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

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 [Formula: see text]), 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 ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text], respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels ([Formula: see text], [Formula: see text]), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels ([Formula: see text], [Formula: see text]). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning ([Formula: see text], [Formula: see text], and [Formula: see text], [Formula: see text] 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: [Formula: see text]; testosterone: [Formula: see text] from 0.1%-ile to 99.9%-ile; SHBG: [Formula: see text] 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.

Two novel forms of ERG oscillation in Drosophila: age and activity dependence.

Over an animal's lifespan, neuronal circuits and systems often decline in an inherently heterogeneous fashion. To compare the age-dependent progression of changes in visual behavior with alterations in retinal physiology, we examined phototaxis and electroretinograms (ERGs) in a wild-type D. melanogaster strain (Canton-S) across their lifespan. In aged flies (beyond 50% median lifespan), we found a marked decline in phototaxis, while motor coordination was less disrupted, as indicated by relatively stronger negative geotaxis. These aged flies displayed substantially reduced ERG transient amplitudes while the receptor potentials (RP) remained largely intact. Using a repetitive light flash protocol, we serendipitously discovered two forms of activity-dependent oscillation in the ERG waveforms of young flies: 'light-off' and 'light-on' oscillations. After repeated 500 ms light flashes, light-off oscillations appeared during the ERG off-transients (frequency: 50-120 Hz, amplitude: ∼1 mV). Light-on oscillations (100-200 Hz, ∼0.3 mV) were induced by a series of 50 ms flashes, and were evident during the ERG on-transients. Both forms of oscillation were observed in other strains of D. melanogaster (Oregon-R, Berlin), additional Drosophila species (D. funerbris, D. euronotus, D. hydei, D. americana), and were evoked by a variety of light sources. Both light-off and light-on oscillations were distinct from previously described ERG oscillations in the visual mutant rosA in terms of location within the waveform and frequency. However, within rosA mutants, light-off oscillations, but not light-on oscillations could be recruited by the repetitive light flash protocol. Importantly though, we found that both forms of oscillation were rarely observed in aged flies. Although the physiological bases of these oscillations remain to be elucidated, they may provide important clues to age-related changes in neuronal excitability and synaptic transmission.