Molecular Psychiatry

Common diseases result from a mix of genetic and environmental factors, often involving inflammation. Complex traits like diabetes and psychiatric disorders are polygenic, influenced by many genetic variants. The omnigenic model suggests all expressed genes can impact disease-related genes. This study examines blood transcriptomic variations in psychiatric and neurological disorders to understand mRNA expression profiles and address field discrepancies. Animal models are explored for similar gen...

ObjectiveAssociations have been seen between suicidal behavior and differential DNA methylation of certain genes, with one study showing significant hypomethylation of ARHGEF38 in postmortem brain samples from individuals with bipolar disorder who died by suicide. Our objective was to explore ARHGEF38 methylation in individuals with bipolar disorder and a history of suicide attempt. MethodWith pyrosequencing, we looked at the previously identified region of interest in ARHGEF38. We investigated...

Only recently have human postmortem brain studies of differential gene expression (DGE) associated with opioid overdose death (OOD) been published; sample sizes from these studies have been modest (N = 40-153). To increase statistical power to identify OOD-associated genes, we leveraged human prefrontal cortex RNAseq data from four independent OOD studies and conducted a transcriptome-wide DGE meta-analysis (N = 285). Using a unified gene expression data processing and analysis framework across ...

BackgroundClinical progression during psychosis has been closely associated with grey matter abnormalities resulting from atypical brain development. However, the complex interplay between psychopathology and heterogeneous maturational trajectories challenges the identification of neuroanatomical features that anticipate symptomatic decline. AimsTo investigate cortical volume longitudinal deviations in FEP using normative modelling, exploring their relationship with long-term cognitive and symp...

Suicide is an urgent public health crisis that claimed over 48,000 lives in the US in 2022. The importance of genetics in suicide risk has been established by classical twin and family studies, and confirmed with recent large genome-wide association studies (GWAS). While the GWAS are beginning to reveal genetic risk due to common variants each with small effect on liability, these results explain only a fraction of the genetic risk. As with other complex health conditions, some of this unexplain...

Background and HypothesisAntipsychotic medications are the first-line treatment for schizophrenia. However, around 40% of people with schizophrenia who are treated with antipsychotics could develop extrapyramidal side-effects (EPSE) including: 1) Dyskinesias, 2) Parkinsonism, 3) Akathisia, and 4) Dystonia. Study DesignWe conducted Genome-wide association (GWAS) and Epigenome-wide association (EWAS) meta-analysis of EPSE utilising data from previous schizophrenia case control studies. We integra...

BackgroundAutism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii)...

Non-coding variants increase risk of neuropsychiatric disease. However, our understanding of the cell-type specific role of the non-coding genome in disease is incomplete. We performed population scale (N=1,393) chromatin accessibility profiling of neurons and non-neurons from two neocortical brain regions: the anterior cingulate cortex and dorsolateral prefrontal cortex. Across both regions, we observed notable differences in neuronal chromatin accessibility between schizophrenia cases and cont...

IntroductionCortical grey matter loss is a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and has been shown to progress with ongoing illness. A major unresolved question concerns whether these changes are driven by the illness itself or represent iatrogenic effects of antipsychotic medication. MethodsWe report findings from a triple-blind randomised placebo-controlled MRI study where 62 antipsychotic- naive people with first episode psychosis (FEP) received...

BackgroundImpairment of the glymphatic system may contribute to atypical brain development and increased vulnerability to psychiatric conditions such as psychosis. In particular, disrupted glymphatic efficiency may affect neurochemical homeostasis during critical maturational windows, leading to structural and circuit-level alterations. However, its role in early neurodevelopmental trajectories remains largely unexplored. MethodsWe combined longitudinal diffusion tensor imaging (DTI) and magnet...

BackgroundMachine learning (ML) can distinguish cases with psychotic disorder from healthy controls based on magnetic resonance imaging (MRI) data, with reported accuracy in the range 60-100%. It is not yet clear which MRI metrics are the most informative for case-control ML. MethodsWe analysed multi-modal MRI data from two independent case-control studies of patients with psychotic disorders (cases, N = 65, 28; controls, N = 59, 80) and compared ML accuracy across 5 MRI metrics. Cortical thick...

ImportancePsychotic illness is associated with anatomically distributed grey matter reductions that can worsen with illness progression, but the mechanisms underlying the specific spatial patterning of these changes is unknown. ObjectiveTo test the hypothesis that brain network architecture constrains cross-sectional and longitudinal grey matter alterations across different stages of psychotic illness and to identify whether certain brain regions act as putative epicentres from which volume los...

Bipolar disorder (BD) is a common and yet poorly elucidated psychiatric disorder, with emerging evidence implicating a role for epigenetic mechanisms, including microRNAs (miRNAs), in its pathophysiology. These molecules are secreted from cells in extracellular vesicles (EVs), which can be isolated from bodily fluids and tested as potential biomarkers. In individuals with BD and control participants (CON), we characterized the miRNA expression profiles of peripheral blood EVs selected for L1CAM,...

Bipolar disorder is an often-severe mental health disorder characterized by alternation between extreme mood states of mania and depression. Despite strong heritability and the recent identification of 64 loci of small effect, pathophysiological mechanisms and much of the genetic risk remain unknown. Here, through genome sequencing and linkage and association analyses, we found that rare variants co-segregating with bipolar disorder in large multiply affected families cluster within gene network...

BackgroundHippocampal hyperactivity in early psychosis may result from excitation-inhibition imbalance within corticolimbic regions. Preclinical evidence suggests that positive allosteric modulation of hippocampal inhibitory 5-{gamma}-aminobutyric acid receptors (5-GABAAR) attenuates hippocampal hyperactivity, striatal hyperdopaminergia, and psychosis-relevant behaviours. Here, we investigated whether hippocampal hyperactivity and 5-GABAAR network covariance are perturbed in people at clinical h...

Brodmann Area 10 (BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning around the average age of onset for Bipolar disorder (BP) and Schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of...

BackgroundBipolar disorder (BPD) is a debilitating mood disorder with an unclear aetiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD. MethodsWe tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-bas...

Background22q11.2 deletion syndrome (22q11DS) is a common microdeletion associated with widespread brain alterations and elevated risk for schizophrenia and other neuropsychiatric conditions. Prospective research studies often exclude individuals with severe cognitive impairment, medical comorbidities, or inability to tolerate research MRI without sedation, features common in 22q11DS. This limits both the generalizability of neuroimaging findings and our understanding of the full phenotypic spec...

Psychiatric disorders like schizophrenia, bipolar disorder, and major depressive disorder exhibit significant genetic and clinical overlap. However, their molecular architecture remains elusive due to their polygenic nature and complex brain cell interactions. Here, we integrated clinical data with genetic susceptibility to investigate gene expression and chromatin accessibility in the orbitofrontal cortex of 92 postmortem human brain samples at the single-cell level. Through single-nucleus (sn)...

22q11.2 deletion syndrome (22q11.2DS) stands out as one of the most significant risk factors for schizophrenia (SCZ), with approximately 40% of individuals with 22q11.2DS experiencing psychosis. The presence of discordant phenotypes among monozygotic twins, along with the involvement of environmental factors in the multiple-hit model hypothesis for psychosis onset, underscores the potential role of epigenetic modifications in the development of neuropsychiatric disorders among individuals with 2...