Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system

Abstract

Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in individuals from diverse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders.

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

“…Recent studies suggest that combinations of miRNAs have been preconfigured through evolution to regulate groups of molecules that function in the same process, such as cell remodelling or synaptic development processes that underpin learning and memory [5][6][7][8] . This is supported by the number of overrepresented miRNA-target sites found in the 3 0 UTRs of mRNAs that make up functional pathways of the nervous system 9 .…”

Transcriptome outlier analysis implicates schizophrenia susceptibility genes and enriches putatively functional rare genetic variants

“…This provided supportive transcriptomic evidence for likely neurodevelopmental abnormalities in SZ (33). Genetic overlap between SZ and various neurodevelopmental disorders has been reported (34,35). Some genetic variants associated with SZ, ASD, X-linked intellectual disability (XLID) and attention deficit hyperactivity disorder (ADHD) occur in the same molecular pathways and functional domains (35).…”

“…Genetic overlap between SZ and various neurodevelopmental disorders has been reported (34,35). Some genetic variants associated with SZ, ASD, X-linked intellectual disability (XLID) and attention deficit hyperactivity disorder (ADHD) occur in the same molecular pathways and functional domains (35). For instance, genes associated with ASD, XLID, ADHD and SZ are mainly distributed in gene networks involved in the regulation of transcription, synaptic transmission, cell-cell communication, intracellular signaling pathways, cell cycle, metabolic processes and nervous system development (35).…”

The intellectual developmental disorders Mexico study: situational diagnosis, burden, genomics and intervention proposal

“…29,30,[34][35][36] Particularly, it has been shown that most of the genes associated to ID and autism have a role in the control of formation and function of synapses. 37,38 Interestingly, a biological systems study indicates that there are up to 4 000 genes that may contribute to neurodevelopmental and neuropsychiatric disorders 39 suggesting that a large number of genes associated with disorders as ID and autism have not been identified yet.…”