Causal association and shared genetics between telomere length and COVID-19 outcomes: New evidence from the latest large-scale summary statistics

作者全名：Zhang, Jingwei; Wen, Jie; Dai, Ziyu; Zhang, Hao; Zhang, Nan; Lei, Ruoyan; Liu, Zhixiong; Peng, Luo; Cheng, Quan

作者地址：[Zhang, Jingwei; Wen, Jie; Dai, Ziyu; Liu, Zhixiong; Cheng, Quan] Cent South Univ, Xiangya Hosp, Dept Neurosurg, Changsha, Peoples R China; [Zhang, Jingwei; Wen, Jie; Dai, Ziyu; Liu, Zhixiong; Cheng, Quan] Cent South Univ, Xiangya Hosp, Hypothalam Pituitary Res Ctr, Changsha, Peoples R China; [Zhang, Jingwei; Wen, Jie; Dai, Ziyu; Liu, Zhixiong; Cheng, Quan] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China; [Zhang, Hao] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing, Peoples R China; [Zhang, Nan] Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Wuhan, Peoples R China; [Lei, Ruoyan] Cent South Univ, Xiangya Sch Publ Hlth, Changsha, Peoples R China; [Peng, Luo] Southern Med Univ, Zhujiang Hosp, Dept Oncol, Guangzhou, Peoples R China

通信作者：Liu, ZX; Cheng, Q (通讯作者)，Cent South Univ, Xiangya Hosp, Dept Neurosurg, Changsha, Peoples R China.; Liu, ZX; Cheng, Q (通讯作者)，Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Changsha, Peoples R China.; Peng, L (通讯作者)，Southern Med Univ, Zhujiang Hosp, Dept Oncol, Guangzhou, Peoples R China.

来源：COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001249318500001

JCR分区：Q2

影响因子：4.4

年份：2024

卷号：23

期号：　

开始页：2429

结束页：2441

文献类型：Article

关键词：Telomere length; COVID-19; Mendelian randomization; Genetic correlation; Mediation analysis

摘要：Background: Observational studies suggested that leukocyte telomere length (LTL) is shortened in COVID-19 patients. However, the genetic association and causality remained unknown. Methods: Based on the genome-wide association of LTL (N = 472,174) and COVID-19 phenotypes (N = 1086,211-2597,856), LDSC and SUPERGNOVA were used to estimate the genetic correlation. Cross-trait GWAS meta-analysis, colocalization, fine-mapping analysis, and transcriptome-wide association study were conducted to explore the shared genetic etiology. Mendelian randomization (MR) was utilized to infer the causality. Upstream and downstream two-step MR was performed to investigate the potential mediating effects. Results: LDSC identified a significant genetic association between LTL and all COVID-19 phenotypes (rG < 0, p < 0.05). Six significant regions were observed for LTL and COVID-19 susceptibility and hospitalization, respectively. Colocalization analysis found rs144204502, rs34517439, and rs56255908 were shared causal variants between LTL and COVID-19 phenotypes. Numerous biological pathways associated with LTL and COVID-19 outcomes were identified, mainly involved in -immune-related pathways. MR showed that longer LTL was significantly associated with a lower risk of COVID-19 severity (OR [95% CI] = 0.81 [0.71-0.92], p = 1.24 x103) and suggestively associated with lower risks of COVID-19 susceptibility (OR [95% CI] = 0.96 [0.92-1.00], p = 3.44 x10-2) and COVID-19 hospitalization (OR [95% CI] = 0.89 [0.80-0.98], p = 1.89 x10-2). LTL partially mediated the effects of BMI, smoking, and education on COVID-19 outcomes. Furthermore, six proteins partially mediated the causality of LTL on COVID-19 outcomes, including BNDF, QPCT, FAS, MPO, SFTPB, and APOF. Conclusions: Our findings suggested that shorter LTL was genetically associated with a higher risk of COVID-19 phenotypes, with shared genetic etiology and potential causality.

基金机构：Hunan Youth Science and Technology Talent Project [2023RC3074]; Natural Science Foundation of Hunan Province [2023JJ30971]

基金资助正文：This research was funded by the Hunan Youth Science and Technology Talent Project (NO.2023RC3074) and the Natural Science Foundation of Hunan Province (NO. 2023JJ30971)