De novo mutations involved in post-transcriptional dysregulation contribute to six neuropsychiatric disorders

Abstract

While deleterious de novo mutations (DNMs) in coding region conferring risk in neuropsychiatric disorders have been revealed by next-generation sequencing, the role of DNMs involved in post-transcriptional regulation in pathogenesis of these disorders remains to be elucidated. Here, we identified 1,736 post-transcriptionally impaired DNMs (piDNMs), and prioritized 1,482 candidate genes in four neuropsychiatric disorders from 7,748 families. Our results revealed higher prevalence of piDNMs in the probands than in controls (P = 8.19x10-17), and piDNM-harboring genes were enriched for epigenetic modifications and neuronal or synaptic functions. Moreover, we identified 86 piDNM-containing genes forming convergent co-expression modules and intensive protein-protein interactions in at least two neuropsychiatric disorders. These cross-disorder genes carrying piDNMs could form interaction network centered on RNA binding proteins, suggesting a shared post-transcriptional etiology underlying these disorders. Our findings illustrate the significant contribution of piDNMs to four neuropsychiatric disorders, and lay emphasis on combining functional and network-based evidences to identify regulatory causes of genetic disorders.