Molecular Psychiatry

Distinguishing causal biology from confounding or downstream consequences of psychiatric disorders remains a key barrier for drug development in psychiatry. We performed a large-scale proteogenomic investigation using a sequential triangulation framework integrating plasma proteomics, Mendelian randomisation, genetic colocalisation, transcriptomics, rare-variant analyses, and clinical phenotyping to identify causal proteins and prioritise therapeutic targets for depression, anxiety, bipolar disorder, and psychotic disorders. Using 2,920 plasma proteins measured in 52,615 UK Biobank participants, we identified 830 protein-disorder associations involving 574 proteins. Mendelian randomisation and colocalisation prioritised 26 proteins with putative causal effects, of which 17 are potentially druggable. Integrating multi-omic and phenotypic evidence ultimately resulted in five high-confidence causal candidates: DDR1 and LTB for depression, DDR1 for anxiety, DSG3 and PBXIP1 for bipolar disorder, and PDIA3 for psychosis. These findings provide convergent evidence implicating neuroimmune and neurodevelopmental pathways in psychiatric disorder biology, while also identifying potentially tractable targets for therapeutic development.

Moderate hypoxia is increasingly recognized as a physiological driver of neuroprotection and neuroregeneration. In this first randomised, double-blind, controlled, four-arm trial, we demonstrate the cognitive and neuroplastic effects of cognitive training under moderate inspiratory hypoxia in humans. Healthy volunteers underwent three weeks of either cognitive or sham training under normobaric hypoxia (12% O2) or normoxia (20% O2) for 3.5 hours daily, six days per week. Participants were assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was change in a broad cognitive composite score. Additional cognitive, blood-based, and neuroimaging outcomes were assessed, including measurement of the presynaptic protein SV2A with [11C]UCB-J positron emission tomography (PET) and neural activity through functional magnetic resonance imaging (fMRI). In total, 126 participants were randomised to hypoxia-cognitive training (H-CT: n=36), hypoxia-sham training (H-ST: n=30), normoxia- cognitive training (N-CT: n=30), or normoxia-sham training (N-ST: n=30). Intention-to-treat analyses showed no effect of H-CT relative to N-ST in the primary outcome at treatment completion (primary endpoint; treatment effect=0.11, 95% CI=[-0.06;0.28], p=0.19), but improvements emerged at follow-up (treatment effect=0.17, 95% CI=[0.01;0.34], p=0.04). N-CT induced transient improvement in the primary outcome at treatment completion (treatment effect=0.20, 95% CI=[0.02;0.38], p=0.03), which rendered non-significant at follow-up. Finally, H-ST showed no significant cognitive change relative to N-ST. Moderate hypoxia was safe and well-tolerated. Cognitive benefits were accompanied by decreased hippocampal presynaptic density measured with [11C]UCB-J PET. In conclusion, three weeks of H-CT can enhance cognition with associated effects on neuroplasticity, although with a delayed onset of effects on cognition.

Cognitive impairment is a debilitating feature of mood disorders (MD) linked to decreased neuroplasticity. Moderate hypoxia upregulates neuroplasticity and may improve cognition when combined with cognitive training. In this outcome assessor-blinded randomized controlled trial, we investigate the effects of three weeks of repeated hypoxia (12% O2) with concurrent cognitive training (H-CT) for 3.5 hours, 5-6 days per week compared with treatment as usual (TAU). Cognitively impaired individuals with remitted MD were randomized to H-CT or TAU and assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was a broad cognitive composite measure. Additional cognitive, functioning, blood-based, and neuroimaging (SV2A as a presynaptic marker with [11C]UCB-J positron emission tomography (PET) and neural activity during working memory functional magnetic resonance imaging (fMRI)) outcomes were assessed. Sixty-four participants were randomized to H-CT (n=34) or TAU (n=30), and 26 H-CT and 29 TAU completed the intervention and assessments. There was no effect of H-CT on the primary outcome (ps[≥]0.24) but H-CT induced improvements in the secondary executive function outcome (treatment effect=0.76, 95% CI=[0.23;1.28], adj. p=0.02) that prevailed at follow-up (treatment effect=1.07, 95% CI=[0.36;1.77], adj. p=0.02). Executive function improvement was accompanied by H-CT-related lower presynaptic [11C]UCB-J binding in the nucleus accumbens (p=0.03). H-CT also produced sustained improvements in everyday functioning (adj. ps[≤]0.049). No effects were observed on dorsolateral prefrontal cortex activity or real-life cognitive skills (ps[≥]0.54). Two serious but treatment-unrelated adverse events occurred. In conclusion, H-CT produces robust effects on executive functions, but not broader cognition, in MD, and H-CT may thus be particularly promising for targeting executive dysfunction in this population.

