Synaptic and Gene Regulatory Mechanisms in Schizophrenia, Autism, and 22q11.2 CNV Mediated Risk for Neuropsychiatric Disorders

Abstract Background 22q11.2 copy number variants (CNVs) are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder ( ASD). However, the specific mechanisms through which they confer risk remain unclear. Methods Using a functional genomicsapproach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASDpost-mortem cortex to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenicrisk for SCZ and ASDacross the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder. Results Polygenicrisk for SCZ and ASDconverged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASDrisk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ- and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5 , PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8and HIRA are candidate drivers of disease-relevant alterations in gene regulation. Conclusions The current approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD, and elucidate the mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.