Translational Psychiatry

BackgroundBipolar disorder (BD) factor models offer limited dimensional understanding due to incomplete integration of psychosocial deficits, long-term outcomes, and transdiagnostic genetics, thus restricting personalised interventions. This study aimed to provide a holistic understanding of BD psychopathology, overcoming this limitation. MethodsExploratory Factor Analysis of 77 OPCRIT items revealed four psychopathological dimensions, and Confirmatory Factor Analysis validated a 20-item, four-...

Circulating miRNAs in small vesicles known as exosomes within blood have been emerging as a new research hotspot in the field of psychiatric disorders. The aim of this work was to characterize the changes in exosomal microRNA profiles, both short-term and long-term, during substance withdrawal using a cross-sectional study design. Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal microRNAs were identified as being associated with withdrawal stag...

Structured AbstractO_ST_ABSImportanceC_ST_ABSPsychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy. ObjectiveTo identify gene expression patterns underlying genetic convergence and divergence across psychiat...

Psychiatric disorders are highly prevalent and display considerable clinical and genetic overlap. Dopaminergic and serotonergic neurotransmission have been shown to have an important role in many psychiatric disorders. Here we aim to assess the genetic contribution of these systems to eight psychiatric disorders (ADHD, ANO, ASD, BIP, MD, OCD, SCZ and TS) using publicly available GWAS analyses performed by the Psychiatric Genomics Consortium. To do so, we elaborated four different gene sets using...

Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune ...

Neurodevelopmental disorder-risk CNVs (NDD CNVs) are associated with complex neuropsychiatric phenotypes. These CNVs also confer risk for a host of medical outcomes in adults yet the long-term health consequences in the context of comorbid psychiatric illness have not been well documented. Twenty-four psychiatric inpatients with treatment-resistant psychosis were identified as carriers of NDD CNVs as part of a larger Pennsylvania State Hospital genomics study. Comprehensive life course phenotypi...

BackgroundMajor depressive disorder (MDD) is a neuro-immune, oxidative, and nitrosative stress (NIMETOX) disorder, in which peripheral immune-redox pathways intersect with metabolic networks leading to neurotoxicity within the limbic-prefrontal affective circuits. Comprehensive metabolomics analysis in well-phenotyped patients is vital to elucidate their metabolic profile. ObjectivesTo identify metabolic abnormalities that differentiate inpatients with severe MDD from healthy controls through h...

BackgroundPreviously, population-based cohort studies have identified the association between epigenetic modifications of OR2L13 related to mental disorders and Gestational diabetes mellitus (GDM). However, the causal nature of these associations remains difficult to establish owing to confounding. AimsThe purpose of the study was to investigate the causal effect of methylation of OR2L13 and offspring mental health outcomes. MethodWe performed two-sample mendelian randomisation to assess the e...

BackgroundSchizophrenia (SCZ) is a highly heritable and heterogeneous disorder with diverse clinical presentations and cognitive deficits. The specific genetic variants contributing to this variability remain largely unknown. This study aims to uncover the genetic bases of various clinical phenotypes such as age at onset (AAO), positive/negative symptoms, self-harm and aggression in SCZ using genome-wide association studies (GWAS). Few large-scale GWAS have explored these phenotypes, especially ...

Previous studies have revealed a significant overlap between ADHD and RLS populations, with shared pathological mechanisms such as dopaminergic function and iron metabolism deficits. However, the genetic mechanisms underlying these connections remain unclear. In our study, we conducted a genome-wide genetic correlation analysis to confirm a shared genetic structure between ADHD and RLS. We identified five pleiotropic loci through PLACO analysis, with colocalization analysis revealing a shared ca...

ImportanceLarge-scale genome-wide association studies (GWASs) are expected to inform the development of pharmacological treatments, however the mechanisms of correspondence between the genetic liability identified through GWASs and disease pathophysiology are not well understood. ObjectiveTo investigate whether functional information from a range of open bioinformatics datasets can elucidate the relationship between GWAS-identified genetic variation and the genes targeted by current treatments ...

