462,666 个英国生物银行全基因组序列中端粒长度的遗传结构。
Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences.
发表日期：2024 Aug 27
作者：
Oliver S Burren, Ryan S Dhindsa, Sri V V Deevi, Sean Wen, Abhishek Nag, Jonathan Mitchell, Fengyuan Hu, Douglas P Loesch, Katherine R Smith, Neetu Razdan, Henric Olsson, Adam Platt, Dimitrios Vitsios, Qiang Wu, , Veryan Codd, Christopher P Nelson, Nilesh J Samani, Ruth E March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N Pangalos, Slavé Petrovski
来源：
HEART & LUNG
摘要：
端粒保护染色体末端免受损伤，其长度与人类疾病和衰老有关。我们开发了一种联合端粒长度指标，结合了 462,666 名英国生物银行参与者的定量 PCR 和全基因组测序测量结果。该指标增加了 SNP 遗传力，表明它可以更好地捕获端粒长度的遗传调控。全外显子组罕见变异和基因水平崩溃关联研究确定了 64 个变异和 30 个与端粒长度显着相关的基因，包括 ACD 和 RTEL1 中的等位基因系列。值得注意的是，这些基因中有 16% 是已知的克隆造血驱动因素，这是一种与年龄相关的体细胞嵌合现象，与骨髓癌和几种非恶性疾病相关。体细胞变异分析揭示了与端粒长度的基因特异性关联，包括具有大SRSF2突变克隆的个体的端粒延长，而具有由其他基因驱动的克隆扩张的个体的端粒缩短。总的来说，我们的研究结果证明了罕见变异对端粒长度的影响，在与克隆造血相关的基因中观察到更大的影响。© 2024。作者。
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.© 2024. The Author(s).