Molecular Psychiatry[JOURNAL]
Sun
200 papers
Genetic architecture of postpartum psychosis: from common to rare genetic variation.
Jung S, Caballero M, Kępińska A … +5 more , Smout S, Munk-Olsen T, Robakis TK, Bergink V, Mahjani B
Mol Psychiatry · 2026 May · PMID 42135523 · Publisher ↗
Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and ra...
Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and whole-genome sequencing-based heritability at 46%. Rare coding variant analysis identified HMGCR as a gene in which rare damaging variants confer risk for postpartum psychosis (FDR < 0.05). Analyses of 240,009 participants from the All of Us Research Program and 58,990 participants from the Mount Sinai BioMe Biobank identified significant associations linking deleterious rare variants in HMGCR to vascular dementia and mental disorder, not otherwise specified, supporting the gene's broader psychiatric relevance. Additionally, among the top 200 genes ranked by association statistics, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorders exhibit a possible association with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.
How muscle talks to brain: apelin protein mediates exercise-induced antidepressant effects.
Yu J, Cheng T, Guo H … +14 more , Song Z, Zhong Y, Lee TH, Li J, Formolo DA, Hussain A, Le K, Yao Y, Abel RL, Cheung WH, Lin K, Xu A, Cheng KK, Yau SY
Mol Psychiatry · 2026 May · PMID 42135522 · Publisher ↗
Physical exercise alleviates depressive symptoms and enhances hippocampal plasticity, but the mediators of muscle-brain crosstalk underlying these effects are not fully understood. We evaluated apelin as a novel mediator...
Physical exercise alleviates depressive symptoms and enhances hippocampal plasticity, but the mediators of muscle-brain crosstalk underlying these effects are not fully understood. We evaluated apelin as a novel mediator of the antidepressant effects of physical exercise, specifically testing the hypothesis that exercise-induced increases in skeletal muscle-derived apelin enhance hippocampal plasticity via apelin and its receptor APJ signaling. Voluntary running for 4 weeks alleviated depression-like behaviors and increased serum and hippocampal apelin levels, with skeletal muscles (tibialis anterior and gastrocnemius) as primary apelin sources. Muscle-specific apelin knockout abolished the antidepressant and pro-neurogenic effects of running, whereas muscle‑targeted apelin overexpression mimicked the benefits of running in wild-type mice. Mechanistically, myokine apelin enhanced NMDA receptor-mediated neurotransmission via receptors APJ on hippocampal glutamatergic neurons. Specific knockdown of APJ diminished the pro-neurogenic and antidepressant effects of running. Furthermore, apelin/APJ signaling activated casein kinase 2, which phosphorylated the GluN2B subunit at serine 1480, thereby enhancing NMDA receptor function and activating downstream calpain-2 signaling. Our findings reveal a muscle-brain axis where exercise-induced myokine apelin coordinates hippocampal neuroplasticity and antidepressant responses, offering new therapeutic avenues for depression.
Grin2a knockout in adolescent dopamine neurons disrupts prediction error signaling and produces a phenotype relevant to schizophrenia.
Kielhold ML, Jacobs DS, Torrado Pacheco A … +7 more , Lefner MJ, Bogachuk AP, Lebowitz JJ, Langdon AJ, Williams JT, Zweifel LS, Moghaddam B
Mol Psychiatry · 2026 May · PMID 42129480 · Publisher ↗
Adolescence is associated with the emergence of several psychiatric disorders including schizophrenia. Recent studies have identified both common and rare variants of the GRIN2A gene as risk factors for schizophrenia. GR...
Adolescence is associated with the emergence of several psychiatric disorders including schizophrenia. Recent studies have identified both common and rare variants of the GRIN2A gene as risk factors for schizophrenia. GRIN2A encodes the GluN2A subunit of the NMDA receptor and is developmentally regulated with low cortical expression at birth that reaches adult levels in adolescence. While global knockouts of Grin2a produce abnormal behavior in mice, little is known about the functional consequences of manipulating this gene specifically in dopamine neurons, a cell type implicated in schizophrenia pathophysiology. We find that, unlike cortical regions where GluN2A levels remain stable throughout adolescence, GluN2A naturally declines in dopamine neuron-containing brain regions in this developmental period. This suggests that adolescent dopamine neurons may be especially vulnerable to further reductions of GluN2A caused by damaging GRIN2A variants. Consistent with this idea, we find that a genetically driven reduction of Grin2a in midbrain dopamine neurons of adolescent rats is sufficient to recapitulate behaviors that are consistent with some aspects of positive symptoms of schizophrenia. These include hypersensitivity to amphetamine, diminished effort optimization, impaired ability to use feedback to modify motivated actions, and disrupted dopamine release during prediction error signaling. Computational modeling of the behavioral data further revealed reduced capacity to gate associative processes based on previous learning. These data describe a novel role for GluN2A-containing dopamine neurons in prediction error signaling and provide a rodent model to explore how mutations in GRIN2A may contribute to the latent presentation of dopamine-related symptoms in schizophrenia.
