Molecular Psychiatry

Divergent transcription from bidirectional promoters is frequently observed in eukaryotic genomes, but the biological relevance of divergent RNA transcripts (DT) is unknown. We identified and characterized BDNF-DT, a novel DT gene, and BDNF-AS-DT, a novel readthrough gene, in the locus containing BDNF, a gene with key roles in neuronal development, differentiation, and synaptic plasticity. BDNF-DT is independent from the known BDNF antisense (BDNF-AS), and its expression is developmentally regulated and positively correlated with BDNF in human postmortem dorsolateral prefrontal cortex (DLPFC). BDNF-DT and BDNF-AS-DT expression increase after induced depolarization, but the temporal dynamics follow expression of BDNF, suggesting a regulatory role. Moreover, CRISPR-mediated upregulation of BDNF in human neural progenitor cells drives BDNF-DT expression. Finally, BDNF-DT shows higher expression in DLPFC from patients diagnosed with schizophrenia compared to neurotypical controls, and genetically predicted lower expression of the BDNF-AS-DT readthrough transcript is associated with schizophrenia and with the schizophrenia-associated C allele of the rs6265 single-nucleotide polymorphism. These data suggest that BDNF-DT and BDNF-AS-DT contribute to BDNF regulation and schizophrenia risk.

Childhood abuse (CA) is one of the strongest lifetime predictors of major depressive disorder (MDD) and suicide. However, some individuals exposed to CA are resilient, avoiding the development of psychopathology. Recently, the locus coeruleus-noradrenergic (LC-NE) system has been involved in resilience following stressful events at adulthood. We investigated how a history of CA affects the integrity of the LC-NE system at the molecular and cellular level in human post-mortem brain samples of depressed suicides, and whether differential neurobiological mechanisms can be revealed in resilient individuals. Anatomical analysis revealed that CA-induced MDD and suicide is associated with decrease in LC-NE neurons density. RNA sequencing of laser captured LC-NE neurons highlighted differentially expressed genes, principally in the RES-CA group. Resilience to CA involves specific neurobiological adaptations in the LC-NE system that potentially protect against the loss of LC-NE neurons and the negative long-term outcome of CA-induced depression and suicide. Our results provide insights into potential therapeutic targets for preventing or treating CA-induced MDD.

Major depressive disorder (MDD) is associated with altered GABAergic and glutamatergic signalling, suggesting altered excitation-inhibition balance (EIB) in cortical mood- and cognition-regulating brain regions. Information processing in cortical microcircuits involves regulation of pyramidal (PYR) cells by Somatostatin-(SST), Parvalbumin-(PV), and Vasoactive intestinal peptide-(VIP) expressing interneurons. Human and rodent studies suggest that impaired PYR-cell dendritic morphology and decreased SST-cell function may mediate altered EIB in MDD. However, knowledge of co-ordinated changes across microcircuit cell types is virtually absent. We thus investigated the co-ordinated transcriptomic effects of UCMS on microcircuit cell types in the medial prefrontal cortex. C57Bl/6 mice, exposed to unpredictable chronic mild stress (UCMS) or control housing for five weeks were assessed for anxiety- and depressive-like behaviours. Microcircuit cell types were laser-microdissected and processed for RNA-sequencing. UCMS-exposed mice displayed predicted elevated behavioural emotionality. Each microcircuit cell type showed a unique transcriptional signature after UCMS. Pre-synaptic functions, oxidative stress response, metabolism, and translational regulation were differentially dysregulated across cell types, whereas nearly all cell types showed down-regulated post-synaptic gene signatures. At the microcircuit level, we observed a shift from distributed transcriptomic co-ordination across cell types in controls towards UCMS-induced increased co-ordination between PYR-, SST- and PV-cells, and a hub-like role for PYR-cells. Lastly, we identified a microcircuit-wide co-expression network enriched in synaptic, bioenergetic, and oxidative stress response genes that correlated with UCMS-induced behaviours. Together, these findings suggest cell-specific deficits, microcircuit-wide synaptic reorganization, and a shift in cortical EIB mediated by increased co-ordinated regulation of PYR-cells by SST- and PV-cells.

Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall, in vitro PTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.

