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
{"title":"Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences","authors":"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","doi":"10.1038/s41588-024-01884-7","DOIUrl":null,"url":null,"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.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":null,"pages":null},"PeriodicalIF":31.7000,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01884-7.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature genetics","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41588-024-01884-7","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
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.
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