Contribution of leukocyte telomere length to cardiovascular disease onset from genome-wide cross-trait analysis
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.
Authors
- Siim Pauklin (ORCID: https://orcid.org/0000-0001-8367-3670)
- Rongjun Zou (ORCID: https://orcid.org/0000-0003-1981-5472)
- Jun Qiao (ORCID: https://orcid.org/0000-0001-7038-4538)
- Miaoran Chen
- Minjing Chang (ORCID: https://orcid.org/0000-0001-8875-9254)
- Lei Jiang (ORCID: https://orcid.org/0000-0002-3505-4020)
- P Zhang
- Shuo Sun (ORCID: https://orcid.org/0000-0003-3812-583X)
- Anil Goud Jegga (ORCID: https://orcid.org/0000-0002-4881-7752)
- Yuhui Zhao (ORCID: https://orcid.org/0000-0002-1362-8791)
- Kaixin Yao (ORCID: https://orcid.org/0009-0002-7874-8564)
- Xiaolong Xing
- Qian Wang (ORCID: https://orcid.org/0009-0009-5004-9148)
- Yuliang Feng (ORCID: https://orcid.org/0000-0002-7997-163X)
- Leilei Zheng (ORCID: https://orcid.org/0000-0002-9238-7681)
- Yining Yang
- Liuyang Cai
Institutions
- Shanxi Medical University (CN)
- State Administration of Traditional Chinese Medicine of the People's Republic of China (CN)
- Nuffield Orthopaedic Centre (GB)
- Southern University of Science and Technology (CN)
- University of Oxford (GB)
- Xinjiang Uygur Autonomous Region Product Quality Supervision and Inspection Institute (CN)
- Key Laboratory of Guangdong Province (CN)
- Guangdong Provincial Hospital of Traditional Chinese Medicine (CN)
- People's Hospital of Xinjiang Uygur Autonomous Region (CN)
- Second Hospital of Shanxi Medical University (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-30
- DOI
- https://doi.org/10.1038/s41467-025-63707-5
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00