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

Abstract

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 $$p<0.05$$ 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 ($$\rho =0.19$$ ρ = 0.19 , $$p=0.004$$ p = 0.004 ; $$\rho =0.2$$ ρ = 0.2 , $$p=0.004$$ p = 0.004 , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ($$t=4.0$$ t = 4.0 , $$p=8.8\times 10^{-5}$$ p = 8.8 × 10 - 5 ), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ($$t=-3.3$$ t = - 3.3 , $$p=0.001$$ p = 0.001 ). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ($$t=-2.3$$ t = - 2.3 , $$p=0.02$$ p = 0.02 , and $$t=4.2$$ t = 4.2 , $$p={3.2\times 10^{-5}}$$ 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: $$-0.22\pm 0.05$$ - 0.22 ± 0.05 ; testosterone: $$-0.35\pm 0.15$$ - 0.35 ± 0.15 from 0.1%-ile to 99.9%-ile; SHBG: $$0.64\pm 0.15$$ 0.64 ± 0.15 from 0.1%-ile to 99.9%-ile). Limitations In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. Conclusions These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.

An investigation of a novel broad autism phenotype: increased facial masculinity among parents of children on the autism spectrum

“…In summary, we have presented evidence that early exposure to elevated testosterone concentrations is associated with more masculinized facial structures for both sexes in adults [19]. Consistent with the androgen hypothesis, we reported increased facial masculinity in three-dimensional images of autistic boys and girls; McKenna et al [23] reported similar results using two-dimensional images of people with neurodevelopmental conditions including autism. Furthermore, we have found increased facial masculinity in the threedimensional images of non-autistic biological siblings of autistic children [7], thereby providing evidence for a physical expression of the broad autism phenotype.…”

“…In a recent study, McKenna et al . [23] replicated our observations using two-dimensional images of 216 males and 129 females diagnosed with a neurodevelopmental condition (including 181 autistic people), and 165 males and 253 females without any such condition. McKenna et al .…”

“…In a recent study, McKenna et al [23] replicated our observations using two-dimensional images of 216 males and 129 females diagnosed with a neurodevelopmental condition (including 181 autistic people), and 165 males and 253 females without any such condition. McKenna et al [23] reported increased facial masculinity among males and females with a neurodevelopmental condition compared to their same-sex counterparts without any condition. The authors further built on these findings by examining the association between facial masculinity and polygenic risk scores associated with sex-hormone binding globulin (SHBG) derived from genomic analyses.…”

“…Thus, low concentrations of SHBG have been associated with heightened levels of biologically active testosterone [24]. McKenna et al [23] found that lower SHBG polygenic risk scores significantly correlated with greater facial masculinity, suggesting that greater facial masculinity associated with neurodevelopmental conditions may be driven by excess biologically active testosterone.…”

“…McKenna et al . [23] reported increased facial masculinity among males and females with a neurodevelopmental condition compared to their same-sex counterparts without any condition. The authors further built on these findings by examining the association between facial masculinity and polygenic risk scores associated with sex-hormone binding globulin (SHBG) derived from genomic analyses.…”