Early childhood poverty is an environmental risk factor for psychiatric and neurodegenerative disorders, yet the cellular mechanisms by which resource scarcity produces persistent brain vulnerability remain poorly understood. The medial prefrontal cortex (mPFC), which regulates executive function and motivated behavior, is sensitive to early environmental conditions. To identify mechanisms linking early resource scarcity to lasting mPFC dysfunction, we used the rat limited bedding and nesting (LBN) model, which recapitulates key features of poverty. Prior work shows LBN disrupts mPFC-mediated behaviors in adulthood, often in a sex-specific manner. Here, we used single-nucleus RNA sequencing (snRNAseq) to identify sex- and cell-type-specific transcriptional alterations in the adult mPFC following brief postnatal LBN exposure or control housing. LBN induced more differentially expressed genes (DEGs) across multiple pyramidal neuron clusters in females than in males. Unexpectedly, the largest transcriptional changes due to LBN occurred in vascular cells in females, whereas male vascular cells exhibited no DEGs. These female-specific vascular genes were enriched for alterations of transcriptional programs regulating angiogenesis and endothelial structure. This molecular profile was orthogonally validated with 3D vascular reconstruction, revealing LBN reduced vascular coverage in the adult female mPFC, driven by decreased vessel volume and shortened vessel length, while males were unaffected. Reduced vascular coverage may constrain metabolic support to this region. The postnatal period is a critical window for vascular maturation, and, taken together, these findings identify persistent, female-specific vascular alterations as a novel and previously unrecognized mechanism through which early resource scarcity may persistently affect brain function and vulnerability.

Major depressive disorder (MDD) lacks accessible molecular markers that reflect brain pathology and monitor treatment response. Using the neuron-specific protein SNAP25, we investigated the cargo of neuron-derived extracellular vesicles (NEVs) isolated from plasma in relation to antidepressant treatment and identified miR-151a-5p as a mediator of treatment response, increasing selectively in responders while remaining low in non-responders. Plasma levels mirrored deficits in human post-mortem brain tissue from the ventral anterior cingulate cortex, a cortical area implicated in MDD. In mice, engineered NEVs enriched with miR-151a-5p delivered cargo selectively to neurons, where miR-151a-5p engaged the RNA-induced silencing complex and regulated genes involved in synaptic networks, including RIMS3 and ELAVL3. Moreover, administration of miR-151a-5p-loaded NEVs in a model of depressive-like behavior produced rapid antidepressant-like effects. Together, these findings identify a vesicle-based mechanism linking peripheral biomarkers to central pathophysiology and demonstrate that miR-151a-5p functions both as a predictor and effector of antidepressant response.

Objective: Polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) often account for a low amount of variance. Ancestry-related differences in PRS scale and variance limit cross-group comparisons. This methodological challenge further complicates gene-by-environment (GxE) analyses, given that socioenvironmental exposures are inequitably distributed across ethnoracial groups. We constructed an ancestry-calibrated polygenic risk score (AC-PRS) for PTSD in the largest longitudinal study of trauma survivors to date and investigated GxE interactions. Method: Recent trauma survivors (N=1,801) provided a blood specimen for genotyping. Six PTSD trajectories were previously identified from PTSD Checklist for DSM-5 (PCL-5) scores at 2-weeks, 8-weeks, 3-months, and 6-months post-trauma. Greenspace (normalized difference vegetation index [NDVI) and socioeconomic disadvantage (area deprivation index [ADI]) were derived from residential addresses. Logistic regressions examined interactions between newly developed AC-PRS and neighborhood factors on trajectories after adjusting for sociodemographic and trauma-related covariates. Secondary linear models considered GxE interactions on 6-month PCL-5 scores. Results: AC-PRS performed well across ethnoracial groups, explaining significant variability in PTSD trajectories (R2=.053). ADI moderated the association between AC-PRS and the likelihood of assignment in a high nonremitting trajectory of PTSD symptoms and severity of symptoms at 6-months (ps < .05). There were no NDVI x AC-PRS interactions in any models. Conclusions: AC-PRS captures genetic risk for PTSD in admixed trauma survivors, demonstrating good discrimination between nonremitting and resilient courses of PTSD. However, neighborhood disadvantage may modify utility of PRS for PTSD, warranting careful consideration when applying these scores across contexts.

