Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Abstract

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

Polygenic Risk in Families With Spontaneous Coronary Artery Dissection

“…Elevated polygenic risk in those with familial disease vs controls has been reported in many complex diseases; notably, in this study, almost half of all affected family members scored in the top quintile of control scores. This is in line with our recent finding that the common variant heritability of SCAD is high in individuals with sporadic SCAD . In other complex conditions, it has been proposed that a high PRS confers an OR for disease that is comparable with a single rare pathogenic variant .…”

“…To address this, we created 1000 seven-SNV scores using the height PRS, and very rarely across the following 1000 analyses did we identify results of the magnitude reported for the SCAD PRS. Ideally, a larger, more sophisticated PRS created from a larger SCAD genome-wide association study would be used; however, due to sample overlap between this study and the current largest SCAD genome-wide association study, this is not currently possible. While the main conclusions were robust in all scenarios, validation of these results with larger independent cohorts and more sophisticated SCAD PRS remains important.…”

“…A total of 1352 individuals were genotyped, either by whole-genome sequencing (WGS) or UK Biobank Axiom array. This data set consisted of 1127 older healthy controls of European ancestry, as described previously, 173 individuals with sporadic SCAD, and 13 families with SCAD, which included 27 affected individuals (with all families contributing at least 2 cases) and 18 SCAD-free relatives. The final 7 individuals represented an additional 2 unrelated individuals with sporadic SCAD and 5 of their first-degree relatives.…”

“…In the last 5 years, our understanding of SCAD genetics has developed rapidly. Beginning in 2019, common variants were identified, and the first polygenic risk score (PRS) for SCAD was reported . Multiple studies have found rare, potentially pathogenic variants in genes associated with vasculopathies or connective tissue disorders (CTDs) in up to 13% of individuals with sporadic SCAD .…”

Using Genomics to Identify Novel Therapeutic Targets for Aortic Disease

“…63 A recent GWAS for spontaneous coronary artery dissection found that risk variants were disproportionately enriched within open chromatin regions in VSMCs and fibroblasts. 64 Similar experiments in aortic cell lines and human tissues undoubtedly have the potential to offer fresh insights into the epigenomic landscape of aortic disease.…”