Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction
Jacqueline Saw, Min‐Lee Yang, Mark Trinder, Catherine Tcheandjieu, Chang Xu, Andrew Starovoytov, Isabelle Birt, Michael R. Mathis, Kristina L. Hunker, Ellen M. Schmidt, Linda Jackson, Natalia Fendrikova-Mahlay, Matthew Zawistowski, Chad M. Brummett, Sebastian Zoellner, Alexander Katz, Dawn M. Coleman, Kirby Swan, Christopher J. O’Donnell, Million Veteran Program, Themistocles L. Assimes, Christopher J. O’Donnell, Xiang Zhou, Jun Z. Li, Heather L. Gornik, Themistocles L. Assimes, James C. Stanley, Liam R. Brunham, Santhi K. Ganesh
Abstract
Abstract Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (N cases = 270/N controls = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 ( P discovery+replication = 2.19 × 10 −12 , OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10 −8 at chromosome 6p24.1 in PHACTR1 , chromosome 12q13.3 in LRP1 , and in females-only, at chromosome 21q22.11 near LINC00310 . A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia ( P = 0.021, OR = 1.82 [95% CI: 1.09–3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank ( P = 1.28 × 10 −17 , HR = 0.91 [95% CI :0.89–0.93], for MI) and Million Veteran Program ( P = 9.33 × 10 −36 , OR = 0.95 [95% CI: 0.94–0.96], for CAD; P = 3.35 × 10 −6 , OR = 0.96 [95% CI: 0.95–0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.