Leinonen Jaakko T, Mars Nina, Lehtonen Leevi E, Ahola-Olli Ari, Ruotsalainen Sanni, Lehtimäki Terho, Kähönen Mika, Raitakari Olli, Piltonen Terhi, Daly Mark, Tuomi Tiinamaija, Ripatti Samuli, Pirinen Matti, Tukiainen Taru
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Department of Clinical Chemistry, Finnish Cardiovascular Research Center, Tampere, Finland.
Commun Med (Lond). 2023 Jan 18;3(1):4. doi: 10.1038/s43856-022-00226-0.
Testosterone 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.
Leveraging 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.
We 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.
Overall, 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.
睾酮水平与人类健康的多种特征相关，但这些关联是反映相关性还是因果关系仍存在争议。在此，我们对基因决定的睾酮在两性复杂疾病中的作用提供了一个广泛的视角。
利用来自英国生物银行和芬兰基因库的遗传和健康登记数据（总数N = 625,650），我们构建了总睾酮、性激素结合球蛋白（SHBG）和游离睾酮的多基因评分（PGS），并将这些评分与芬兰基因库中不同疾病类别的36个终点相关联。这些分析与孟德尔随机化（MR）和跨性别PGS分析相结合以探讨因果关系。
我们发现睾酮和SHBG水平与代谢健康密切相关，但报告指出大多数关联背后缺乏因果关系，包括2型糖尿病（T2D）。在其他疾病领域，包括13种行为和神经疾病，我们同样几乎没有发现睾酮水平的正常变异有实质性贡献的证据。尽管如此，我们发现基因预测的睾酮会影响许多性别特异性特征，对女性生殖健康有显著影响，包括对多毛症和绝经后出血（PMB）等与多囊卵巢综合征（PCOS）相关特征的因果贡献。我们还说明了睾酮水平如何与两性中风风险和生殖终点的拮抗作用相关联。
总体而言，这些发现深入了解了基因决定的睾酮如何与两性的几个健康参数相关。然而，除了性别特异性健康之外，缺乏对大多数特征有因果贡献的证据，这凸显了将睾酮水平与疾病风险和性别差异联系起来的机制的复杂性。
