Unraveling the causal genes and transcriptomic determinants of human telomere length

Ying Chang, Yao Zhou, Junrui Zhou, Wen Li, Jiasong Cao, Yaqing Jing, Shan Zhang, Yongmei Shen, Qimei Lin, Xutong Fan, Hongxi Yang, Xiaobao Dong, Shijie Zhang, Xianfu Yi, Ling Shuai, Lei Shi, Zhe Liu, Jie Yang, Xin Ma, Jihui Hao, Kexin Chen, Mulin Jun Li (), Feng Wang () and Dandan Huang ()
Additional contact information
Ying Chang: Nankai University
Yao Zhou: Tianjin Medical University
Junrui Zhou: Tianjin Medical University
Wen Li: Nankai University
Jiasong Cao: Nankai University
Yaqing Jing: Tianjin Medical University
Shan Zhang: Tianjin Medical University
Yongmei Shen: Nankai University
Qimei Lin: Nankai University
Xutong Fan: Tianjin Medical University
Hongxi Yang: Tianjin Medical University
Xiaobao Dong: Tianjin Medical University
Shijie Zhang: Tianjin Medical University
Xianfu Yi: Tianjin Medical University
Ling Shuai: Nankai University
Lei Shi: Tianjin Medical University
Zhe Liu: Tianjin Medical University
Jie Yang: Tianjin Medical University
Xin Ma: Jiangnan University
Jihui Hao: Tianjin Medical University Cancer Institute and Hospital
Kexin Chen: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University
Mulin Jun Li: Tianjin Medical University
Feng Wang: Tianjin Medical University
Dandan Huang: Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Telomere length (TL) shortening is a pivotal indicator of biological aging and is associated with many human diseases. The genetic determinates of human TL have been widely investigated, however, most existing studies were conducted based on adult tissues which are heavily influenced by lifetime exposure. Based on the analyses of terminal restriction fragment (TRF) length of telomere, individual genotypes, and gene expressions on 166 healthy placental tissues, we systematically interrogate TL-modulated genes and their potential functions. We discover that the TL in the placenta is comparatively longer than in other adult tissues, but exhibiting an intra-tissue homogeneity. Trans-ancestral TL genome-wide association studies (GWASs) on 644,553 individuals identify 20 newly discovered genetic associations and provide increased polygenic determination of human TL. Next, we integrate the powerful TL GWAS with placental expression quantitative trait locus (eQTL) mapping to prioritize 23 likely causal genes, among which 4 are functionally validated, including MMUT, RRM1, KIAA1429, and YWHAZ. Finally, modeling transcriptomic signatures and TRF-based TL improve the prediction performance of human TL. This study deepens our understanding of causal genes and transcriptomic determinants of human TL, promoting the mechanistic research on fine-grained TL regulation.

Date: 2023
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DOI: 10.1038/s41467-023-44355-z

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