Exploring the shared genetic architecture between testosterone traits and major depressive disorder

The association between major depressive disorder (MDD) and testosterone levels is controversial, and whether they are genetically correlated remains unclear. The present study aimed to investigate the shared genetic architecture between MDD and three testosterone traits.

We acquired genetic datasets of MDD and testosterone traits from publicly available genome-wide association studies. The bivariate causal mixture modeling (MiXeR) method was applied to estimate the polygenic overlap between MDD and testosterone, and the conjunctional false discovery rate (conjFDR) tool was used to identify shared genomic loci.

Analysis with MiXeR suggested total testosterone (TT) and sex hormone-binding globulin (SHBG) were negative correlated with MDD, while the correlation between bioavailable testosterone (BT) and MDD was negligible. At least 47% of testosterone-related variants were predicted to influence MDD. The conjFDR identified a range of 28 to 79 genomic loci that were jointly associated with testosterone traits and MDD. Among these loci, NT5C2 was simultaneously associated with SHBG, TT and MDD. Functional annotation revealed that the mapped genes were mainly enriched in immune-related pathways.

The present study reported extensive polygenic overlap between MDD and testosterone traits, identified multiple targets delivering shared biological mechanisms, and highlighted the role of the hypothalamic-pituitary-adrenal axis in the pathophysiological processes of MDD and testosterone regulation.