Contribution of leukocyte telomere length to cardiovascular disease onset from genome-wide cross-trait analysis

Jun Qiao, Qian Wang, Yuhui Zhao, Minjing Chang, Shuo Sun, Pengwei Zhang, Kaixin Yao, Miaoran Chen, Leilei Zheng, Xiaolong Xing, Liuyang Cai, Anil G. Jegga, Lei Jiang (), Siim Pauklin (), Rongjun Zou (), Yining Yang () and Yuliang Feng ()
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Jun Qiao: Southern University of Science and Technology
Qian Wang: The Fifth Clinical Medical College of Shanxi Medical University
Yuhui Zhao: Second Hospital of Shanxi Medical University
Minjing Chang: Southern University of Science and Technology
Shuo Sun: Southern Medical University
Pengwei Zhang: Southern University of Science and Technology
Kaixin Yao: Second Hospital of Shanxi Medical University
Miaoran Chen: Second Hospital of Shanxi Medical University
Leilei Zheng: Second Hospital of Shanxi Medical University
Xiaolong Xing: Second Hospital of Shanxi Medical University
Liuyang Cai: Southern University of Science and Technology
Anil G. Jegga: University of Cincinnati College of Medicine
Lei Jiang: Southern Medical University
Siim Pauklin: Headington
Rongjun Zou: Guangdong Provincial Hospital of Chinese Medicine
Yining Yang: People’s Hospital of Xinjiang Uygur Autonomous Region
Yuliang Feng: Southern University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Telomere shortening is a well-established marker of cellular aging and genomic instability. While the relationship between leukocyte telomere length and cardiovascular diseases has long been of interest, their genetic interplay remains incompletely understood. In this study, we observe substantial genetic overlap beyond genome-wide correlations and identify a potential causal relationship between leukocyte telomere length and coronary artery disease. Specifically, we discover 248 pleiotropic loci, 22 of which show strong evidence of colocalization. Some shared loci implicate multiple pleiotropic genes across different trait pairs, including ALDH2, ACAD10, TMEM116, SH2B3 (all at 12q24.12), TMED6 (16q22.1), SERPINF1 (17p13.3), and XPO7 (8p21.3). Functional analysis highlights key pathways involved in DNA biosynthesis and telomere maintenance. Notably, SH2B3 is validated through proteome-wide Mendelian randomization analysis, suggesting its potential as a therapeutic target. Here we report the shared genetic basis between leukocyte telomere length and cardiovascular diseases, providing valuable insights into future therapeutic developments.

Date: 2025
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DOI: 10.1038/s41467-025-63707-5

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