BackgroundDifferences in age of psychosis onset (AOO) in schizophrenia (SCZ) are associated with different illness trajectories. Determining whether AOO differences can be explained by genome-wide or pathway-partitioned polygenic risk for SCZ (SCZ-PRS) may elucidate mechanisms underlying clinical variability. This study examined relationships between AOO, genome-wide SCZ-PRS, and pathway-partitioned SCZ-PRS in a harmonized, multi-ancestry North American dataset (SCZ-NA) and in UK Biobank (SCZ-UKBB). MethodsFor each cohort, we computed one genome-wide SCZ-PRS and 18 mutually-exclusive pathway-based PRS derived from previous published and validated neurodevelopmental gene-sets. We evaluated 13 SNP-to-gene mapping strategies, including comparing non-coding SNP-to-gene mappings informed by functional annotations versus distance-based windows. SCZ case-control prediction and AOO associations were tested using logistic and linear mixed models, respectively, controlling for sex, ancestry principal components, and genetic relatedness. ResultsGenome-wide SCZ-PRS robustly predicted SCZ case-control status in both cohorts but not AOO. In contrast, pathway-based analyses identified AOO associations for a fetal angiogenesis and a postnatal synaptic signaling and plasticity gene-set across both cohorts (p < .05), alongside nominal cohort-specific associations in other gene-sets. Associations depended on SNP-to-gene mapping definitions; experimentally informed strategies, particularly those incorporating brain expression Quantitative Trait Locus (eQTL) annotations performed best. ConclusionFindings suggest that neurovascular and postnatal synaptic signaling and refinement mechanisms contribute to AOO variation in SCZ, and that pathway-informed PRS, especially with brain-specific non-coding SNP-to-gene mappings, can help identify mechanisms contributing to variability in AOO. Replication in larger, prospectively phenotyped cohorts with harmonized AOO definitions will further clarify genetic mechanisms underlying clinical variability in SCZ.

ObjectivesULK4 is an established candidate gene for mental disorders and antipsychotic treatment response and codes for a serine/threonine kinase that regulates the neural stem cell pool and controls cortex development. We investigated the effects of functional genetic variation at the ULK4 locus on the human extended dopaminergic reward system using functional magnetic resonance imaging (fMRI) during performance of a well-established reward paradigm. Methods234 study participants with functional neuroimaging (fMRI) data of the extended reward system and with ULK4 genotype data were included in this study. Effects of genetic variation in the ULK4 gene on reward system functioning were determined using the Desire-Reason-Dilemma (DRD) paradigm which allows to assess brain activation in response to conditioned reward stimuli (Diekhof et al. 2010). ResultsAmong common missense variants of the ULK4 gene, variant prioritization revealed strongest functional signatures for variant rs17215589, coding for amino acid exchange Ala715Thr. For rs17215589 minor allele carriers, we detected increased activation responses to conditioned reward stimuli in the ventral tegmental area, the nucleus accumbens and several cortical brain regions of the extended reward system. ConclusionsOur findings provide further evidence in humans that genetic variation in ULK4 may increase the vulnerability to mental disorders by modulating the function of the extended reward system. Future studies are needed to confirm the functional modulation of the extended reward system by ULK4 and to specify the role of this mechanism in the pathogenesis of psychiatric disorders.

Suicide is a leading cause of death worldwide, yet the biological mechanisms underlying suicide remain poorly understood. A clearer understanding at the molecular level is essential for developing objective biomarkers and targeted interventions. In this study, we used transcriptomic profiling to investigate gene expression patterns associated with suicidal thoughts and behaviors across peripheral blood (n=264) and postmortem brain tissue from two prefrontal regions (dorsolateral prefrontal cortex, DLPFC; subgenual anterior cingulate cortex, sgACC) of individuals with and without psychiatric illness (n=249). Peripheral analyses revealed broad transcriptional changes associated with suicidal thoughts and behaviors, marked by dysregulated immune-related and inflammatory processes. Longitudinal modeling further revealed gene co-expression modules that predicted future suicide attempts over a 12-month follow-up, highlighting processes related to apoptosis, mitochondrial function, and immune regulation. By contrast, transcriptomic analyses of postmortem tissue derived from the DLPFC and sgACC revealed largely suppressed neuroimmune activity. Gene co-expression analyses in the brain identified suicide-associated modules enriched for synaptic plasticity, oxidative stress, and neuroimmune function, some of which displayed regional specificity. Cross-tissue comparison showed minimal gene-level overlap between brain and blood, although shared pathway-level themes emerged in immune, sensory, and cellular stress processes. Taken together, these findings suggest that suicide is associated with distinct but functionally convergent transcriptional alterations across brain and blood. By integrating tissue-specific and systems-level molecular signatures, this work provides insight into the biological architecture of suicide and lays the groundwork for developing novel biomarkers and therapeutic targets to improve prevention and treatment outcomes.

