BACKGROUND:Mosaic genetic variation has been implicated in the pathogenesis of both malignant and nonmalignant immunologic diseases. OBJECTIVE:We sought to investigate a unique case of postnatal acquisition of a gain-of-function (GoF) KRAS variant, with an additional GoF STAT5B variant, in an 18-year-old woman with inflammatory bowel disease, splenomegaly, thrombocytopenia, bronchiectasis, monocytosis, and eosinophilia. METHODS:Diagnostic panel, whole-genome, and targeted amplicon sequencing were performed on longitudinal blood and tissue samples to reveal germline and mosaic variants and their allele frequencies across different cell populations. Short- and long-read single-cell RNA sequencing and flow cytometry were used to measure the effect of variants on RNA, protein, and leukocyte cell state. RESULTS:Both mosaic variants were present across multiple leukocyte subsets and historical blood and tissue samples, with the emergence of both variants coinciding with the clinical presentation. Both variants were expressed in a unique population of monocytes, associated with dysregulated cytokine signaling and the presence of a distinct population of highly granular CD24+ leukocytes. CONCLUSIONS:Taken together with the clinical presentation, these findings led to a diagnosis of combined Ras-associated autoimmune leukoproliferative disorder and nonclonal STAT5B GoF disease. To our knowledge, this is the first reported combination of 2 distinct acquired errors of immunity causing a mixed clinical phenotype, and this highlights the importance of considering acquired monogenic diseases within a broader genomic context.

Oxidative stress is one of the most important environmental exposures associated with psychiatric disorders, but the underlying molecular mechanisms remain to be elucidated. In a previous study, we observed a substantial alteration of the gene expression landscape in neuron-like cells that were differentiated from SH-SY5Y cells after or during exposure to oxidative stress, with a subset of dysregulated genes being enriched for neurodevelopmental processes. To further explore the regulatory mechanisms that might account for such profound perturbations, we have now applied small RNA-sequencing to investigate changes in the expression of miRNAs. These molecules are known to play crucial roles in brain development and response to stress through their capacity to suppress gene expression and influence complex biological networks. Through these analyses, we observed more than a hundred differentially expressed miRNAs, including 80 previously reported to be dysregulated in psychiatric disorders. The seven most influential miRNAs associated with pre-treatment exposure, including miR-138-5p, miR-96-5p, miR-34c-5p, miR-1287-5p, miR-497-5p, miR-195-5p, and miR-16-5p, supported by at least 10 negatively correlated mRNA connections, formed hubs in the interaction network with 134 genes enriched with neurobiological function, whereas in the co-treatment condition, miRNA-mRNA interaction pairs were enriched in cardiovascular and immunity-related disease ontologies. Interestingly, 12 differentially expressed miRNAs originated from the DLK1-DIO3 location, which encodes a schizophrenia-associated miRNA signature. Collectively, our findings suggest that early exposure to oxidative stress, before and during prenatal neuronal differentiation, might increase the risk of mental illnesses in adulthood by disturbing the expression of miRNAs that regulate neurodevelopmentally significant genes and networks.

PurposeWe investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing.MethodsProbands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis.ResultsInitial GS analysis in 2019 (n=111) identified a molecular diagnosis in 11.7% (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2% (8/111); 3.6% (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6% (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants.ConclusionGS data reanalysis increased the diagnostic yield from 11.7% to 18.9%, with potential extension up to 22.5%. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