Nitrous oxide controls the DCN to VTA dopamine circuit by enhancing AMPA receptor functions during rewarding behavior.
Zhang F, Fan S, Li S … +12 more , Xu Y, Ren Y, Wang Y, Liu X, Ma W, Zhang J, Ding F, Yin F, Zhou L, Feng S, Sun J, Ma T
Mol Psychiatry · 2026 May · PMID 42129479 · Publisher ↗
Nitrous oxide (NO) is a frequently used recreational drug with significant addictive potential. The ventral tegmental area (VTA) is a key brain region associated with the rewarding effects of drugs of abuse. However, how...
Nitrous oxide (NO) is a frequently used recreational drug with significant addictive potential. The ventral tegmental area (VTA) is a key brain region associated with the rewarding effects of drugs of abuse. However, how NO influences VTA functions to mediate reward-related behavior remains poorly understood. We reported that exposure to 60% NO, but not 30%, effectively induced conditioned place preference (CPP) reward behavior and simultaneously increased the excitability and glutamatergic transmission of VTA dopamine neurons. Furthermore, we depicted upstream brain regions that send afferent inputs to the VTA and observed that NO specifically elevated homocysteine levels in the deep cerebellar nuclei (DCN). Interestingly, pharmacological inhibition of homocysteine production did not significantly reduce NO-induced rewarding behavior or the glutamatergic transmission to VTA neurons. Instead, despite being an NMDA receptor antagonist, NO directly enhanced the AMPA receptor-mediated glutamatergic transmission and functionally increased the activity of both DCN and VTA dopamine neurons. Both the optogenetic induction of long-term depression (LTD) in the DCN-VTA neural circuit and the chemogenetic inhibition of VTA dopamine neurons attenuated NO-induced CPP. Taken together, our findings suggest that attenuating NO-induced potentiation of the DCN-VTA circuit may provide a novel therapeutic strategy for treating NO-related reward behavior.
Thalamo-cortical white matter connectivity-defined thalamic subarea volumes predict individual delay discounting.
Yoon BY, Park H, Jung WH
Mol Psychiatry · 2026 May · PMID 42129478 · Publisher ↗
Delay discounting (DD), the tendency to favor smaller, immediate rewards over larger, delayed rewards, is associated with impulsivity and various psychiatric disorders. In this study, we investigated the role of the thal...
Delay discounting (DD), the tendency to favor smaller, immediate rewards over larger, delayed rewards, is associated with impulsivity and various psychiatric disorders. In this study, we investigated the role of the thalamus, a brain structure with multiple subdivisions that relays information to cortical regions, in influencing DD. We hypothesized that thalamic subdivisions play distinct roles in modulating individual impulsivity. After quality control, we included diffusion tensor imaging and DD behavioral task data from 149 participants, who were asked to choose between immediate and delayed rewards. Using a probabilistic tractography approach, the thalamus was segmented into connectivity-defined regions (CDRs) based on cortical connections. This allowed us to examine how the relative volumes of these specific subthalamic regions connected to the cortical areas influence DD. Our findings showed that larger thalamic CDRs linked to the medial prefrontal cortex (MPFC) were correlated with higher DD, indicating greater impulsivity. Supplementary analyses using exponential and extended hyperbolic models for calculating DD confirmed the association with the MPFC-connected thalamic region, demonstrating the robustness of the finding across different models. The study concludes that the thalamus, particularly its connections with the MPFC, plays a crucial role in modulating impulsivity and temporal decision-making. This illustrates how the interactions between the thalamus and different cortical regions affect impulsive decision-making and has implications for understanding human behaviors characterized by impulsivity.
The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis.
Hoertel N, Mühle C, Müller CP … +6 more , Chaieb H, Scheer V, Fayad M, Sánchez-Rico M, Limosin F, Kornhuber J
Mol Psychiatry · 2026 May · PMID 42129477 · Publisher ↗
Major depressive disorder (MDD) represents a leading cause of disability. Despite decades of research focused on monoaminergic dysregulation, the exact pathophysiological mechanisms underlying MDD remain incompletely und...
