Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohorts

Background Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. Methods Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort ( N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. Results We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all p<0.05 ), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior ( ρ =0.19 , p=0.004 ; ρ =0.2 , p=0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ( t=4.0 , p=8.8× 10^-5 ), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ( t=-3.3 , p=0.001 ). Finally, using the SPARK cohort ( N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ( t=-2.3 , p=0.02 , and t=4.2 , p=3.2× 10^-5 for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male: -0.22± 0.05 ; testosterone: -0.35± 0.15 from 0.1