BackgroundWhile previous genome-wide association studies (GWAS) identified multiple risk loci for suicide ideation (SI) and suicide attempt (SA), there is still a limited understanding of the genetic predisposition underlying suicidal behaviors in diverse populations. This study aimed to conduct a large-scale investigation of the suicidality spectrum (SP) to generate new insights into its biology and epidemiology. MethodsLeveraging ancestrally diverse participants (SI Ncase/control=179 881/1 013 900; SA Ncase/control=66 867/1 654 798) from the UK Biobank, All of Us Research Program, Million Veteran Program, FinnGen, and Psychiatric Genomics Consortium, we performed GWAS meta-analyses for SI and SA, and a multivariate GWAS of SP. We applied multiple analytical approaches to identify genomic loci associated with suicide traits and to functionally annotate these significant signals. Phenome-wide genetic correlation and genetically informed causal analyses were further conducted to provide convergent evidence on the relationships of suicidal behaviors with health outcomes, brain imaging-derived phenotypes, and metabolomic traits. We identified 90 independent lead single-nucleotide polymorphisms (SNPs) for suicidal behaviors, of which 49 were novel. SNP-based heritability was higher for SA (SNP-h2=0.115{+/-}0.005) than for SI (SNP-h2=0.040{+/-}0.002) and SP (SNP-h2=0.050{+/-}0.002), and their genetic correlations ranged from 0.639 to 0.960. Functional annotation analyses highlighted associated genes (e.g., UGGT2, GMPPB, BRWD1), enriched gene sets (e.g., cellular response to stress), and potential therapeutic drug candidates (e.g., cariprazine, paliperidone, droperidol), with some signals shared across suicide traits but more specific to SI or SA. Suicide behaviors were genetically associated with a broad spectrum of complex traits, primarily in the domains of mental health, physical health, behaviors, and socioeconomic factors, some of which revealed causal relationships. InterpretationThis study provides convergent genetic evidence for both shared and phenotype-specific components of suicidal behaviors and delineates their associated factors spanning from proximal clinical and behavioral traits to more distal social determinants. These findings refine our understanding of the etiology of suicidal behaviors and may inform targeted strategies for suicide prevention in both clinical and public health settings. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSuicidal behaviors remain a serious public health concern and contribute to substantial mortality globally. However, their genetic predisposition and risk profiles associated with them are not yet fully established although multiple approaches, including genome-wide association studies (GWAS), have been applied. We searched PubMed, medRxiv, and bioRxiv for publications and preprints in English from Jan 1, 2000, to Nov 1, 2025, using the search terms "suicid*" and "GWAS". The largest previously published GWASs identified four genome-wide loci for suicide ideation and 12 for suicide attempt, and a recent preprint reported 77 loci for suicidal behaviors. These associations were mainly derived from individuals of European ancestry, with only one significant locus for suicide ideation reported in East Asian ancestry. Previous studies also attempted to prioritize putative risk genes, but most did not leverage multi-omic approaches, such as transcriptome-wide and proteome-wide association studies. Moreover, earlier work investigated the relationships between suicidal behaviors and psychiatric and behavioral traits mainly through genetic correlation analysis, without conducting phenome-wide genetically informed causal analysis. Added value of this studyOur study identified 90 genome-wide significant associations for suicidality. These associations were distributed across European, African, Admixed American, and Asian ancestries for both suicide ideation and suicide attempt. SNP-based heritability for suicidal behaviors ranged from 4% to 12% and remained significant after conditioning on major psychiatric disorders. We prioritized 1052 genes associated with suicidal behaviors and identified 33 loci with convergent evidence across five or more gene-discovery analyses. Sixteen genes were shared across suicide ideation, suicide attempt, and suicidality spectrum, while most other loci appeared to be phenotype-specific. Drug-repurposing analysis suggested five potential therapeutic drug candidates: cariprazine, droperidol, molindone, paliperidone, and chlorprothixene. Using phenome-wide genetically informed analyses, we identified loneliness, medical abortion, and age at first sexual intercourse as putative causal risk factors for suicidal behaviors. Suicidal behaviors were also associated with adverse consequences, including hospital admissions and multiple mental health and physical conditions. Implications of all the available evidenceThe predisposition to suicidal behaviors is due to genetic mechanisms acting through molecular changes across multiple omic domains in brain and peripheral systems. Although psychiatric disorders may mediate the genetic liability of suicidal behaviors, a proportion of the risk appears to be independent of psychiatric diagnosis. Suicidal behaviors are influenced by diverse genetic and causal risk factors, and can also lead to broad adverse health consequences.

The neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2) and rs4818766 (ADARB1). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.

