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 = 8.8e-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=9,419) 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 = 3.2e-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%-ile to 99.9%-ile; SHBG: 0.64 +/- 0.15 from 0.1%-ile to 99.9%-ile). 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.

中文翻译：

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雄激素暴露的遗传和形态学估计可预测多发性神经发育障碍人群的社会缺陷

背景：自闭症谱系障碍（ASD）等神经发育障碍（NDD）表现出强烈的男性偏见。在典型的男性发育过程中，雄激素暴露量显着增加，但在男女之间也有所不同，并且以前的工作试图将雄激素暴露的形态学指标（包括手指比例和面部形态）与神经发育结局联系起来。这些研究的结果参差不齐，雄激素暴露与行为之间的关系仍不清楚。方法：在这里，我们在同一神经发育队列（N = 763）中测量了数字比例阳刚度（DRM）和面部界标阳刚度（FLM），并将这些雄激素暴露与临床和父母报告的特征以及多基因风险评分进行了比较。 。结果：我们发现FLM与NDD诊断（ASD，ADHD，ID；所有p <0.05），而DRM不是。在测试与父母报告的问题的关联时，我们发现FLM和DRM都与对社会行为的关注成正相关（分别为ρ= 0.19，p = 0.004；ρ= 0.2，p = 0.004）。此外，我们通过多基因风险评分（PRS）发现，DRM通过睾丸激素水平来指示男性气质（t = 4.0，p = 8.8e-5），而FLM通过与性激素结合球蛋白（SHBG）水平呈负相关来指示男性气质（ t = -3.3，p = 0.001）。最后，使用SPARK队列（N = 9,419），我们复制了睾丸激素，SHBG和社会功能的多基因估计值之间的观察关系（t = -2.3，p = 0.02，t = 4.2，p = 3.2e-5，睾丸激素和SHBG）。值得注意的是，当考虑每个变量的极端值时，这些对社会功能的定量性影响与双性行为本身的影响相当（双性男性：-0.22 +/- 0.05;睾丸激素：-0.35 +/- 0.15，从0.1％到99.9％ile; SHBG：0.64 + /-0.15，从0.1％ile到99.9％ile）。结论：这些发现及其在大型SPARK队列中的复制为以下假说提供了支持：净雄激素暴露增加会降低男性和女性社交功能的能力。