BACKGROUND Spontaneous coronary artery dissection (SCAD) is defined as a splitting of the coronary artery wall exclusive of iatrogenesis or trauma. Since the last decades, our knowledge of the diagnosis and prognosis and therapy for SCAD has advanced; however, its causes remain unknown. OBJECTIVES This study sought to identify genes associated with SCAD development in the Chinese Han population. METHODS Between November 2011 and January 2018, the authors enrolled 85 SCAD cases and 296 non-SCAD controls from the Chinese Han population. All 381 subjects enrolled underwent detection with whole exome sequencing, followed by Sanger sequencing for confirmation. Principle component analysis was used to evaluate the structure of the population. Haploview was used to analyze the linkage disequilibrium statistics of the variants. The author used 2 gene-based association tests, optimal sequence kernel association test and mixed effects score test, to identify the causal genes or variants of SCAD. Immunohistochemistry was used to detect the expression of TSR1 in coronary artery tissues. RESULTS Four genes with a suggestive association with SCAD (p < 5.41 x 10(-5) in both the optimal sequence kernel association and mixed effects score tests) were identified, and TSR1 was the top hit. All TSR1 germline variants were either highly conserved across distinct species or lead to premature termination of protein syntheses. Furthermore, the expression of TSR1 was detectable in human coronary artery tissues. CONCLUSIONS This study describes the clinical characteristics of the Chinese Han population with SCAD and identified TSR1 as a potential causal gene, which might bring about a further progress in diagnosis and treatment of the disorder. (C) 2019 by the American College of Cardiology Foundation.