Dissecting the shared genetic architecture between testosterone traits and attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with sex differences, possibly linked to testosterone; however, the relationship remains unclear. This study aimed to clarify the genetic correlation and polygenic overlap between ADHD and testosterone traits, identify shared genomic loci, and investigate the underlying biological mechanisms through functional annotation. Genomic data on ADHD and three testosterone traits (total testosterone [TT], bioavailable testosterone [BT], and sex hormone-binding globulin [SHBG]) were obtained from publicly accessible genome-wide association studies. Employing the MiXeR bivariate causal mixture model, we quantified the polygenic overlap between ADHD and these testosterone traits. Subsequently, we applied the conjunctional false discovery rate (conjFDR) method to identify genomic loci and performed functional annotation with the Functional Mapping and Annotation tool to aid biological interpretation. Using MiXeR, we found negative correlations between TT and ADHD, and SHBG and ADHD, but a positive correlation between BT and ADHD. Over one-third of testosterone-associated variants were predicted to affect ADHD. Using the conjFDR approach, we identified 22-51 genomic loci shared between testosterone traits and ADHD, including MCM9 and MANBA. Functional enrichment analysis highlighted the predominant involvement of these mapped genes in signal transduction pathways, synapses, cell differentiation, and neurogenesis. In conclusion, we reported a substantial polygenic overlap between ADHD and testosterone traits, identified multiple shared genomic loci implicating common biological mechanisms, and highlighted the association of glutamatergic synapses and neurogenesis with ADHD and testosterone levels.