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

Nat Commun. 2025 May 2;16(1):4104. doi: 10.1038/s41467-025-57372-x.

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.

PMID:40316537 | DOI:10.1038/s41467-025-57372-x