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

Abstract

Word Count: 244 Main Text Word Count: 4761 Number of Figures: 7 Number of Tables: 2Supplements: 1 supplementary information file + 1 excel file containing 2 supplementary data tables 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 genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and pathophysiological signatures of SCZ and ASD to: 1) organize genes into the developmental cellular and molecular systems within which they operate; 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum; and 3) elucidate pathways and individual genes through which 22q11.2 CNVs may confer risk for each disorder.Results: Polygenic risk for SCZ and ASD converged on partially overlapping gene networks involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for networks involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network that disproportionately affected SCZ-and ASD-associated neurodevelopmental networks, 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 DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. Conclusions:The current approach provides a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant multi-gene CNVs contribute to disease risk.(M4,M6,M7,M12,M13,M15). M1 was consistently enriched for ASD risk variants, but not for down-regulated genes in ASD cortex. However, M1 was highly enriched for genes expressed specifically during fetal development, suggesting that this likely reflects a floor effect in postnatal expression of these genes. Down-regulated genes in ASD and SCZ cortextherefore appear to at least partially reflect direct effects of genetic risk, and we focused on 22qBD-PPI network overlap with down-regulated genes for subsequent analyses.Given the size of the 22qBD-PPI network and each DGE gene-set, the 22qBD-PPI network was significantly enriched for down-regulated genes in both SCZ (~11% of the 22qBD-PPI network; p=0.006) and ASD (~14% of the 22qBD-PPI network;p=2.0x10 -4 ). Additionally, compared to all regions of the genome (i.e., Genomic-RegionBD-PPI networks), the 22qBD-PPI network was in the ~93 rd and ~96 th percentiles for overlap with down-regulated genes in SCZ and ASD, respectively ( Fig. 6B; Table S4). Compared to the connectivity of random sets of 38 seed genes (i.e...

Schizophrenia Genomics: Convergence on Synaptic Development, Adult Synaptic Plasticity, or Both?

“…The foregoing suggests a model in which genetic risk for schizophrenia operates not only on the formation and maintenance of synaptic networks during brain development, but also through direct effects on synaptic function and plasticity in the adult brain. This is supported by a recent study where pronounced enrichment of common genetic risk variation for schizophrenia was found in human brain gene co-expression modules involved in synaptic transmission and neuronal excitability that are maintained, or increased, in expression from birth into adulthood (91). Such a model is also consistent with key aspects of several other neurobiological theories of schizophrenia based on epidemiological, neuropathological, neuroimaging, neuropharmacological and cognitive findings (e.g.…”

Embryonic cortical layer 5 pyramidal neurons form an active, transient circuit motif perturbed by autism-associated mutations

“…Neurodevelopmental disorders, such as autism spectrum disorder, have been associated with defects in cortical circuits (Birnbaum and Weinberger, 2017;Del Pino et al, 2018;Ebert and Greenberg, 2013;Forrest et al, 2018;Forsyth et al, 2020;Gilman et al, 2011;Jabaudon, 2017;Mullins et al, 2016;Stoner et al, 2014; Writing Committee for the Attention-Deficit/Hyperactivity Disorder et al, 2021). Notably, a recent genetic study of autistic patients suggested that, during development, autism-associated genes are strongly enriched in maturing excitatory neurons, compared to immature progenitors.…”

“…Because neurodevelopmental disorders have been associated with cortical circuit dysfunction (Birnbaum and Weinberger, 2017;Del Pino et al, 2018;Ebert and Greenberg, 2013;Forrest et al, 2018;Forsyth et al, 2020;Gilman et al, 2011;Jabaudon, 2017;Mullins et al, 2016;Stoner et al, 2014), we analyzed the expression of neurodevelopmental disease-associated genes in embryonic layer 5 pyramidal neurons and compared this with expression in adult layer 5 pyramidal neurons (Tasic et al, 2018). A number of genes associated with schizophrenia (Lee et al, 2019;Ripke et al, 2014) and autism spectrum disorder (Abrahams et al, 2013) were expressed across all three embryonic types of Rbp4-Cre cells (Fig.…”

Genetics of Childhood-onset Schizophrenia 2019 Update

“…Interestingly, CNVs at many of these specific loci have pleiotropic effects, as they are also associated with broader neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID) 47,51,52 . Similar to common variants associated with schizophrenia, as well as other rare and de novo variants, schizophrenia-associated CNVs disproportionately affect neuronal and synaptic gene-sets 53 , including components of the postsynaptic density, and NMDAR and Arc complexes, 47,54 , and sets of genes that are involved in excitatory and inhibitory neurotransmission 55 .…”