AbstractBackgroundRecent breakthroughs in psychiatric genetics have implicated biological pathways onto which genetic risk for psychiatric disorders converges. However, these studies do not reveal the developmental time point(s) at which these pathways are relevant.MethodsWe aimed to determine the relationship between psychiatric risk and developmental gene expression relating to discrete biological pathways. We used post-mortem RNA sequencing data (BrainSeq and BrainSpan) from brain tissue at multiple pre- and post-natal timepoints and summary statistics from recent genome-wide association studies of schizophrenia, bipolar disorder and major depressive disorder. We prioritised gene sets for overall enrichment of association with each disorder, and then tested the relationship between the association of each of their constituent genes with their relative expression at each developmental stage.ResultsWe observed relationships between the expression of genes involved involtage-gated cation channel activityduring Early Midfetal, Adolescence and Early Adulthood timepoints and association with schizophrenia and bipolar disorder, such that genes more strongly associated with these disorders had relatively low expression during Early Midfetal development and higher expression during Adolescence and Early Adulthood. The relationship with schizophrenia was strongest for the subset of genes related to calcium channel activity, whilst for bipolar disorder the relationship was distributed between calcium and potassium channel activity genes.ConclusionsOur results indicate periods during development when biological pathways related to the activity of calcium and potassium channels may be most vulnerable to the effects of genetic variants conferring risk to psychiatric disorders. Furthermore, they indicate key time points and potential targets for disorder-specific therapeutic interventions.

AbstractGenes encoding the mRNA targets of Fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. We then explored the partitioning of genetic association between overrepresented functional categories. High-confidence targets of FMRP were enriched for common schizophrenia risk alleles, as well as rare loss-of-function andde novononsynonymous variants in cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by membership of other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders, across traditional diagnostic boundaries.

Abstract
. Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A LOF may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.

Genes encoding the mRNA targets of fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. High-confidence targets of FMRP, derived from studies of multiple tissue types, were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in schizophrenia cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders.

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.

Common genetic variation contributes a substantial proportion of risk for both schizophrenia and bipolar disorder. Furthermore, there is evidence of significant, but not complete, overlap in genetic risk between the two disorders. It has been hypothesised that genetic variants conferring risk for these disorders do so by influencing brain development, leading to the later emergence of symptoms. The comparative profile of risk gene expression for schizophrenia and bipolar disorder across development over different brain regions however remains unclear. Using genotypes derived from genome-wide associations studies of the largest available cohorts of patients and control subjects, we investigated whether genes enriched for schizophrenia and bipolar disorder association show a bias for expression across any of 13 developmental stages in prefrontal cortical and subcortical brain regions. We show that genetic association with schizophrenia is positively correlated with expression in the prefrontal cortex during early midfetal development and early infancy, and negatively correlated with expression during late childhood, which stabilises in adolescence. In contrast, risk-associated genes for bipolar disorder did not exhibit a bias towards expression at any prenatal stage, although the pattern of postnatal expression was similar to that of schizophrenia. These results highlight the dynamic expression of genes harbouring risk for schizophrenia and bipolar disorder across prefrontal cortex development and support the hypothesis that prenatal neurodevelopmental events are more strongly associated with schizophrenia than bipolar disorder.

Alterations in synaptic signaling and plasticity occur during the refinement of neural circuits over the course of development and the adult processes of learning and memory. Synaptic plasticity requires the rearrangement of protein complexes in the postsynaptic density (PSD), trafficking of receptors and ion channels and the synthesis of new proteins. Activity-induced short Homer proteins, Homer1a and Ania-3, are recruited to active excitatory synapses, where they act as dominant negative regulators of constitutively expressed, longer Homer isoforms. The expression of Homer1a and Ania-3 initiates critical processes of PSD remodeling, the modulation of glutamate receptor-mediated functions, and the regulation of calcium signaling. Together, available data support the view that Homer1a and Ania-3 are responsible for the selective, transient destabilization of postsynaptic signaling complexes to facilitate plasticity of the excitatory synapse. The interruption of activity-dependent Homer proteins disrupts disease-relevant processes and leads to memory impairments, reflecting their likely contribution to neurological disorders.

<i>CACNA1C</i>encodes the Ca<sub>v</sub>1.2 L-type voltage-gated calcium channel. Generic variation in CACNA1C has been consistently identified as associated with risk for psychiatric disorders including schizophrenia, bipolar disorder, major depressive disorder and autism. Psychiatric risk loci are also enriched for genes involved in the regulation of synaptic plasticity. Here, we show that the expression of <i>Cacna1c</i> is regulated in the rat hippocampus after context exposure, contextual fear conditioning and fear memory retrieval in a manner that correlates to specific memory processes. Using quantitative in situ hybridisation, the expression was down-regulated in CA1 by brief exposure to a novel context and to a conditioned context, and up-regulated in the dentate gyrus after contextual fear conditioning. No changes were measured after prolonged context exposure followed by conditioning, a procedure that retards fear conditioning (latent inhibition), nor with fear memory recall leading to extinction. These results are consistent with a selective role for Ca<sub>v</sub>1.2 in the consolidation of context memory and contextual fear memory, and with processes associated with the maintenance of the fear memory after recall. The dysregulation of <i>CACNA1C</i> may thus be related to associative memory dysfunction in schizophrenia and other psychiatric disorders.

Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.