Genetic associations of protein-coding variants in venous thromboembolism

Xiao-Yu He; Bang-Sheng Wu; Liu Yang; Yu Guo; Yue-Ting Deng; Ze-Yu Li; Chen-Jie Fei; Wei-Shi Liu; Yi-Jun Ge; Jujiao Kang; Jianfeng Feng; Wei Cheng; Qiang Dong; Jin-Tai Yu

doi:10.1038/s41467-024-47178-8

Genetic associations of protein-coding variants in venous thromboembolism

Nat Commun. 2024 Apr 1;15(1):2819. doi: 10.1038/s41467-024-47178-8.

Authors

Xiao-Yu He^#¹, Bang-Sheng Wu^#¹, Liu Yang^#¹, Yu Guo^#¹, Yue-Ting Deng^#¹, Ze-Yu Li², Chen-Jie Fei¹, Wei-Shi Liu¹, Yi-Jun Ge¹, Jujiao Kang², Jianfeng Feng^{2

3

4}, Wei Cheng^{5

6

7

8}, Qiang Dong⁹, Jin-Tai Yu¹⁰

Affiliations

¹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
² Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
³ Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China.
⁴ Department of Computer Science, University of Warwick, Coventry, UK.
⁵ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. wcheng@fudan.edu.cn.
⁶ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China. wcheng@fudan.edu.cn.
⁷ Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China. wcheng@fudan.edu.cn.
⁸ Department of Computer Science, University of Warwick, Coventry, UK. wcheng@fudan.edu.cn.
⁹ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. dong_qiang@fudan.edu.cn.
¹⁰ Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China. jintai_yu@fudan.edu.cn.

^# Contributed equally.

Abstract

Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

MeSH terms

Blood Coagulation Factors / genetics
Exome
Genome-Wide Association Study
Humans
Phosphoproteins / genetics
Risk Factors
Serine-Arginine Splicing Factors / genetics
Venous Thromboembolism* / genetics

Substances

Blood Coagulation Factors
SRSF6 protein, human
Serine-Arginine Splicing Factors
Phosphoproteins