IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57315-6.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57315-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57315-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Samvida S. Venkatesh & Habib Ganjgahi & Duncan S. Palmer & Kayesha Coley & Gregorio V. Linchangco & Qin Hui & Peter Wilson & Yuk-Lam Ho & Kelly Cho & Kadri Arumäe & Laura B. L. Wittemans & Christoffer, 2024. "Characterising the genetic architecture of changes in adiposity during adulthood using electronic health records," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Chun Shen & Ruohan Zhang & Jintai Yu & Barbara J. Sahakian & Wei Cheng & Jianfeng Feng, 2025. "Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality," Nature Human Behaviour, Nature, vol. 9(3), pages 569-583, March.
    3. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Sylvia Hartmann & Summaira Yasmeen & Benjamin M. Jacobs & Spiros Denaxas & Munir Pirmohamed & Eric R. Gamazon & Mark J. Caulfield & Harry Hemingway & Maik Pietzner & Claudia Langenberg, 2023. "ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    5. Jujiao Kang & Yue-Ting Deng & Bang-Sheng Wu & Wei-Shi Liu & Ze-Yu Li & Shitong Xiang & Liu Yang & Jia You & Xiaohong Gong & Tianye Jia & Jin-Tai Yu & Wei Cheng & Jianfeng Feng, 2024. "Whole exome sequencing analysis identifies genes for alcohol consumption," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Zhaotong Lin & Wei Pan, 2024. "A robust cis-Mendelian randomization method with application to drug target discovery," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    7. Xingjie Hao & Zhonghe Shao & Ning Zhang & Minghui Jiang & Xi Cao & Si Li & Yunlong Guan & Chaolong Wang, 2023. "Integrative genome-wide analyses identify novel loci associated with kidney stones and provide insights into its genetic architecture," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    8. Shiyu Zhang & Zheng Wang & Yijing Wang & Yixiao Zhu & Qiao Zhou & Xingxing Jian & Guihu Zhao & Jian Qiu & Kun Xia & Beisha Tang & Julian Mutz & Jinchen Li & Bin Li, 2024. "A metabolomic profile of biological aging in 250,341 individuals from the UK Biobank," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    9. Magdalena Zimoń & Yunfeng Huang & Anthi Trasta & Aliaksandr Halavatyi & Jimmy Z. Liu & Chia-Yen Chen & Peter Blattmann & Bernd Klaus & Christopher D. Whelan & David Sexton & Sally John & Wolfgang Hube, 2021. "Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    10. Guanghao Qi & Surya B. Chhetri & Debashree Ray & Diptavo Dutta & Alexis Battle & Samsiddhi Bhattacharjee & Nilanjan Chatterjee, 2024. "Genome-wide large-scale multi-trait analysis characterizes global patterns of pleiotropy and unique trait-specific variants," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    11. Xiaofeng Zhu & Yihe Yang & Noah Lorincz-Comi & Gen Li & Amy R. Bentley & Paul S. de Vries & Michael Brown & Alanna C. Morrison & Charles N. Rotimi & W. James Gauderman & Dabeeru C. Rao & Hugues Aschar, 2024. "An approach to identify gene-environment interactions and reveal new biological insight in complex traits," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. Richard Burns & William J. Young & Nay Aung & Luis R. Lopes & Perry M. Elliott & Petros Syrris & Roberto Barriales-Villa & Catrin Sohrabi & Steffen E. Petersen & Julia Ramírez & Alistair Young & Patri, 2024. "Genetic basis of right and left ventricular heart shape," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    13. Yuji Yamamoto & Yuya Shirai & Kyuto Sonehara & Shinichi Namba & Takafumi Ojima & Kenichi Yamamoto & Ryuya Edahiro & Ken Suzuki & Akinori Kanai & Yoshiya Oda & Yutaka Suzuki & Takayuki Morisaki & Akira, 2025. "Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    14. Hung-Lin Chen & Hsiu-Yin Chiang & David Ray Chang & Chi-Fung Cheng & Charles C. N. Wang & Tzu-Pin Lu & Chien-Yueh Lee & Amrita Chattopadhyay & Yu-Ting Lin & Che-Chen Lin & Pei-Tzu Yu & Chien-Fong Huan, 2024. "Discovery and prioritization of genetic determinants of kidney function in 297,355 individuals from Taiwan and Japan," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    15. Abolfazl Doostparast Torshizi & Dongnhu T. Truong & Liping Hou & Bart Smets & Christopher D. Whelan & Shuwei Li, 2024. "Proteogenomic network analysis reveals dysregulated mechanisms and potential mediators in Parkinson’s disease," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    16. Wei Xu & Ines Mesa-Eguiagaray & David M. Morris & Chengjia Wang & Calum D. Gray & Samuel Sjöström & Giorgos Papanastasiou & Sammy Badr & Julien Paccou & Xue Li & Paul R. H. J. Timmers & Maria Timofeev, 2025. "Deep learning and genome-wide association meta-analyses of bone marrow adiposity in the UK Biobank," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    17. Suzanne Vogelezang & Jonathan P Bradfield & Tarunveer S Ahluwalia & John A Curtin & Timo A Lakka & Niels Grarup & Markus Scholz & Peter J van der Most & Claire Monnereau & Evie Stergiakouli & Anni Hei, 2020. "Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits," PLOS Genetics, Public Library of Science, vol. 16(10), pages 1-26, October.
    18. Liza Darrous & Gibran Hemani & George Davey Smith & Zoltán Kutalik, 2024. "PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    19. Gareth Hawkes & Robin N. Beaumont & Zilin Li & Ravi Mandla & Xihao Li & Christine M. Albert & Donna K. Arnett & Allison E. Ashley-Koch & Aneel A. Ashrani & Kathleen C. Barnes & Eric Boerwinkle & Jenni, 2024. "Whole-genome sequencing in 333,100 individuals reveals rare non-coding single variant and aggregate associations with height," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    20. Dongfang You & Yaqian Wu & Mengyi Lu & Fang Shao & Yingdan Tang & Sisi Liu & Liya Liu & Zewei Zhou & Ruyang Zhang & Sipeng Shen & Theis Lange & Hongyang Xu & Hongxia Ma & Yongmei Yin & Hongbing Shen &, 2025. "A genome-wide cross-trait analysis characterizes the shared genetic architecture between lung and gastrointestinal diseases," Nature Communications, Nature, vol. 16(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57315-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.