Recent large-scale studies have enabled new knowledge about genetic underpinnings of morphological and electrophysiological alterations of the retina. Variation in retinal traits, often of neurodevelopmental origin, have been linked to major psychiatric disorders (MPDs). Here, we investigate the genetic overlap between MPDs and key retinal traits to identify underlying molecular mechanisms. We obtained genome-wide associations studies data for bipolar disorder (BD), major depression (MD), schizophrenia (SCZ), and the retinal traits retinal nerve fibre layer thickness (RNFL), ganglion cell inner plexiform layer thickness (GCIPL), and vertical cup-disc ratio (VCDR). We estimated the number of trait-influencing variants shared between traits with MiXeR and identified shared genetic loci with condFDR. Subsequently, we examined the biological pathways of the genes mapped to shared loci. This revealed that GCIPL shared the most genetic variants with MPDs (~60%), followed by RNFL (~40%), and VCDR (~20%). The genetic variants shared between retinal traits and MPDs showed disorder-specific patterns with more pronounced overlaps of SCZ and BD with RNFL, and MD negatively correlated with GCIPL. Gene-pathway analysis highlighted the importance of GABAergic neurotransmission and a two-stage neurodevelopmental process in SCZ, whereas the role of mitochondria and a weaker developmental component were observed in BD. The results also implicated synaptic functioning and gene-expression processes in MD. Furthermore, polygenic analysis suggested that the genetic architecture of retinal traits can distinguish between MPDs. Our findings indicate shared genetic underpinnings between retinal traits and SCZ, BD, and MD, implicating altered neurodevelopment and neurotransmission underlying the retinal link to major psychiatric disorders.

Major depressive disorder (MDD) has been associated with accelerated structural brain aging, yet whether this reflects a pre-existing neurobiological vulnerability, a dynamic acute state effect, or an accumulating biological residual remains unresolved. Across two longitudinal cohorts (N=3220), including a unique sample of 78 initially healthy individuals who transitioned into their first depressive episode during the study course, we systematically tested all three hypotheses. Patients with diagnosed MDD showed elevated MRI-derived brain age relative to healthy controls (1.4 and 2.5 years across cohorts). For the vulnerability hypothesis, individuals scanned prior to their first episode showed no baseline elevation, despite already demonstrating subclinical elevations in self-reported symptom severity, indicating that advanced brain age does not precede illness onset. For the state hypothesis, we found no acceleration of brain aging following the first depressive episode, and longitudinal brain age trajectories were independent of acute clinical symptom severity. Finally, neither episode duration nor recurrence scaled with brain age. Accelerated brain aging in depression is therefore neither an antecedent vulnerability nor an acute state marker of the first episode, but rather a stable biological feature of a long term illness course.

In the past two decades, the focus on genome-wide association studies in large samples of unrelated patients has overshadowed family genetic studies. Therefore, little is still known about the levels and effects of the transmission of polygenic risk scores (PRS) among familial cases of schizophrenia (SZ) or bipolar disorder (BD) and their unaffected relatives. Prior research has shown that PRS are elevated in both patients and young individuals at familial risk for BD and SZ. We sought to study the transmission of PRS in affected multigenerational families and non-affected adult relatives (NAARs) with or without other non-mood nonpsychotic DSM-IV diagnoses and unrelated non-affected individuals from the same population. We genotyped 1,117 participants divided in 48 families from the Eastern Quebec Schizophrenia and Bipolar Disorder Kindreds. PRSs for both SZ and BD were computed using Multivariate Lassosum. For both SZ PRS and BD PRS, SZ and BD cases present higher PRS compared to controls, replicating previous findings. Regardless of a diagnosis of other non-psychotic and non-mood conditions, NAARs presented higher PRS than the unrelated cohort. Crucially, a subset of families presented consistently low PRS transmission profiles across generations, falling below expectations from our polygenic inheritance model. When the effect of individual PRs is accounted for, we observed sex-specific associations between familial PRS and patients' symptom dimensions. Our results clearly demonstrate that polygenic inheritance alone does not adequately explain disease transmission in families. Such an approach may also clarify why some families exhibit dense clustering of cases despite minimal polygenic burden.

