IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57372-x.html
   My bibliography  Save this article

Discovery of novel ancestry specific genes for androgens and hypogonadism in Million Veteran Program Men

Author

Listed:
  • Meghana S. Pagadala

    (VA San Diego Healthcare System
    University of California San Diego
    University of California San Diego)

  • Craig C. Teerlink

    (VA Salt Lake City Healthcare System
    University of Utah School of Medicine)

  • Guneet K. Jasuja

    (VA Bedford Healthcare System
    Boston University School of Medicine
    Boston University School of Public Health)

  • Madhuri Palnati

    (VA Bedford Healthcare System)

  • Tori Anglin-Foote

    (VA Salt Lake City Healthcare System)

  • Nai-Chung N. Chang

    (VA Salt Lake City Healthcare System)

  • Rishi Deka

    (VA San Diego Healthcare System
    University of California San Diego
    University of California San Diego)

  • Kyung M. Lee

    (VA Salt Lake City Healthcare System)

  • Fatai Y. Agiri

    (VA Salt Lake City Healthcare System)

  • Tiffany Amariuta

    (University of California San Diego
    University of California San Diego)

  • Tyler M. Seibert

    (VA San Diego Healthcare System
    University of California San Diego
    University of California San Diego
    University of California San Diego)

  • Brent S. Rose

    (VA San Diego Healthcare System
    University of California San Diego
    University of California San Diego)

  • Kathryn M. Pridgen

    (VA Salt Lake City Healthcare System)

  • Julie A. Lynch

    (VA Salt Lake City Healthcare System
    University of Utah School of Medicine)

  • Hannah K. Carter

    (University of California San Diego)

  • Matthew S. Panizzon

    (VA San Diego Healthcare System
    University of California San Diego
    University of California San Diego)

  • Richard L. Hauger

    (University of California San Diego
    University of California San Diego
    VA San Diego Healthcare System)

Abstract

Given the various roles of testosterone in men’s health, we conducted a multi-ancestral genetic analysis of total testosterone, free testosterone, SHBG, and hypogonadism in men within the Million Veteran Program (MVP). Here we identified 157 significant testosterone genetic variants, of which 8 have significant ancestry-specific associations. These variants implicate several genes, including SERPINF2, PRPF8, BAIAP2L1, SHBG, PRMT6, and PPIF, related to liver function. Genetic regulators of testosterone have cell type-specific effects in the testes, liver, and adrenal gland and are associated with disease risk. We conducted a meta-analysis amongst ancestry groups to identify 188 variants significantly associated with testosterone, of which 22 are novel associations. We constructed genetic scores for total testosterone, SHBG levels, and hypogonadism and find that men with higher testosterone genetic scores have lower odds of diabetes, hyperlipidemia, gout, and cardiac disorders. These findings provide insight into androgen regulation and identify novel variants for disease risk stratification.

Suggested Citation

  • Meghana S. Pagadala & Craig C. Teerlink & Guneet K. Jasuja & Madhuri Palnati & Tori Anglin-Foote & Nai-Chung N. Chang & Rishi Deka & Kyung M. Lee & Fatai Y. Agiri & Tiffany Amariuta & Tyler M. Seibert, 2025. "Discovery of novel ancestry specific genes for androgens and hypogonadism in Million Veteran Program Men," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57372-x
    DOI: 10.1038/s41467-025-57372-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57372-x
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-57372-x?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. 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. Raha Pazoki & Marijana Vujkovic & Joshua Elliott & Evangelos Evangelou & Dipender Gill & Mohsen Ghanbari & Peter J. van der Most & Rui Climaco Pinto & Matthias Wielscher & Matthias Farlik & Verena Zub, 2021. "Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    3. Claes Ohlsson & Henri Wallaschofski & Kathryn L Lunetta & Lisette Stolk & John R B Perry & Annemarie Koster & Ann-Kristin Petersen & Joel Eriksson & Terho Lehtimäki & Ilpo T Huhtaniemi & Geoffrey L Ha, 2011. "Genetic Determinants of Serum Testosterone Concentrations in Men," PLOS Genetics, Public Library of Science, vol. 7(10), pages 1-11, October.
    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. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
    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. 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.
    2. Eeva Sliz & Jaakko S. Tyrmi & Nilufer Rahmioglu & Krina T. Zondervan & Christian M. Becker & Outi Uimari & Johannes Kettunen, 2023. "Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Marie C. Sadler & Chiara Auwerx & Kaido Lepik & Eleonora Porcu & Zoltán Kutalik, 2022. "Quantifying the role of transcript levels in mediating DNA methylation effects on complex traits and diseases," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. 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.
    5. 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.
    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. Yuandan Wei & Jianxin Zhen & Liang Hu & Yuqin Gu & Yanhong Liu & Xinxin Guo & Zijing Yang & Hao Zheng & Shiyao Cheng & Fengxiang Wei & Likuan Xiong & Siyang Liu, 2024. "Genome-wide association studies of thyroid-related hormones, dysfunction, and autoimmunity among 85,421 Chinese pregnancies," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Emma Hazelwood & Daffodil M. Canson & Benedita Deslandes & Xuemin Wang & Pik Fang Kho & Danny Legge & Andrei-Emil Constantinescu & Matthew A. Lee & D. Timothy Bishop & Andrew T. Chan & Stephen B. Grub, 2025. "Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    9. 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.
    10. 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.
    11. 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.
    12. 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.
    13. 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.
    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. Molly Went & Laura Duran-Lozano & Gisli H. Halldorsson & Andrea Gunnell & Nerea Ugidos-Damboriena & Philip Law & Ludvig Ekdahl & Amit Sud & Gudmar Thorleifsson & Malte Thodberg & Thorunn Olafsdottir &, 2024. "Deciphering the genetics and mechanisms of predisposition to multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    16. Danielle Rasooly & Gina M. Peloso & Alexandre C. Pereira & Hesam Dashti & Claudia Giambartolomei & Eleanor Wheeler & Nay Aung & Brian R. Ferolito & Maik Pietzner & Eric H. Farber-Eger & Quinn Stanton , 2023. "Genome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. 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.
    18. 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.
    19. Xueyan Wu & Hui Ying & Qianqian Yang & Qian Yang & Haoyu Liu & Yilan Ding & Huiling Zhao & Zhihe Chen & Ruizhi Zheng & Hong Lin & Shuangyuan Wang & Mian Li & Tiange Wang & Zhiyun Zhao & Min Xu & Yuhon, 2024. "Transcriptome-wide Mendelian randomization during CD4+ T cell activation reveals immune-related drug targets for cardiometabolic diseases," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    20. Lucas A. Mavromatis & Daniel B. Rosoff & Andrew S. Bell & Jeesun Jung & Josephin Wagner & Falk W. Lohoff, 2023. "Multi-omic underpinnings of epigenetic aging and human longevity," Nature Communications, Nature, vol. 14(1), pages 1-15, 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_s41467-025-57372-x. 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.