Ancestry-Specific Genome-Wide Association Analyses Identify Shared and Unique Genetic Architecture for Venous Thrombosis in the Han Chinese Population

Background: Venous thromboembolism (VTE) is a complex disease caused by both genetic and environmental risk factors. Although genetic determinants are known to be associated with VTE for individuals with European (EUR) ancestry, a large proportion of the VTE heritability remains unexplained, particularly the genetic architecture of VTE in the East Asian (EAS) population. Findings: We identified three independent genetic loci (FGG, ABO, AKAP12) associated with VTE from GWAS analysis, where AKAP12 is novel. TWAS further identified six (LRAT , KLKB1, GGT7, GSS, EDEM2 and PROCR) independent regulatory signals, of which three are associated with coagulation functions, and three are novel genes with metabolic functions (LRAT, GGT7, GSS). There are shared genetic effects of common variants between Han Chinese and EUR populations (genetic correlation = 0.93 ± 0.27). The individuals with the top 10% polygenic risk score had over three-fold increased risk for VTE relative to the general Han Chinese population. Interpretation: Our results suggest both shared and unique genetic characteristics of VTE between EAS and EUR populations. We identified novel loci suggesting the involvement of metabolic pathways in VTE occurrence in the Han Chinese population. Funding Information: The National Key Research and Development Program of China (No. 2016YFC0905600) National Natural Science Foundation of China (No. 81570049; 81970058); Beijing Natural Science Foundation (No.7152062). Declaration of Interests: Authors report no relevant conflicts of interest. Ethics Approval Statement: This study was conducted under the human and ethical research principles of The Ministry of Science and Technology, People's Republic of China (Regulation of the Administration of Human Genetic Resources, July 1, 2019). All the participants provided informed consent and agreed to participate in this research under a protocol approved by the Ethical Committee of China-Japan Friendship Hospital (Cases) and WeGene (Controls). The study's ethical approval was obtained from the Ethics Committee in China-Japan Friendship Hospital (2016-SSW-7).