Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications

外显子组测序 生物 端粒 遗传学 外显子组 基因 等位基因 生命银行 表型 全基因组关联研究 基因型 单核苷酸多态性
作者
Weishi Liu,Bang‐Sheng Wu,Yang Liu,Shi-Dong Chen,Ya-Ru Zhang,Yue‐Ting Deng,Xinrui Wu,Xiao‐Yu He,Jing Yang,Jianfeng Feng,Wei Cheng,Yuming Xu,Jin‐Tai Yu
出处
期刊:GeroScience [Springer International Publishing]
卷期号:46 (5): 5365-5385
标识
DOI:10.1007/s11357-024-01203-2
摘要

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.
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