BACKGROUND: Unpacking molecular perturbations associated with features of schizophrenia is a critical step toward understanding phenotypic heterogeneity in this disorder. Recent epigenome-wide association studies have uncovered pervasive dysregulation of DNA methylation in schizophrenia; however, clinical features of the disorder that account for a large proportion of phenotypic variability are relatively underexplored. METHODS: We comprehensively analyzed patterns of DNA methylation in a cohort of 381 individuals with schizophrenia from the deeply phenotyped Australian Schizophrenia Research Bank. Epigenetic changes were investigated in association with cognitive status, age of onset, treatment resistance, Global Assessment of Functioning scores, and common variant polygenic risk scores for schizophrenia. We subsequently explored alterations within genes previously associated with psychiatric illness, phenome-wide epigenetic covariance, and epigenetic scores. RESULTS: Epigenome-wide association studies of the 5 primary traits identified 662 suggestively significant (p , 6.72 3 1025) differentially methylated probes, with a further 432 revealed after controlling for schizophrenia polygenic risk on the remaining 4 traits. Interestingly, we uncovered many probes within genes associated with a variety of psychiatric conditions as well as significant epigenetic covariance with phenotypes and exposures including acute myocardial infarction, C -reactive protein, and lung cancer. Epigenetic scores for treatment -resistant schizophrenia strikingly exhibited association with clozapine administration, while epigenetic proxies of plasma protein expression, such as CCL17, MMP10, and PRG2, were associated with several features of schizophrenia. CONCLUSIONS: Our findings collectively provide novel evidence suggesting that several features of schizophrenia are associated with alteration of DNA methylation, which may contribute to interindividual phenotypic variation in affected individuals.

While RNA expression appears to be altered in several brain disorders, the constraints of postmortem analysis make it impractical for well-powered population studies and biomarker development. Given that the unique molecular composition of neurons are reflected in their extracellular vesicles (EVs), we hypothesized that the fractionation of neuron derived EVs provides an opportunity to specifically profile their encapsulated contents noninvasively from blood. To investigate this hypothesis, we determined miRNA expression in microtubule associated protein 1B (MAP1B)–enriched serum EVs derived from neurons from a large cohort of individuals with schizophrenia and nonpsychiatric comparison participants. We observed dysregulation of miRNA in schizophrenia subjects, in particular those with treatment-resistance and severe cognitive deficits. These data support the hypothesis that schizophrenia is associated with alterations in posttranscriptional regulation of synaptic gene expression and provides an example of the potential utility of tissue-specific EV analysis in brain disorders.

The molecular composition of neurons is specific to the functional state and is altered during disease. While these alterations may be detected in postmortem analyses, the ethical constraints, small sample sizes and other confounders are insurmountable for well-powered population studies and biomarker development. Given that neurons release extracellular vesicles (EVs) which reflect their origin, we hypothesized that the fractionation of neuron derived EVs provides an opportunity to specifically profile their encapsulated contents non-invasively from blood. To explore this possibility, we determined miRNA expression MAP1B-enriched serum EVs derived from neurons from a large cohort of individuals with schizophrenia or no history of psychiatric illness. Aliquots of serum from the Australian Schizophrenia Research Bank (ASRB) cohort (n=477) were incubated with MAP1B antibody-coupled magnetic beads to capture neuronal origin extracellular vesicles. Total RNA was extracted for small RNA library preparation and sequenced. Differential expression based on diagnostic and cognitive criteria was performed using edgeR, adjusting for batch, sex and age. Dysregulation of miRNA was observed in individuals with schizophrenia and included brain enriched molecules such as hsa-miR-92a-3p and has-miR-486-5p, with demonstrated roles in synaptic plasticity and corticogenesis. Importantly, individuals with severe disease (cognitive impairments and treatment resistance) showed greater alterations than those observed in non-severe disease counterparts. Overall, there was a trend for increased vesicular expression of miRNA in schizophrenia subjects, suggesting the cell of origin hosts an abundance of regulatory molecules. Predicted target genes of miRNA differentially expressed in schizophrenia are enriched for neuronal, synaptic and neurotransmitter annotations. Additionally, miRNA targets were also enriched with genes genetically associated with schizophrenia. We observed profound dysregulation of brain expressed miRNA in cognitive deficit and treatment resistant schizophrenia in serum EVs from neural origin. Many of the altered miRNA identified in the current work have previously been found to be dysregulated in schizophrenia from analyses of CNS tissues, suggesting our non-invasive method can detect disease related molecules. The individual miRNA, the transcripts they target and genetic association with schizophrenia suggest functional consequences for adult neurogenesis and synaptic neuropathology.