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 22q11.2DS. To gain a deeper understanding of the underlying biological mechanisms, we conducted a translational study using three datasets: a genome-wide methylation dataset from peripheral blood of individuals with 22q11.2DS with or without SCZ, a microRNA expression dataset from the same cohort, and a second genome-wide methylation dataset obtained from a mouse model exploring gene-environment interactions. Human recruitment was carried out at a specialized center focusing on rare psychiatric disorders and included one pair of monozygotic twins discordant for SCZ. In the animal model, DNA extraction was performed from the prefrontal cortex among four groups : wild-type and Df(h22q11)/+ mice, with or without exposure to acute stress. This study identified alterations in DNA methylation and microRNA expression linked to the 22q11.2 deletion as well as SCZ within the context of the deletion in humans. The results were then compared to the effects of the corresponding deletion and stress in the mouse model. Notably, four genes (ZBTB20, SHANK3, GRAMD1B, XKR4) overlapped across all comparisons. Pathway analysis evealed epigenetic differences in the Wnt pathway associated with stress and SCZ within the context of the deletion. These findings support the hypothesis that the onset of SCZ in individuals with 22q11.2DS may be influenced by epigenetic mechanisms, both within and outside the implicated region, under the influence of environmental stressors. If replicated, these findings could be used to develop biomarkers for early diagnosis in del22q11 carriers and to explore new targeted therapeutic strategies.

An increasingly compelling body of literature indicates the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51) is a promising target for novel psychiatric therapeutics. However, the mechanisms regulating the corresponding FKBP5 gene directly in the human brain remain largely unknown yet are needed to facilitate the development of precise mechanism-based treatment approaches. Here, we examined FKBP5 DNA methylation patterns in postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depression, or bipolar disorder; n=329) and controls n=231. We identified that cytosine-phosphate-guanine-dinucleotide (CpG) specific FKBP5 DNA methylation is altered in psychiatric disorders across the FKBP5 locus, and that these changes are differentially associated with age and genotype (rs1360780 CC vs CT/TT). Individuals with schizophrenia had significantly lower levels of DNA methylation in the proximal enhancer of FKBP5, which also negatively correlated with FKBP5 gene expression. These changes were also associated with predicted glucocorticoid response elements (GREs) in the proximal enhancer, but not other transcription factor binding sites. This evidence supports that in the human cortex, FKBP5 DNA methylation is associated with both genetic and ageing effects, and that the associations between these factors vary at a diagnosis-specific level in psychopathology. This may have implications for developing FKBP5-targeted therapeutics and defining a subgroup of patients who will benefit from such treatments.

Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+ microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

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.

Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell-types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n=1024) of FKBP5/1 examining prefrontal cortex (BA9, BA11, BA24) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease-state, aging and genotype on cortical FKBP5/1 expression including in a cell-type specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq) and targeted histology, we established that these disease- and aging-effects on FKBP5/1 expression were most pronounced in excitatory supragranular neurons. We then found that this increase in FKBP5 levels likely impacts on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in supragranular neurons. These findings pinpoint a novel cellular and molecular mechanism that has significant potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.

Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)--key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24- hour cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes related to vesicle-mediated transport and membrane trafficking in the NAc and platelet derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.

AbstractVitamin B12 deficiency can lead to pernicious anemia, various neuropsychiatric diseases, and cognitive decline. However, it is unclear whether increasing vitamin B12 levels can help to prevent the onset of psychiatric disorders and cognitive impairment in the general population. Leveraging large-scale genome-wide association studies (GWASs), we conducted Mendelian randomization (MR) analyses to estimate the potential effects of serum vitamin B12 levels on eight psychiatric disorders, as well as educational attainment and cognitive performance. We performed sensitivity analyses by excluding genetic instruments that demonstrated potential horizontal pleiotropy. We conducted additional MR analyses utilizing within-sibship studies for depressive symptoms, educational attainment, and cognitive performance to mitigate bias due to potential residual confounding in GWASs. As a positive control, we confirmed that a one standard deviation increase in genetically increased vitamin B12 levels was strongly associated with a decreased odds of developing pernicious anemia (odds ratio, OR = 0.24; 95% confidence interval, CI: 0.15-0.40; p-value = 2.1x10-8). In contrast, MR estimates of vitamin B12 effects on all eight psychiatric disorders, educational attainment and cognitive performance largely overlapped with the null. In particular, based on the three most well-powered GWASs, a one standard deviation increase in genetically predicted vitamin B12 levels was associated with an OR of 1.01 for depression (95% CI: 0.97-1.04; p-value = 0.74), a 7.7x10-3 standard deviation increase in educational attainment (95% CI: -1.0x10-2-2.5x10-2; p-value = 0.39) and a 1.3x10-2 standard deviation increase in cognitive performance (95% CI: -8.8x10-3-3.5x10-2; p-value = 0.24). No significant associations between genetically predicted vitamin B12 levels and any of the outcomes were identified in sensitivity analyses excluding pleiotropic genetic instruments or MR analyses based on within-sibship studies. In summary, our findings suggest that increasing serum vitamin B12 levels may not protect against the investigated psychiatric disorders or cognitive impairment in the general population.

