Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences

IF 31.7 1区 生物学 Q1 GENETICS & HEREDITY Nature genetics Pub Date : 2024-08-27 DOI:10.1038/s41588-024-01884-7
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, AstraZeneca Genomics Initiative, Veryan Codd, Christopher P. Nelson, Nilesh J. Samani, Ruth E. March, Sebastian Wasilewski, Keren Carss, Margarete Fabre, Quanli Wang, Menelas N. Pangalos, Slavé Petrovski
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Abstract

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. Genome-wide association analysis of an improved telomere length score, calculated from quantitative PCR and whole-genome sequencing measurements in 462,666 individuals in the UK Biobank, identifies novel genes and variants underlying this trait.

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462,666 个英国生物库全基因组序列中端粒长度的遗传结构。
端粒保护染色体末端免受损伤,端粒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度量方法,将定量 PCR 和全基因组测序测量结果相结合,这些测量结果来自 462,666 名英国生物库参与者。该指标提高了SNP遗传率,表明它能更好地捕捉端粒长度的遗传调控。全外显子罕见变体和基因水平的折叠关联研究发现了与端粒长度显著相关的64个变体和30个基因,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% 是已知的克隆造血的驱动因素--一种与年龄相关的体细胞镶嵌现象,与骨髓癌和一些非恶性疾病相关。体细胞变异分析揭示了基因与端粒长度的特异性关联,包括SRSF2基因突变克隆大的个体端粒变长,而其他基因驱动的克隆扩增个体端粒变短。总之,我们的研究结果表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了更大的影响。
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来源期刊
Nature genetics
Nature genetics 生物-遗传学
CiteScore
43.00
自引率
2.60%
发文量
241
审稿时长
3 months
期刊介绍: Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human and plant traits and on other model organisms. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation. Integrative genetic topics comprise, but are not limited to: -Genes in the pathology of human disease -Molecular analysis of simple and complex genetic traits -Cancer genetics -Agricultural genomics -Developmental genetics -Regulatory variation in gene expression -Strategies and technologies for extracting function from genomic data -Pharmacological genomics -Genome evolution
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