Psychiatric disorders have a polygenic architecture, often associated with dozens or hundreds of independent genomic loci. Most associated loci impact noncoding regions of the genome, suggesting that the majority of disease heritability originates from the disruption of regulatory sequences. While most research has focused on variants that modify regulatory DNA elements, those affecting cis-acting RNA sequences, such as miRNA binding sites, are also likely to have a significant impact. We intersected genome-wide association study (GWAS) summary statistics with the dbMTS database of predictions for miRNA binding site variants (MBSVs). We compared the distributions of MBSV association statistics to non-MBSVs within brain-expressed 3'UTR regions. We aggregated GWAS p values at the gene, pathway, and miRNA family levels to investigate cellular functions and miRNA families strongly associated with each trait. We performed these analyses in several psychiatric disorders as well as nonpsychiatric traits for comparison. We observed significant enrichment of MBSVs in schizophrenia, depression, bipolar disorder, and anorexia nervosa, particularly in genes targeted by several miRNA families, including miR-335-5p, miR-21-5p/590-5p, miR-361-5p, and miR-557, and a nominally significant association between miR-323b-3p MBSVs and schizophrenia risk. We identified evidence for the association between MBSVs in synaptic gene sets in schizophrenia and bipolar disorder. We also observed a significant association of MBSVs in other complex traits including type 2 diabetes. These observations support the role of miRNA in the pathophysiology of psychiatric disorders and suggest that MBSVs are an important class of regulatory variants that have functional implications for many disorders, as well as other complex human traits.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells ( r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes ( r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

There is a long-standing interest in exploring the relationship between blood-based biomarkers and psychiatric disorders, despite their causal role being difficult to resolve in observational studies. In this study, we leverage genome-wide association study data for a large panel of heritable serum biochemical traits to refine our understanding of causal effect in biochemical-psychiatric trait pairings. We observed widespread positive and negative genetic correlation between psychiatric disorders and biochemical traits. Causal inference was then implemented to distinguish causation from correlation, with strong evidence that C-reactive protein (CRP) exerts a causal effect on psychiatric disorders. Notably, CRP demonstrated both protective and risk-increasing effects on different disorders. Multivariable models that conditioned CRP effects on interleukin-6 signaling and body mass index supported that the CRP-schizophrenia relationship was not driven by these factors. Collectively, these data suggest that there are shared pathways that influence both biochemical traits and psychiatric illness.

Schizophrenia is a neurodevelopmental disorder associated with abnormal dopamine (DA) signalling and disruptions in early brain development. We have shown that developmental vitamin D-deficiency (DVD-deficiency) increases the risk of schizophrenia in offspring and impairs various aspects of brain development in rodents, particularly that of DA neurons, however the molecular basis of these impairments remains unclear. Here, we explore whether small non-coding microRNAs (miRNAs) are involved. miRNAs regulate gene expression post-transcriptionally via translational repression and destabilisation of mRNA. While dysregulation of multiple miRNAs has been reported in post-mortem brain of patients with schizophrenia, the biological pathways affected by these small RNAs are not clear. Here we identified differential expression of 18 miRNAs in DA neurons isolated from DVD-deficient embryos. Three miRNAs were selected for further functional studies of dopaminergic neuron differentiation based on their interactions with transcripts involved in neuronal maturation. In particular, we show upregulation of miR-181c-5p suppresses neurite outgrowth of dopaminergic neurons. These findings provide further evidence that an environmental risk factor for schizophrenia - DVD-deficiency - disrupts the development of DA neurons and suggests increased miRNA expression may be one possible mechanism. This disruption potentially underlies the long-term alterations in DA mediated brain function in DVD-deficient offspring, and by inference in schizophrenia.

Genetically informed drug development and repurposing is an attractive prospect for improving patient outcomes in psychiatry; however, the effectiveness of these endeavors is confounded by heterogeneity. We propose an approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritize individual “directional anchor” genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, which we call a pharmagenic enrichment score (PES), identify individuals with a higher burden of genetic risk, localized in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

