In young children, ASD is diagnosed approximately four times more frequently in boys than girls, yet the underlying mechanism for this sex skewing is unclear. In the first phase of the Simons Sex Differences Collaboration, this team proposed, reviewed and tested an epistatic model, where risk factors (e.g., genetic variants) interact with aspects of biological sex to produce greater variance in male liability and thus differential diagnostic outcomes in males and females. This model is supported by the discovery of a greater role for genetic factors (heritability) in males and the discovery of individual genetic variants with differential association to ASD between sexes, suggesting individual genetic risk factors have differential consequences during male and female brain development. The model is further informed by previous examination of the downstream effects of biological mediators of sex (i.e., sex chromosomes, hormones) on gene expression in the human brain and on gene expression, brain organization and behavior in rodent models. Similar to other SSDC teams hypothesizing strong roles for hormonal influences, or sex chromosomes, these data reveal that both contribute to social circuit regulation and potentially interact with genetic risk in rodents.

In the last year of the project, the team aims to replicate and extend these discoveries. In collaboration with other SSDC teams, they will examine how sex and autism risk alter the transcriptomic organization of sexually divergent regions of the human brain, and in parallel dissect the role of hormones in regulating gene expression in humans (Dougherty). This will parallel studies of how maternal hormone levels during pregnancy influenced autism risk in the population (Sandin) and describe the hormone and metabolomic composition of human infant cerebrospinal fluid (Marrus).