Linear and non-linear proteome-wide association studies provide novel insight into venous thromboembolism

Yifan Kong, Wangxia Tang, Haonan Kang, Yunlong Guan, Si Li, Xi Cao, Zhonghe Shao, Yi Jiang (), Chaolong Wang () and Xingjie Hao ()
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Yifan Kong: Huazhong University of Science and Technology
Wangxia Tang: Huazhong University of Science and Technology
Haonan Kang: Huazhong University of Science and Technology
Yunlong Guan: Huazhong University of Science and Technology
Si Li: Huazhong University of Science and Technology
Xi Cao: Huazhong University of Science and Technology
Zhonghe Shao: Huazhong University of Science and Technology
Yi Jiang: Huazhong University of Science and Technology
Chaolong Wang: Huazhong University of Science and Technology
Xingjie Hao: Huazhong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Venous thromboembolism is a life-threatening vascular event with high prevalence and genetic determinants. PWAS has become a popular strategy to identify therapeutic targets of complex diseases. However, the current PWAS model only considers the linear relationship between protein and disease. Here, we propose a novel non-linear PWAS pipeline and identify 43 proteins exhibiting non-linear associations with venous thromboembolism in the UK Biobank, of which eight proteins cannot be captured by linear PWAS. We further conduct prospective cohort replication in the UK Biobank Pharma Proteomics Project, and replicate eight proteins with similar non-linear trends, including ULBP2, IL18BP, MAN1A2, CCL25, ICAM2, LGALS4, VSIG2 and ABO. Pathway enrichment analysis suggests that the identified non-linear proteins are involved in endothelium development, fluid shear stress and atherosclerosis pathways. In summary, we develop a novel non-linear PWAS analysis pipeline, and identify 43 non-linear proteins with venous thromboembolism, highlighting the importance of incorporating non-linear analysis in PWAS.

Date: 2025
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DOI: 10.1038/s41467-025-61874-z

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