Genetically informed drug development and repurposing is an attractive prospect for improving outcomes in patients with psychiatric illness; however, the effectiveness of these endeavours can be confounded by heterogeneity. In this study, we propose a novel approach that links interventions implicated by disorder-associated genetic risk, at the population level, to a framework that can target these compounds to individuals. Specifically, results from genome-wide association studies are integrated with expression data to prioritise individual 'directional anchor' genes for which the predicted risk-increasing direction of expression could be counteracted by an existing drug. While these compounds represent plausible therapeutic candidates, they are not likely to be equally efficacious for all individuals. To account for this heterogeneity, we constructed polygenic scores restricted to variants annotated to the network of genes that interact with each directional anchor gene. These metrics, we call pharmagenic enrichment scores (PES), identify individuals with a higher burden of genetic risk, localised in biological processes related to the candidate drug target, to inform precision drug repurposing. We used this approach to investigate schizophrenia and bipolar disorder and reveal several compounds targeting specific directional anchor genes that could be plausibly repurposed, including antioxidants, vitamins, antiarrhythmics, and lipid modifying agents. These genetic risk scores, mapped to the networks associated with target genes, revealed biological insights that cannot be observed in undifferentiated genome-wide polygenic risk score (PRS). For example, an enrichment of these partitioned scores in schizophrenia cases with otherwise low PRS and distinct correlations with measured biochemical traits. In summary, genetic risk could be used more specifically to direct drug repurposing candidates that target particular genes implicated in psychiatric and other complex disorders.

Pneumonia remains one of the leading causes of death worldwide. In this study, we use genome-wide meta-analysis of lifetime pneumonia diagnosis ( N = 391,044) to identify four association signals outside of the previously implicated major histocompatibility complex region. Integrative analyses and finemapping of these signals support clinically tractable targets, including the mucin MUC5AC and tumour necrosis factor receptor superfamily member TNFRSF1A . Moreover, we demonstrate widespread evidence of genetic overlap with pneumonia susceptibility across the human phenome, including particularly significant correlations with psychiatric phenotypes that remain significant after testing differing phenotype definitions for pneumonia or genetically conditioning on smoking behaviour. Finally, we show how polygenic risk could be utilised for precision treatment formulation or drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide insights into the genetic architecture of pneumonia susceptibility and genetics informed targets for drug development or repositioning.

Among the various biological effects of asbestos such as fibrogenesis and carcinogenesis, we have been focusing on the immunological effects becausesilica (SiO2) and asbestos chemically is a mineral silicate of silica. Observations of the effects of asbestos on CD4+ T cells showed reduction of CXCR3 chemokine receptor and reduced capacity of interferon γ production. In particular, use of theHTLV-1 immortalized human T cell line, MT-2, and cDNA array analysis have helped to identify the modification of CXCR3. We investigated alteration of protein expression among MT-2 original cells that had no contact with asbestos, and six chrysotile-continuously exposed independent sublines using ProteinChip and two-dimensional gel electrophoresis (2DGE) assays. Further confirmation of the changes in protein expression due to asbestos exposure was obtained after the 2DGE method indicated protein modification of β-actin. β-actin was upregulated in mRNA, as were the levels of protein expression and phosphorylation. Moreover, a binding assay between cells and chrysotile showed that various molecules related to the cytoskeleton such as vimentin, myosin-9 and tubulin-β2, as well as β-actin, exhibited enhanced bindings in asbestos-exposed cells. The overall findings indicate that the cell surface cytoskeleton may play an important role in inducing the cellular changes caused by asbestos in immune cells, since fibers are not incorporated to the cells and how the alterations of cytoskeleton determined cell destiny to cause the reduction of tumor immunity is important to consider the biological effects of asbestos. Further studies to target several cytoskeleton-related molecules associated with the effects of asbestos will result in a better understanding of the immunological effects of asbestos and support the development of chemo-prevention to recover anti-tumor immunity in asbestos-exposed patients.

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug–gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.

ABSTRACT Pneumonia remains one of the leading causes of death worldwide, particularly amongst the elderly and young children. We performed a genome-wide meta-analysis of lifetime pneumonia diagnosis (N=266,277), that encompassed the largest collection of cases published to date. Genome-wide significant associations with pneumonia were uncovered for the first time beyond the major histocompatibility complex region, with three novel loci, including a signal fine-mapped to a cluster of mucin genes. Moreover, we demonstrated evidence of a polygenic effect of common and low frequency pneumonia associated variation impacting several other mucin genes and O -glycosylation, further suggesting a role for these processes in pneumonia pathophysiology. The pneumonia GWAS was then leveraged to identify drug repurposing opportunities, including evidence that supports the use of lipid modifying agents in the prevention and treatment of the disorder. We also propose how polygenic risk could be utilised for precision drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide novel insights into the genetic architecture of pneumonia susceptibility, with future study warranted to functionally interrogate novel association signals and evaluate the suitability of the compounds prioritised by this study as repositioning candidates.