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.

Bipolar disorder (BD) is a chronic mood disorder characterized by alternating manic and depressive episodes, often in conjunction with cognitive deficits. Dysregulation of neuroplasticity and calcium homeostasis as a result of complex genetic environment interactions are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that a BD-associated microRNA, miR-499-5p, regulates neuronal dendrite development and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients and healthy subjects at risk of developing the disorder due to a history of childhood maltreatment. This up-regulation is paralleled in the hippocampus of rats which underwent juvenile social isolation. Elevating miR-499-5p levels in rat hippocampal pyramidal neurons impairs dendritogenesis and reduces surface expression and activity of the voltage-gated L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory {beta}-subunit of Cav1.2, as a direct target of miR-499-5p in neurons. CACNB2 downregulation is required for the miR-499-5p dependent impairment of dendritogenesis, suggesting that CACNB2 is an important downstream target of miR-499-5p in the regulation of neuroplasticity. Finally, elevating miR-499-5p in the hippocampus in vivo is sufficient to induce short-term memory impairments in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. Taken together, we propose that stress-induced upregulation of miR-499-5p contributes to dendritic impairments and deregulated calcium homeostasis in BD, with specific implications for the neurocognitive dysfunction frequently observed in BD patients.

BackgroundThe close relationships between mental disorders and suicidality are frequently seen in epidemiology. Shared genetic liabilities and brain structure variation may underlie these associations. Therefore, we aimed to investigate the phenotypic and polygenetic associations between multiple mental disorders and different levels of suicidality, as well as mediation by grey morphology and white matter tracts. MethodsUsing raw data from the UK Biobank (UKB) European population, we first evaluated the phenotypic and polygenic relationships between 12 mental disorders and gradient scales of suicidality. We then accessed data from the All of Us (AoU) diverse cohort to replicate findings in European and African American populations. Demographic and social factors, including age, sex, BMI, education, deprivation, income, smoking, and chronic pain were included as covariates. Second, we used existing genome-wide association study (GWAS) summary statistics from 12 major mental conditions to estimate genetic correlations and identify pleiotropic genes using a combination of statistical genetics tools. Third, we further explored the potential mediation effects of brain structure on the relationship between mental disorders and suicidality through structural equation modeling and Mendelian randomization analyses. ResultsIn the UKB European population, 150,861 eligible individuals were retained after standard GWAS quality control. Nine out of 12 mental disorders showed both significant phenotypic and polygenic correlations with gradient suicidality (Pbonferroni <0.05). Using GWAS summary statistics, we also observed positive global and regional genetic correlations between the 12 mental disorders and suicidality (rg ranging from 0.25 to 0.68, Pbonferroni <0.05). Across pairs of suicidality and other mental disorders, we identified 73 out of 136 pleiotropic functional genes (including 58 novel ones associated with suicidality) shared by two or more pairs. These genes were enriched in pathways including regulation of immune system process and DNA, nucleosome and chromatin organization, and phenotypes as common mental disorders and brain morphology. Finally, the association between mental disorders and suicidality was significantly mediated by several structural brain imaging features. ConclusionThis study underscores the urgent need to address the shared and distinct genetic architecture of suicidality and its related mental conditions. Combining longitudinal population-level biobanks with disease-ascertained GWAS data is warranted to further enhance our understanding of this complex phenomenon. Our research findings will guide future suicide prevention and precise treatment among individuals with or without major mental disorders.

Cognitive deficits are known to be related to most forms of psychopathology. Here, we perform local genetic correlation analysis as a means of identifying independent segments of the genome that show biologically interpretable pleiotropic associations between cognitive dimensions and psychopathology. We identified collective segments of the genome, which we call "meta-loci", that showed differential pleiotropic patterns for psychopathology relative to either General Cognitive Ability (GCA) or Non-Cognitive Skills (NCS). We observed that neurodevelopmental gene sets expressed during the prenatal-early childhood predominated in GCA-relevant meta-loci, while post-natal synaptic gene sets were more involved in NCS-relevant meta-loci. Notably, we found that GABA-ergic, cholinergic, and glutamatergic genes drove pleiotropic relationships within dissociable NCS meta-loci.