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

Abstract

Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute 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). Through a meta-analysis of genome-wide association studies including 1917 cases and 9292 controls of European ancestry, we identified 17 risk loci, including 12 new, with odds ratios ranging from 2.04 (95%CI 1.77-2.35) on chr21 to 1.25 (95%CI 1.16-1.35) on chr4. A locus on chr1 containing the tissue factor gene (F3), which is involved in blood coagulation cascade, appears to be specific for SCAD risk. Prioritized genes were mainly expressed in vascular smooth muscle cells and fibroblasts of arteries and are implicated predominantly in extracellular matrix biology (e.g. COL4A1/A2, HTRA1 and TIMP3). We found that several variants associated with SCAD had diametrically opposite associations with CAD suggesting that shared biological processes contribute to both diseases but through different mechanisms. We also demonstrated an inferred causal role for high blood pressure, but not other CAD risk factors, 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 prevention for this disease.

Dissecting the Genomics of Spontaneous Coronary Artery Dissection

“…The work presented by Tarr et al 16 in this Journal on the genetic architecture of SCAD has revealed novel insight into the rare monogenic and common polygenic underpinnings of this disease (Figure ). This report is an important addition of recent work in this area from wholeexome sequencing 17 and GWAS studies [10][11][12][13] which highlight the importance of genetic mechanisms influencing the onset of SCAD. With their report of ≈20% of patients with actionable genetic findings, it raises the important question on if genetic testing for SCAD should be integrated in the clinical practice.…”

“…In a series of GWAS studies in SCAD, 5 regions of the genome had been identified to meet genome-wide significance including 1q21.2 (C1orf51), 10,11 6p24.1 (PHACTR1/EDN1), [10][11][12] 12q13.3 (LRP1), 10,11 15q21.1 (FBN1), 11 and 21q22.11 (LINC00310). 10,11 This list of 5 loci has just recently been expanded in a new preprint, where Adlam et al 13 have revealed a meta-analysis of SCAD GWAS revealing 12 new loci, making a total of 17 loci to meet genome-wide significance for SCAD. Indeed, further population level genetic analysis with a polygenic risk score has confirmed that there are opposing genetic mechanisms between SCAD-related MI and atherosclerotic MI.…”

“…Indeed, further population level genetic analysis with a polygenic risk score has confirmed that there are opposing genetic mechanisms between SCAD-related MI and atherosclerotic MI. 10,13 However, the complex disease genetics of SCAD appears limited and increasing reports of SCAD associated with heritable connective tissue disorders (CTDs) 14 and multigenerational family pedigrees with SCAD 15 further suggests an underappreciated rare disease genetics component to this condition.…”

Complex Genetic Architecture of Spontaneous Coronary Artery Dissection

“…Remarkably, hazard ratios (HRs) for this SCAD PRS are roughly similar to contemporary CAD PRS including millions of variants from genome-wide association studies with a few hundred associated gene regions. This may be expected as the HRs for all individually significant common variants for SCAD from only approximately 2000 cases to date are of larger effect sizes than all of those for CAD from approximately 200 000 cases . Of note, the current study did not use the latest SCAD genome-wide association study to prevent overfitting as the present study participants were included in that discovery study.…”

Genetic Testing in High-risk Spontaneous Coronary Artery Dissection—Searching for Clinical Utility Among Background Genetic Noise

“…As such, monogenic/mendelian inheritance in SCAD appears to be the exception rather than the rule . Instead, the underlying genetic susceptibility to SCAD likely arises secondary to oligogenic or polygenic inheritance caused by an increased burden of relatively common genetic variants, including 17 genetic loci identified via genome-wide association studies (GWAS) and a recent GWAS meta-analysis . As a result of the (1) low yield of pathogenic/likely pathogenic (P/LP) variants in CTD/arteriopathy-susceptibility genes and (2) potential danger of overinterpreting ambiguous variants of uncertain significance (VUS) in individuals without an extracoronary CTD/arteriopathy phenotype, the current consensus is to reserve genetic testing in SCAD for those cases where there is reasonable clinical suspicion for an underlying inherited CTD/arteriopathy …”