Non-suicidal self-injury (NSSI) is common among adolescents with emotional disorders, yet biological indicators of current NSSI status remain limited. We developed a genome-aware multi-omics modeling framework in 107 adolescents with emotional disorders, including 53 without NSSI and 54 with current NSSI. The model integrated metabolomic, inflammatory, clinical blood and genome-derived features, with polygenic risk score and rare variant burden used as genetic-context variables. The fusion model achieved the strongest classification performance (mean AUC = 0.811) and outperformed single-omics alternatives, indicating that NSSI status was better represented by distributed multi-omics patterns than by a single biomarker layer. Repeated modeling prioritized 42 stable features, many of which were not significant in conventional univariate testing. Group-specific network reconstruction further revealed peripheral reorganization, including convergence of non-NSSI modules into an NSSI-associated module that linked inflammatory recruitment with weaker immune-communication, repair and support-related signals. Exploratory MRI, gut-related and stress-endocrine analyses provided additional biological anchors, while a compact sentinel marker panel translated the full model into clinically readable profiles. These findings support a distributed, genome-aware peripheral state associated with current NSSI and provide a framework for future validation of multi-omics state markers in adolescent emotional disorders.

Psychiatric disorders are complex conditions characterized by substantial overlap in genetic risk and shared biological mechanisms. However, how individual risk genes contribute to shared disease mechanisms and disorder-specific phenotypes remains poorly understood. BRD1 has emerged as a chromatin-associated regulator with transdiagnostic relevance across psychiatric disorders and a central role in gene regulatory networks enriched for psychiatric risk genes. To investigate the biological consequences of reduced BRD1 function in a translationally relevant system, we generated a minipig model harboring a monoallelic deletion in BRD1 and performed longitudinal neuroimaging together with behavioral and multi-omics profiling. BRD1 haploinsufficient minipigs displayed normal growth and exploratory behavior but exhibited subtle age-dependent differences in motivational behavior. Despite the absence of overt developmental abnormalities, longitudinal neuroimaging revealed genotype-associated structural differences primarily involving the cerebral cortex and caudate nucleus, suggestive of altered neurodevelopmental trajectories. Integrated multi-omics analyses revealed striking convergence across transcriptomic and metabolomic datasets, identifying coordinated perturbations of mitochondrial function, redox regulation, and phospholipid metabolism across multiple brain regions. Notably, these molecular alterations were not restricted to the central nervous system, as peripheral multi-omics profiling revealed systemic metabolic alterations, including altered phospholipid composition and glucose metabolism. Together, these findings indicate that BRD1 haploinsufficiency is associated with coordinated neurodevelopmental and metabolic alterations across brain and peripheral tissues. More broadly, this study provides systems-level insight into how a psychiatric risk gene influences interconnected neurodevelopmental and metabolic processes across multiple levels of biological organization and highlights the value of large-animal multi-omics models for translational neuropsychiatric research.

Child maltreatment is a leading cause of preventable harm, yet how diverse risk factors accumulate to precipitate caregiving failure remains unclear. In non-human mammals, fatal abandonment or aggression toward offspring occurs under specific ecological conditions, suggesting evolutionarily conserved pathways for caregiving breakdown. To test whether similar structures apply to humans, we conducted a case-control study enrolling 39 caregivers imprisoned for (near-) lethal child maltreatment and 351 control caregivers in Japan. Across 70 examined factors spanning caregivers' childhood, socioeconomic, neurobiological, and proximate environmental profiles, severe maltreatment was associated with 4.6- and 5.9-fold higher exposure to cross-species factors in men and women, respectively. Developmental pathway modeling identified significant standardized total effects of low educational attainment, non-kin caregiving, isolated parenting, behavioral addiction, and maternal absence before age 15. This proof-of-concept study presents an integrated framework bridging evolutionary biology with contemporary human caregiving and suggests targets for actionable intervention.

