Fig. 4: A strategy for combining human brain expression data and high-confidence risk genes to identify spatiotemporal convergence.

Willsey et al. [112] established co-expression networks for the nine highest confidence ASD-risk genes at the time of publication. There networks were established by setting a high threshold for gene expression correlation irrespective of sign—based on the hypothesis that coordinated gene activity, whether in the same or opposite directions, is a useful proxy for shared biological function. Networks were created for spatiotemporal periods defined in the Brainspan database [113], using their time windows. Co-expression networks based on the highest confidence genes were then examined for enrichment of an independent list of probable ASD-risk genes and compared to the null expectation, looking for enrichment of genes that have evidence for ASD risk within any of the predefined networks. In this case, statistically significant evidence was found for enrichment of PFC in mid-fetal development at approximately 18–24 weeks, and additional signal was identified in medial dorsal thalamus and cerebellum later in development (in early infancy).