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Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes

Author

Listed:
  • Junyoung Park

    (Stanford University)

  • Andrés Peña-Tauber

    (Stanford University)

  • Lia Talozzi

    (Stanford University)

  • Michael D. Greicius

    (Stanford University)

  • Yann Guen

    (Stanford University)

Abstract

Human lifespan is shaped by genetic and environmental factors. To enable precision health, understanding how genetic variants influence mortality is essential. We conducted a survival analysis in European ancestry participants of the UK Biobank, using age-at-death (N=35,551) and last-known-age (N=358,282). The associations identified were predominantly driven by cancer. We found lifespan-associated loci (APOE, ZSCAN23) for common variants and six genes where burden of loss-of-function variants were linked to reduced lifespan (TET2, ATM, BRCA2, CKMT1B, BRCA1, ASXL1). Additionally, eight genes with pathogenic missense variants were associated with reduced lifespan (DNMT3A, SF3B1, TET2, PTEN, SOX21, TP53, SRSF2, RLIM). Many of these genes are involved in oncogenic pathways and clonal hematopoiesis. Our findings highlight the importance of understanding genetic factors driving the most prevalent causes of mortality at a population level, highlighting the potential of early genetic testing to identify germline and somatic variants increasing one’s susceptibility to cancer and/or early death.

Suggested Citation

  • Junyoung Park & Andrés Peña-Tauber & Lia Talozzi & Michael D. Greicius & Yann Guen, 2025. "Rare genetic associations with human lifespan in UK Biobank are enriched for oncogenic genes," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57315-6
    DOI: 10.1038/s41467-025-57315-6
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    1. Claudia Giambartolomei & Damjan Vukcevic & Eric E Schadt & Lude Franke & Aroon D Hingorani & Chris Wallace & Vincent Plagnol, 2014. "Bayesian Test for Colocalisation between Pairs of Genetic Association Studies Using Summary Statistics," PLOS Genetics, Public Library of Science, vol. 10(5), pages 1-15, May.
    2. Peter K. Joshi & Krista Fischer & Katharina E. Schraut & Harry Campbell & Tõnu Esko & James F. Wilson, 2016. "Variants near CHRNA3/5 and APOE have age- and sex-related effects on human lifespan," Nature Communications, Nature, vol. 7(1), pages 1-7, September.
    3. Peter K. Joshi & Nicola Pirastu & Katherine A. Kentistou & Krista Fischer & Edith Hofer & Katharina E. Schraut & David W. Clark & Teresa Nutile & Catriona L. K. Barnes & Paul R. H. J. Timmers & Xia Sh, 2017. "Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    4. Clare Bycroft & Colin Freeman & Desislava Petkova & Gavin Band & Lloyd T. Elliott & Kevin Sharp & Allan Motyer & Damjan Vukcevic & Olivier Delaneau & Jared O’Connell & Adrian Cortes & Samantha Welsh &, 2018. "The UK Biobank resource with deep phenotyping and genomic data," Nature, Nature, vol. 562(7726), pages 203-209, October.
    5. João Vinagre & Ana Almeida & Helena Pópulo & Rui Batista & Joana Lyra & Vasco Pinto & Ricardo Coelho & Ricardo Celestino & Hugo Prazeres & Luis Lima & Miguel Melo & Adriana Gaspar da Rocha & Ana Preto, 2013. "Frequency of TERT promoter mutations in human cancers," Nature Communications, Nature, vol. 4(1), pages 1-6, October.
    6. Loïc Yengo & Sailaja Vedantam & Eirini Marouli & Julia Sidorenko & Eric Bartell & Saori Sakaue & Marielisa Graff & Anders U. Eliasen & Yunxuan Jiang & Sridharan Raghavan & Jenkai Miao & Joshua D. Aria, 2022. "A saturated map of common genetic variants associated with human height," Nature, Nature, vol. 610(7933), pages 704-712, October.
    7. Cathie Sudlow & John Gallacher & Naomi Allen & Valerie Beral & Paul Burton & John Danesh & Paul Downey & Paul Elliott & Jane Green & Martin Landray & Bette Liu & Paul Matthews & Giok Ong & Jill Pell &, 2015. "UK Biobank: An Open Access Resource for Identifying the Causes of a Wide Range of Complex Diseases of Middle and Old Age," PLOS Medicine, Public Library of Science, vol. 12(3), pages 1-10, March.
    8. Michael D. Kessler & Amy Damask & Sean O’Keeffe & Nilanjana Banerjee & Dadong Li & Kyoko Watanabe & Anthony Marketta & Michael Meter & Stefan Semrau & Julie Horowitz & Jing Tang & Jack A. Kosmicki & V, 2022. "Common and rare variant associations with clonal haematopoiesis phenotypes," Nature, Nature, vol. 612(7939), pages 301-309, December.
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