Psychosis has long been conceptualized as a disorder of disrupted hierarchical integration across distributed brain systems, yet it remains unclear whether alterations in macroscale cortical hierarchy are already present before illness onset and are associated with subsequent transition to psychosis. Using connectome gradient mapping, we characterized baseline cortical hierarchical architecture along the unimodal-to-transmodal axis in 580 participants from the NAPLS-3 cohort, including converters (CHR-C, n = 56), non-converters (CHR-NC, n = 434), and healthy controls (HC, n = 90). Group differences were assessed at regional, network, and global levels. Group comparisons revealed that CHR-C individuals, relative to the other two groups, exhibited bidirectional alterations selectively along the sensorimotor-to-association gradient, with reduced values in the visual network alongside elevated values in the default mode network, indicating greater separation between sensory and transmodal systems along the gradient. At the global level, CHR-C showed increased explained variance, range, and variation of this gradient, collectively indicating hierarchical expansion. Notably, greater explained variance of this gradient was associated with a shorter time to conversion to psychosis, while increased gradient range and variation were associated with higher positive symptom severity across CHR individuals. These findings indicate that expansion of the sensorimotor-to-association connectome hierarchy is already present before psychosis onset in individuals who subsequently convert to psychosis. This altered hierarchical organization may reflect greater decoupling between sensory and transmodal systems and may characterize neurobiological changes associated with progression from a clinical high-risk state to psychotic illness.

The current study assessed whether N-acetylcysteine (NAC), which inhibits the kynurenic acid (KYNA)-synthesizing enzyme kynurenine aminotransferase (KAT) II, affects tryptophan (TRYP)-induced peripheral formation of the kynurenine pathway metabolites kynurenine and KYNA and improves selected functional outcome measures in people with schizophrenia. Fifty-eight participants with DSM-5 schizophrenia or schizoaffective disorder entered a double-blind, placebo-controlled, randomized cross-over challenge study, in which they were pretreated with either NAC (up to a maximum of 15 g) or placebo, then received TRYP, 6 g. Prior to and after receiving the study medications, participants underwent laboratory (serum kynurenine and KYNA), symptom (BPRS, SANS, and CDS), cognitive (6 MCCB tests) and brain MRI (ASL, DTI, 1H-MRS) assessments. In contrast to placebo pre-treatment, NAC significantly reduced the TRYP-induced increase in peripheral serum levels of kynurenine (t=-2.02; p<0.05) and KYNA (t=-3.21; p=0.002). NAC pre-treatment was associated with significantly smaller increases in total white matter (WM) cerebral blood flow (CBF) (t=-2.15; p=0.04) and a trend for smaller increases in total gray matter (GM) CBF (t=-1.81; p=0.08). NAC pre-treatment significantly reduced the TRYP-induced decrease in MCCB composite score (t=2.07; p=0.04). There was no differential treatment effect on DTI or 1H-MRS or symptom measures. The observation that NAC attenuated the de novo formation of KYNA, reduced WM CBF elevations, tended to decrease GM CBF, and blocked the worsening of cognitive performance in participants following TRYP administration, supports the concept that KAT II inhibition is a promising novel strategy for the treatment of cognitive impairments in people with schizophrenia.

