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.

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.

1AbstractLanguage is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis — and how it compares to that of more general cognitive functioning— remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few “language genes”.

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Bladder cancer is the ninth most common malignancy in the world. Transitional cell carcinoma (TCC), also referred to as urothelial carcinoma (UC) is the most common form of bladder cancer, occurring in 90% of cases. In this study, we explore urine-derived, 3-dimensional, canine TCC organoids as a possible model to study bladder TCC ex vivo. After establishing the cell lines, we subjected the 3D cells to RNA in situ hybridization (RNA-ISH) and cell viability assays. Overall, 3D cell culture from urine samples of TCC diagnosed canines expressed RNA biomarkers in a similar manner to parent tumors via RNA-ISH and showed more sensitivity to cisplatin treatment when compared to 2D human TCC cells. With further experimentation, canine TCC organoids could become an ideal model to study TCC ex vivo.