Thoracic aortic dissection (TAD) without familial clustering or syndromic features is known as sporadic TAD (STAD). So far, the genetic basis of STAD remains unknown. Whole exome sequencing was performed in 223 STAD patients and 414 healthy controls from the Chinese Han population (N = 637). After population structure and genetic relationship and ancestry analyses, we used the optimal sequence kernel association test to identify the candidate genes or variants of STAD. We found that COL3A1 was significantly relevant to STAD (P = 7.35 x 10(-6)) after 10 000 times permutation test (P = 2.49 x 10(-3)). Moreover, another independent cohort, including 423 cases and 734 non-STAD subjects (N = 1157), replicated our results (P = 0.021). Further bioinformatics analysis showed that COL3A1 was highly expressed in dissected aortic tissues, and its expression was related to the extracellular matrix (ECM) pathway. Our study identified a profile of known heritable TAD genes in the Chinese STAD population and found that COL3A1 could increase the risk of STAD through the ECM pathway. We wanted to expand the knowledge of the genetic basis and pathology of STAD, which may further help in providing better genetic counseling to the patients.