Identifying generalizable brain-based biotypes across independent cohorts is critical for parsing heterogeneity in Major Depressive Disorder (MDD), yet robust subtypes spanning micro- and macroscales remain poorly defined. We applied stability-based clustering to cortical thickness data from 1,531 MDD individuals in UK Biobank (UKB), with external validation in 144 inpatients from IRCCS Ospedale San Raffaele (HSR). Two distinguishable clusters emerged (accuracy=87.5%), with one showing widespread cortical thinning, anergy-related symptoms, childhood trauma, and diabetes comorbidity. This profile generalized with 96.5% accuracy in a hold-out UKB sample and 80.6% in HSR. Mapping clusters cortical profiles onto Neurosynth meta-analytic activation patterns revealed a ventral-dorsal gradient linked with emotion regulation, interoceptive, and motivational processes. Spatial correlations with 19 neurotransmitter receptors and transporters obtained from positron emission tomography identified dopamine transporter as the dominant contributor in UKB, and histamine receptor H3 in HSR. These findings provide a reproducible framework linking MDD subtypes to multiscale biological complexity.

Suicidal behavior results from complex behavioral and biological changes. Previous cross-sectional studies indicate that proinflammatory immunobiological factors are often increased in close temporal proximity to a suicide attempt. Suicidal individuals may also exhibit a biological trait vulnerability to stress and inflammation, due to persistent epigenetic modifications. We enrolled 130 individuals with major depressive disorder (MDD), 83 with suicidal behavior at intake, and followed them for 12 months with up to eight clinical assessments. Quantification of plasma inflammatory markers and metabolites was performed by high-sensitivity electrochemiluminescence and Ultra High-Performance-Liquid-Mass Spectrometry (UPLC-MS), respectively. Epigenetic changes were identified using Illumina EPIC arrays. We identified 15 genes with altered DNA-methylation associated with suicidal behavior and attempts at baseline. Childhood trauma predicted lifetime suicide attempts and was associated with altered methylation of seven genes. Increased neutrophils and lower plasma serotonin at baseline predicted future suicide attempts over the following year (neutrophil estimate = 0.42, P = 0.016; serotonin OR = 0.58, 95% CI: 0.39-1.13). Utilizing biomarkers from baseline and epigenetic data from the genes with highest predictive values (STBD1 ,PRDM8, and TRIM15), we achieved an area under the curve (AUC) of 0.84 for suicide attempts over the year. Suicidal behavior in MDD was associated with specific epigenetic signatures. Several of the identified genes, such as MAD1L1, have been implicated in psychiatric disease, suicidal behavior and the immune response. These findings support the usefulness of epigenetic and immunometabolic blood markers for identifying suicidal individuals in clinical settings, potentially enhancing preventative efforts.

Major depressive disorder (MDD) is strongly associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic inflammation, and gut microbiota dysbiosis. Although selective serotonin reuptake inhibitors such as escitalopram are standard treatments, their efficacy is often constrained by partial response and gastrointestinal adverse effects. In this 12-week, randomized, double-blind, placebo-controlled trial, we evaluated the clinical efficacy and microecological mechanisms of adjunctive Lactiplantibacillus plantarum PS128 (PS128; 6*1010CFU/day) in MDD patients on stable escitalopram therapy. Adjunctive PS128 significantly enhanced clinical response compared to placebo, yielding substantial reductions in HAMD-17 and MADRS, alongside a higher remission rate. 16S rRNA sequencing and PICRUSt2 profiling revealed that PS128 enriched key short-chain fatty acid producers (Faecalibacterium, Coprococcus), counteracting the Klebsiella expansion seen in placebo. Functionally, PS128 up-regulated neuroprotective cofactor, B vitamins, biosynthesis and down-regulated the neurotoxic kynurenine pathway. Network analysis demonstrated that PS128 maintained a resilient, integrated microbial co-occurrence topology, whereas the placebo network showed structural segregation. This stabilized ecosystem attenuated peripheral inflammatory signaling and normalized salivary cortisol levels. Overall, adjunctive PS128 augments escitalopram efficacy by enhancing gut network stability, supporting cellular energetics, and modulating neuroendocrine activity, offering a promising multimodal strategy for MDD.

