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. 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. 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 ( $$\rho =0.19$$ , $$p=0.004$$ ; $$\rho =0.2$$ , $$p=0.004$$ , respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ( $$t=4.0$$ , $$p=8.8\times 10^{-5}$$ ), 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 $$t=4.2$$ , $$p={3.2\times 10^{-5}}$$ 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: $$-0.22\pm 0.05$$ ; testosterone: $$-0.35\pm 0.15$$ from 0.1%-ile to 99.9%-ile; SHBG: $$0.64\pm 0.15$$ from 0.1%-ile to 99.9%-ile). In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. 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：

---

雄激素暴露的遗传和形态学估计可预测多个神经发育障碍人群的社交缺陷


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，但在性别之间也存在差异，之前的工作试图将雄激素暴露的形态指标（包括手指比例和面部形态）与神经发育结果联系起来。这些研究的结果好坏参半，雄激素暴露与行为之间的关系仍不清楚。在这里，我们测量了同一神经发育队列 (N = 763) 中的手指比例男性气质 (DRM) 和面部标志男性气质 (FLM)，并将这些雄激素暴露指标与临床和家长报告的特征以及多基因风险评分进行比较。我们发现 FLM 与 NDD 诊断（ASD、ADHD、ID；所有 $$p<0.05$$ ）显着相关，而 DRM 则不然。在测试与家长报告的问题的关联时，我们发现 FLM 和 DRM 都与对社交行为的担忧呈正相关（ $$\rho =0.19$$ 、 $$p=0.004$$ ；$$\rho =0.2$ $ ， $$p=0.004$$ ，分别）。此外，我们通过多基因风险评分 (PRS) 发现证据表明，DRM 通过睾酮水平来衡量男性气质（ $$t=4.0$$ 、 $$p=8.8\times 10^{-5}$$ ），而 FLM 通过睾酮水平来衡量男性气质与性激素结合球蛋白 (SHBG) 水平呈负相关 ( $$t=-3.3$$ , $$p=0.001$$ )。最后，使用 SPARK 队列 (N = 9419)，我们复制了睾酮、性激素结合球蛋白 (SHBG) 和社会功能的多基因估计值之间观察到的关系（ $$t=-2.3$$ 、 $$p=0.02$$ 和 $$t= 4.2$$ , $$p={3.2\times 10^{-5}}$$ 分别为睾酮和性激素结合球蛋白 (SHBG)。 值得注意的是，当考虑每个变量的极端情况时，这些定量的性别对社会功能的影响与二元性别本身的影响相当（二元男性：$$-0.22\pm 0.05$$；睾酮：$$-0.35\pm 0.15 $$ 从 0.1%-ile 到 99.9%-ile；SHBG：$$0.64\pm 0.15$$ 从 0.1%-ile 到 99.9%-ile）。在 devGenes 和 SPARK 队列中，我们的分析依赖于雄激素和相关分子的间接测量，而不是直接测量。这些发现及其在大型 SPARK 队列中的复制支持了这样的假设：增加净雄激素暴露会降低男性和女性的社会功能能力。