Tianjin Key Lab of Human Development and Reproductive Regulation, Tianjin Central Hospital of Obstetrics and Gynecology, Nankai University, Tianjin, China.
Department of Bioinformatics, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Nat Commun. 2023 Dec 21;14(1):8517. doi: 10.1038/s41467-023-44355-z.
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.
端粒长度（TL）缩短是生物衰老的关键指标，与许多人类疾病有关。人类 TL 的遗传决定因素已被广泛研究，然而，大多数现有研究都是基于受终生暴露影响较大的成人组织进行的。基于对 166 个健康胎盘组织中端粒末端限制性片段（TRF）长度、个体基因型和基因表达的分析，我们系统地研究了 TL 调节基因及其潜在功能。我们发现胎盘中的 TL 比其他成人组织中的 TL 要长得多，但表现出组织内的同质性。对 644553 个人进行跨祖先 TL 全基因组关联研究（GWAS）发现了 20 个新发现的遗传关联，并增加了人类 TL 的多基因决定因素。接下来，我们将强大的 TL GWAS 与胎盘表达数量性状基因座（eQTL）图谱相结合，优先考虑 23 个可能的因果基因，其中 4 个已得到功能验证，包括 MMUT、RRM1、KIAA1429 和 YWHAZ。最后，对转录组特征和基于 TRF 的 TL 进行建模可提高人类 TL 的预测性能。这项研究加深了我们对人类 TL 的因果基因和转录组决定因素的理解，促进了对精细 TL 调控的机制研究。