Major depressive disorder (MDD) represents a leading cause of disability. Despite decades of research focused on monoaminergic dysregulation, the exact pathophysiological mechanisms underlying MDD remain incompletely understood. This gap in knowledge has contributed to suboptimal therapeutic outcomes, with approximately one-third of MDD patients showing resistance to conventional treatments. Recent advances in lipidomics support that sphingolipids-including ceramides, sphingomyelins, and their metabolites-could play important roles in depression pathophysiology. This review examines the role of sphingolipid dysregulation in MDD and associated cognitive impairment, with a particular focus on interactions with neurogenesis and apoptosis, monoaminergic signaling, neuroinflammation, mitochondrial dysfunction and oxidative stress, glutamatergic signaling, and synaptic plasticity. Several clinical studies demonstrate altered sphingolipid profiles in MDD patients, with elevated ceramide levels correlating with depression severity. Preclinical evidence supports potential causal relationships between sphingolipid alterations and depressive behaviors through effects on neurotransmission, neuroplasticity, neurogenesis, mitochondrial function, and inflammatory processes. Many established antidepressants influence sphingolipid metabolism through distinct mechanisms-acting directly as functional inhibitors of acid sphingomyelinase (ASM) or modulating this pathway indirectly. This mechanistic convergence positions sphingolipid dysregulation as a potential central mediating node across major pathophysiological pathways in MDD and as a common pathway through which key risk factors may converge, potentially explaining its biological heterogeneity. Sphingolipid metabolism also offers a potential mechanistic explanation for the frequently observed cognitive deficits in MDD. This review synthesizes current evidence regarding sphingolipid involvement in depression pathophysiology and outlines promising avenues for personalized medicine through biomarker development and sphingolipid-targeted therapeutics.
Associations between REM sleep EEG slowing and brain cholinergic denervation in aging and Mild Cognitive Impairment.
André C, Bédard MA, Daneault V … +11 more , Wickens R, Fliaguine O, Soucy JP, Gauthier S, Lorrain D, Bastien C, Hudon C, Marchi NA, Montplaisir J, Gosselin N, Carrier J
Mol Psychiatry · 2026 May · PMID 42120556 · Publisher ↗
Cholinergic activity supports cortical activation during REM sleep, while other neurotransmitter systems are almost silent. Here, we tested the long-standing hypothesis that early cholinergic denervation may be associate...
Cholinergic activity supports cortical activation during REM sleep, while other neurotransmitter systems are almost silent. Here, we tested the long-standing hypothesis that early cholinergic denervation may be associated with REM sleep EEG slowing in older adults. Twenty-four older participants without dementia (mean age: 71.29 ± 4.85 years; 58.33% women; 25% participants with amnestic Mild Cognitive Impairment) underwent a night of in-laboratory polysomnography, comprehensive neuropsychological evaluation, structural MRI and molecular PET imaging with [F]-Fluoroethoxybenzovesamicol (FEOBV) to quantify brain cholinergic innervation. Voxel-wise multiple regressions assessed the associations between REM sleep characteristics (i.e., REM sleep percentage, relative theta power and EEG slowing ratios, defined as [delta + theta]/[alpha + beta] power) and FEOBV-PET standard uptake value ratio maps, controlling for sex. Given that FEOBV uptake was higher in women compared to men, we also performed exploratory sex-stratified analyses adjusted for age. Higher REM sleep EEG slowing over frontal (F3-F4), central (C3-C4), parietal (P3-P4), occipital (O1-O2) and temporal (T5-T6) derivations was significantly associated with cortical cholinergic denervation, notably in fronto-parietal areas and the medial temporal lobe. Sex-stratified analyses showed that higher REM sleep EEG slowing ratios were associated with cholinergic denervation mainly in medial temporal regions in women, and neocortical regions in men. These findings suggest that global REM sleep EEG slowing may represent a sensitive marker of cortical cholinergic denervation in older adults without dementia, and may constitute a promising marker for early diagnosis and disease-modifying interventions in Alzheimer's disease.
Revolutionizing MDD diagnosis: the integrated role of circRNAs and biosensor technology.
Zhu W, Wang Y, Yu C … +12 more , Pires N, Yang Z, Karlsen H, Jing W, Yao H, Han B, Ouyang J, Zhu M, Correia JH, Demarchi D, Jiang Z, Dong T
Mol Psychiatry · 2026 May · PMID 42120555 · Publisher ↗
Major Depressive Disorder (MDD) is a globally widespread mental health disorder that frequently remains underdiagnosed and inadequately treated. Recent advancements in circular RNAs (circRNAs) have illuminated their pote...
