Peripheral gene interactions define interpretable clusters of core ASD genes in a network-based investigation of the omnigenic theory

Abstract According to the recently proposed omnigenic theory, all expressed genes in a relevant tissue are contributing directly or indirectly to the manifestation of complex disorders such as autism. Thus, holistic approaches can be complementary in studying genetics of these complex disorders to focusing on a limited number of candidate genes. Gene interaction networks can be used for holistic studies of the omnigenic nature of autism. We used Louvain clustering on tissue-specific gene interaction networks and their subgraphs exclusively containing autism-related genes to study the effects of peripheral gene interactions. We observed that the autism gene clusters are significantly weaker connected to each other and the peripheral genes in non-neuronal tissues than in brain-related tissues. The biological functions of the brain clusters correlated well with previous findings on autism, such as synaptic signaling, regulation of DNA methylation, or regulation of lymphocyte activation, however, on the other tissues they did not enrich as significantly. Furthermore, ASD subjects with disruptive mutations in specific gene clusters show phenotypical differences compared to other disruptive variants carrying ASD individuals. Our results strengthen the omnigenic theory and can advance our understanding of the genetic background of autism.