Genetic analyses implicate complex links between adult testosterone levels and health and disease

BackgroundTestosterone levels are linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of genetically determined testosterone on complex diseases in both sexes.MethodsLeveraging genetic and health registry data from the UK Biobank and FinnGen (total N = 625,650), we constructed polygenic scores (PGS) for total testosterone, sex-hormone binding globulin (SHBG) and free testosterone, associating these with 36 endpoints across different disease categories in the FinnGen. These analyses were combined with Mendelian Randomization (MR) and cross-sex PGS analyses to address causality.ResultsWe show testosterone and SHBG levels are intricately tied to metabolic health, but report lack of causality behind most associations, including type 2 diabetes (T2D). Across other disease domains, including 13 behavioral and neurological diseases, we similarly find little evidence for a substantial contribution from normal variation in testosterone levels. We nonetheless find genetically predicted testosterone affects many sex-specific traits, with a pronounced impact on female reproductive health, including causal contribution to PCOS-related traits like hirsutism and post-menopausal bleeding (PMB). We also illustrate how testosterone levels associate with antagonistic effects on stroke risk and reproductive endpoints between the sexes.ConclusionsOverall, these findings provide insight into how genetically determined testosterone correlates with several health parameters in both sexes. Yet the lack of evidence for a causal contribution to most traits beyond sex-specific health underscores the complexity of the mechanisms linking testosterone levels to disease risk and sex differences. Plain language summaryHormones, such as testosterone, travel around the body communicating between the different parts. Testosterone is present at higher levels in men, but also present in women. Variable testosterone levels explain some differences in human traits and disease prevalence. Here, we study how adult testosterone levels relate to health and disease. Genetic, i.e. inherited, differences in testosterone levels contribute to many traits specific to men or women, such as women's reproductive health, hormonal cancers, and hair growth typical in males. However, testosterone levels do not appear as a major cause of most traits studied, including psychiatric diseases and metabolic health. Normal variation in baseline testosterone levels thus seems to have a relatively minor impact on health and disease. Leinonen et al. investigate correlations between testosterone levels and disease using genetic and health registry data from the UK Biobank and FinnGen. There is a lack of evidence for normal variation in testosterone levels having a causal contribution to most non-sex-specific traits.

Automated summary

This study examines the relationship between testosterone levels and human health. The analysis of genetic and health registry data reveals that while testosterone levels are associated with various health characteristics, the causality of these associations is debated. The study shows that testosterone levels are intricately tied to metabolic health but lack of evidence for causality is found in most associations. However, genetically predicted testosterone levels do affect many sex-specific traits.