lower risk than SCAD cases (WGS only: p-value = 2.08e-07). Multiple PRS derived from comorbid disorders are currently being investigated in this cohort. Conclusions: We have shown that there is a common genetic risk element to SCAD, while genetic risk for, and, therefore, genetic overlap with, reported comorbidities in SCAD will be further discussed. These findings illustrate the role of common variants in SCAD etiology and may further contribute to our understanding of the mechanisms leading to SCAD formation.