Computational Framework for the Identification of Neural Circuits Underlying Psychiatric Disorders

Autism spectrum disorders (ASDs) are characterized by phenotypic and genetic heterogeneity. Our analysis of functional networks perturbed in ASD suggests that both truncating and non-truncating de novo mutations contribute to autism. Moreover, we find that truncating mutations affecting the same exon lead to strikingly similar intellectual phenotypes in unrelated ASD probands and propose that exons, rather than genes, represent a unit of effective phenotypic impact for truncating mutations in autism. The phenotypic effects are likely mediated by nonsense-mediated decay of splicing isoforms and similar patterns may be observed in other genetic disorders. While multiple cell types and brain areas are affected, the impact of ASD mutations converge on a strongly interconnected system of neural structures that involve basal ganglia loops and the limbic system. We observe that distant projections constitute a disproportionately large fraction of the network composition, suggesting that the integration of diverse brain regions is a key property of the neural circuit. We demonstrate that individual de novo mutations impact several disparate components of the network and may further explain the phenotypic variability. Overall, our study presents a method that, to our knowledge, is the first unbiased approach using genetic variants to comprehensively discover and identify the neural circuitry affected in a psychiatric disorder.