Glucocorticoids and hypoxia are two essential factors affecting the brain development during labor and delivery. In addition to the neurobehavioral alterations induced separately by these factors, glucocorticoids can attenuate the deleterious consequences of severe hypoxia-ischemia on the brain development, acting as a neuroprotective agent in combination with hypoxia. The role of hypoxia in the combined action with corticosteroids is less clear. Severe hypoxia-ischemia results in the massive activation of caspase-3, masking any other effects of hypoxia on the neonatal brain exposed to glucocorticoids. As a result, the effects of mild hypoxia on the developing brain pretreated with glucocorticoids remain unclear.To analyze this problem, 2-day-old male rats were treated with dexamethasone (DEX) before the subsequent exposure to mild 10-min anoxia or normoxia. The treatment with only DEX resulted in the delay in the development of the negative geotaxis reaction and in the decrease in locomotor activity of the neonatal male pups. The mild anoxic event attenuated these DEX-induced neurobehavioral alterations. The treatment with DEX, but not the mild anoxic exposure alone, resulted in the delayed upregulation of active caspase-3 in the prefrontal cortex and in the brainstem of the male pups. This glucocorticoid-induced upregulation of active caspase-3 was prevented by the anoxic event.The present findings evidence that mild anoxia is capable of ameliorating the glucocorticoid-induced neurodevelopmental alterations in the neonatal rats if the artificial or the naturally occurring increase in the levels of glucocorticoids occurred just before the episode of hypoxia.

Pneumonia remains one of the leading causes of death worldwide, particularly amongst the elderly and young children. We performed a genome-wide meta-analysis of lifetime pneumonia diagnosis (N=266,277), that encompassed the largest collection of cases published to date. Genome-wide significant associations with pneumonia were uncovered for the first time beyond the major histocompatibility complex region, with three novel loci, including a signal fine-mapped to a cluster of mucin genes. Moreover, we demonstrated evidence of a polygenic effect of common and low frequency pneumonia associated variation impacting several other mucin genes and O-glycosylation, further suggesting a role for these processes in pneumonia pathophysiology. The pneumonia GWAS was then leveraged to identify drug repurposing opportunities, including evidence that supports the use of lipid modifying agents in the prevention and treatment of the disorder. We also propose how polygenic risk could be utilised for precision drug repurposing through pneumonia risk scores constructed using variants mapped to pathways with known drug targets. In summary, we provide novel insights into the genetic architecture of pneumonia susceptibility, with future study warranted to functionally interrogate novel association signals and evaluate the suitability of the compounds prioritised by this study as repositioning candidates.

ABSTRACT Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a unit increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR = 0.48 [95% CI: 0.33-0.71] – inverse-variance weighted estimate. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.

Prenatal environmental exposures that have been shown to induce oxidative stress (OS) during pregnancy, such as smoking and alcohol consumption, are risk factors for the onset of schizophrenia and other neurodevelopmental disorders (NDDs). While the OS role in the etiology of neurodegenerative diseases is well known, its contribution to the genomic dysregulation associated with psychiatric disorders is less well defined. In this study we used the SH-SY5Y cell line and applied RNA-sequencing to explore transcriptomic changes in response to OS before or during neural differentiation. We observed differential expression of many genes, most of which localised to the synapse and were involved in neuronal differentiation. These genes were enriched in schizophrenia-associated signalling pathways, including PI3K/Akt, axon guidance, and signalling by retinoic acid. Interestingly, circulatory system development was affected by both treatments, which is concordant with observations of increased prevalence of cardiovascular disease in patients with NDDs. We also observed a very significant increase in the expression of immunity-related genes, supporting current hypotheses of immune system involvement in psychiatric disorders. While further investigation of this influence in other cell and animal models is warranted, our data suggest that early life exposure to OS has a disruptive influence on neuronal gene expression that may perturb normal differentiation and neurodevelopment, thereby contributing towards overall risk for developing psychiatric diseases.