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

Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is one paradigm for investigating this male bias, 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 inconsistent and the relationships between androgen exposure and behavior remains unclear. 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. We found that FLM was significantly associated with diagnostic burden in males and females (Z=3.1, p=0.002), while DRM was not (Z=-1.6, p=0.11). When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior (Z=3.1, p=0.002; Z=2.1, p=0.03, respectively), also in a sex-invariant manner. Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels (t=2.0, p=0.04), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels (t=-2.3, p=0.02). Finally, using the SPARK cohort (N=9,419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning (t=-2.5, p=0.01, and t=4.5, p=6e-6 for testosterone and SHBG, respectively). Remarkably, these quantitative sex effects on social functioning were on the same order of magnitude as the effect of binary sex itself (binary male:-0.23 +/- 0.05; testosterone:-0.07 +/- 0.026 per SD of PRS; SHBG: 0.11 +/- 0.026 per SD of PRS). These findings and their replication in the large SPARK cohort lend strong support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.