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

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, Brent S. Rose, Kathryn M. Pridgen, Julie A. Lynch, Hannah K. Carter, Matthew S. Panizzon and Richard L. Hauger ()
Additional contact information
Meghana S. Pagadala: VA San Diego Healthcare System
Craig C. Teerlink: VA Salt Lake City Healthcare System
Guneet K. Jasuja: VA Bedford Healthcare System
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
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
Tyler M. Seibert: VA San Diego Healthcare System
Brent S. Rose: VA San Diego Healthcare System
Kathryn M. Pridgen: VA Salt Lake City Healthcare System
Julie A. Lynch: VA Salt Lake City Healthcare System
Hannah K. Carter: University of California San Diego
Matthew S. Panizzon: VA San Diego Healthcare System
Richard L. Hauger: University of California San Diego

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57372-x

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