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, but its genetic architecture remains incompletely characterized. Rare coding variants, which can profoundly impact gene function, represent an underexplored dimension of ADHD risk. In this study, we analyzed large-scale DNA sequencing datasets from ancestrally diverse cohorts and observed significant enrichment of rare protein-truncating and deleterious missense variants in highly evolutionarily co...

Substance use disorders commonly co-occur with one another and with other psychiatric disorders. They share common features including high impulsivity, negative affect, and lower executive function. We tested whether a common genetic factor undergirds liability to problematic alcohol use (PAU), problematic tobacco use (PTU), cannabis use disorder (CUD), and opioid use disorder (OUD) by applying genomic structural equation modelling to genome-wide association study summary statistics for individu...

BackgroundMajor depressive disorder (MDD) is a neuro-immune-metabolic-oxidative (NIMETOX) disorder. Nevertheless, the effects of alterations in immune responsiveness, oxidative stress, antioxidant defenses, gut-derived short-chain fatty acids (SCFAs), metabolic hormones and adipokines on metabolomic modules and the MDD phenome have remained elusive. MethodsSerum samples from 125 MDD inpatients and 40 healthy controls were analyzed using high-resolution metabolomics assays (liquid chromatography...

Current phenotype classifiers for large biobanks with coupled electronic health records EHR and multi-omic data rely on ICD-10 codes for definition. However, ICD-10 codes are primarily designed for billing purposes, and may be insufficient for research. Nuanced phenotypes composed of a patients experience in the EHR will allow us to create precision psychiatry to predict disease risk, severity, and trajectories in EHR and clinical populations. Here, we create a phenotype risk score (PheRS) for m...

Major depressive disorder (MDD) impacts females and males differently and post-mortem gene expression profiling reveals distinct transcriptomic signatures of the disorder in each sex. Using genes that are transcriptionally altered in MDD in both sexes, we recently developed a novel transcriptome-based polygenic risk score (tPRS), which had sex-specific associations with brain structure and depressive symptoms in both adolescents and adults. Identifying the neurodevelopmental signatures of geneti...

IntroductionCurrent understanding of the differences in sleep disturbance (SD) and associated risk factors in patients with alcohol use disorders (AUD), major depressive disorders (MDD), and comorbid AUD+MDD is limited. MethodsData from the UK Biobank (UKB) (n=47,825) were utilized to categorize subjects into those with MDD (n=5,991), AUD (n=12,952), both (MDD+AUD)(n=3,219), and controls (n=25,663). We used generalized linear models (GLMs) to test whether rates of SD and sleep duration differed...

Most epigenetic research on post-traumatic stress disorder (PTSD) has primarily focused on DNA methylation (5mC) in peripheral tissues, particularly at CpG sites. DNA hydroxymethylation (5hmC) has been found to be highly enriched in the mammalian brain, while 5mC at non-CpG sites shows high enrichment in neurons. However, little is known about their role in PTSD. Here, we characterize genome-wide differential 5mC and 5hmC at both CpG and non-CpG sites in postmortem orbitofrontal neurons from PTS...

Aims/hypothesisObservational studies have shown a bidirectional association between major depressive disorder (MDD), Insulin resistance (IR), and related diseases, which varies between sexes and ancestries. We conducted a sex-specific two-sample bidirectional Mendelian randomization (MR) study to assess the causal associations of MDD with Insulin resistance measured through the TG: HDL-C ratio and vice versa using Caucasian and East Asian data. MethodsWe extracted summary-level data for MDD and...

BackgroundInflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear. This study investigates associations between depression, structural neuroimaging measures and two measures of inflammation: serum-based C-reactive protein (CRP) and a methylation-based score for CRP (DNAm CRP) in a large community-based sample. MethodsSerum CRP and DNAm CRP were assessed fo...