Background: Bipolar disorder (BIP) and obsessive-compulsive disorder (OCD) frequently co-occur and show evidence of genetic overlap, yet the specific pleiotropic loci and their functional mechanisms remain unclear. Methods: We conducted large-scale genetic analyses using GWAS summary statistics for BIP and OCD, excluding 23andMe data. We applied conjunctional FDR analysis to identify pleiotropic variants jointly associated with BIP and OCD, followed by integrative annotation through transcriptomic (eQTL, sQTL), epigenomic (mQTL, haQTL), and proteomic (pQTL, histone PTM) data. SMR analysis was used to prioritize putative regulatory effects, while AlphaGenome predictions and targeted histone proteomics were employed to evaluate allele-specific chromatin changes. Results: We observed a significant genetic correlation (rg = 0.38, P = 3.8 x 10-29) and extensive polygenic overlap between BIP and OCD. Bidirectional MR supported causal effects in both directions, with stronger evidence for BIP influencing OCD risk. ConjFDR analysis revealed 2,143 pleiotropic SNPs jointly associated with BIP and OCD, with convergent signals at the ITIH3/ITIH4 locus. Summary-data-based Mendelian randomization (SMR) and colocalization with multi-omic QTLs (eQTL, pQTL, mQTL, and haQTL) further prioritized the ITIH3/4 locus, where multiple SNPs (e.g., rs3774364) colocalized with H3K27ac histone acetylation QTLs in the prefrontal cortex (PP_H4 > 0.5). Integrated PBMC RNA-seq and complementary histone mass spectrometry linked immune--ECM transcriptional activity to exploratory global histone acetylation changes in BIP and OCS-BIP, with suggestive alterations in H3K27ac-containing peptides. Conclusions: Our multi-omic analysis highlights ITIH3/ITIH4 as a prioritized pleiotropic locus for BIP and OCD. Epigenetic regulation, particularly through histone acetylation, may underlie shared susceptibility and offers a novel mechanistic link between these psychiatric disorders.

Schizophrenia (SZ) is a severe psychiatric disorder characterized by psychosis, cognitive deficits, and disrupted social functioning. Mitochondria are essential for neuronal function, synaptic plasticity, and behavior, all impaired in SZ. A major driver of mitochondrial dysfunction in SZ is Complex I, particularly its NDUFV2 core subunit, whose alterations occur post-transcriptionally. We previously showed that the NDUFV2 pseudogene (NDUFV2P1; PG) is upregulated in brain and peripheral cells of SZ patients and inversely correlates with NDUFV2 expression and mitochondrial respiration in Epstein-Barr-virus-transformed lymphocyte cells lines (LCLs). In-silico analyses excluded small RNA interference with NDUFV2, implicating PG as an interfering factor. To study PG effects on NDUFV2 expression, mitochondrial function, and neuronal activity, we modulated PG abundance in LCLs. PG overexpression in healthy-derived LCLs impaired mitochondrial function, altering {Delta}{psi}m, mitochondrial network dynamics, and oxygen consumption, while PG downregulation in SZ-derived LCLs restored these parameters to normal levels. In rat cortical neurons, PG overexpression induced comparable mitochondrial disruptions alongside impaired synapse formation and reduced spontaneous neuronal firing. This study provides evidence for a mechanistic pathway through which PG interferes with NDUFV2, leading to SZ-related mitochondrial and neuronal deficits, and suggests therapeutic potential for PG downregulation in diseases with bioenergetic impairments such as SZ.

Neuropsychiatric symptoms are considered the most common feature of long COVID disease. Recent studies have demonstrated structural brain changes and highlighted the importance of neuroinflammation in the development of cognitive deficits as seen in long COVID patients. In addition, peripheral studies have demonstrated heterogeneous molecular subtypes of long COVID pathology. However, it is unknown which peripheral metabolomic alterations occur in patients with neuropsychiatric long COVID syndrome and how these relate to symptom severity. In the present study, we investigated differences in the peripheral serum metabolome profiles of healthy controls and patients with long COVID syndrome with neuropsychiatric symptoms. We found that patients with long COVID showed peripheral alterations in lipid species such as triacylglycerides and acylcarnitines. Furthermore, metabolites altered in patients with long COVID syndrome were also associated with depressive and fatigue symptom burden as well as with differences in cortical thickness in multiple brain regions. Our results demonstrate a metabolic phenotype of long COVID patients that may reflect a dysregulation of lipid metabolism and deficits in mitochondrial energy production as potential contributors to symptom burden and brain structural alterations. These data may serve as a resource and basis for further studies aimed at investigating peripheral molecular alterations in patients with neuropsychiatric long COVID syndrome.