AbstractSpontaneous 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.