Major Depressive Disorder (MDD) is a globally widespread mental health disorder that frequently remains underdiagnosed and inadequately treated. Recent advancements in circular RNAs (circRNAs) have illuminated their potential as biomarkers for a variety of diseases, including MDD. This review emphasizes the advantages of circRNA enrichment methodologies over traditional techniques, particularly isotachophoresis. Furthermore, the intricate role of circRNAs in the pathophysiological processes underlying MDD, as well as their integration with biosensor technology to improve diagnostic accuracy and efficiency, are synthesised. However, the clinical translation of circRNA-based diagnostics faces significant challenges, including the low abundance of circRNAs in bodily fluids, the need for highly sensitive and rapid detection platforms, and the lack of standardized, point-of-care compatible methods. A comprehensive overview of current circRNA detection methods, delineating their similarities and differences, is discussed. Insights for the anticipated advancements in quantitative and rapid circRNA detection is proposed. This review not only presents a thorough assessment of emerging trends in circRNA detection but also elaborates on primary techniques, traditional approaches, and recent innovations within the field of biosensor-based MDD diagnostics.
Dynamic immune and metabolic dysregulation in women with post-traumatic stress disorder: Longitudinal transcriptomic insights following sexual assault.
Bugiga AVG, Ota VK, Kajitani GS … +11 more , Der Agopian Guardia G, Rueda BEV, Rosa JS, Oliveira AM, Coimbra BM, Asprino PF, Galante PAF, Mello AF, Carvalho CM, Mello MF, Belangero SI
Mol Psychiatry · 2026 May · PMID 42120554 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a chronic and debilitating psychiatric condition, and sexual assault represents the leading risk factor for PTSD in women, with up to 50% of survivors developing the disorder. How...
Post-traumatic stress disorder (PTSD) is a chronic and debilitating psychiatric condition, and sexual assault represents the leading risk factor for PTSD in women, with up to 50% of survivors developing the disorder. However, most transcriptomic studies have focused on male military veterans, limiting insight into the molecular mechanisms underlying PTSD in women. We conducted a longitudinal RNA sequencing study of blood samples from 65 women with PTSD and 65 healthy controls (HC). One-year follow-up assessments were performed in 35 PTSD participants after completion of treatment with either sertraline or Interpersonal Psychotherapy adapted for PTSD (IPT-PTSD), and in 12 HC participants, who did not receive treatment but were reassessed for longitudinal comparison of transcriptomic profiles. Differential gene expression analyses were conducted across diagnostic groups (PTSD vs HC), symptom trajectories (persistent vs remitting), and treatment arms (sertraline vs IPT-PTSD), using both cross-sectional and longitudinal designs. Pathway enrichment and co-expression network analyses were performed to identify dysregulated biological processes and gene modules. At baseline, women with PTSD exhibited downregulation of immune-related pathways and upregulation of erythropoietic and metabolic processes compared to HC, consistent with systemic immune suppression and compensatory transcriptomic adaptations. Persistent PTSD was characterized by sustained immune suppression, dysregulated apoptotic signaling, and elevated mitochondrial activity, whereas the remitting trajectory showed upregulation of immune response and cell communication pathways, suggesting partial immune restoration. Comparing PTSD cases at baseline and after one year of treatment, both sertraline and IPT-PTSD were associated with overlapping transcriptomic changes, suggesting shared molecular mechanisms. Overall, this study reveals dynamic peripheral transcriptomic dysregulation in women with PTSD. Although we cannot fully disentangle whether these changes reflect the disorder itself or traumatic exposure, our findings identify molecular signatures of symptom persistence, remission, and treatment response, supporting the potential utility of transcriptomic biomarkers to inform therapeutic strategies.
Maternal fasting during early gestation induces epigenetic alterations and schizophrenia-related phenotypes.
Wang H, Bundo M, Nakachi Y … +12 more , Kanai A, Yamamoto Y, Miyazaki H, Toyoshima F, Shima Y, Sakai M, Yu Z, Tomita H, Suzuki Y, Iwamoto K, Owada Y, Maekawa M
Mol Psychiatry · 2026 May · PMID 42120553 · Publisher ↗
Schizophrenia is a severe neurodevelopmental disorder whose etiology remains incompletely understood. Epidemiological studies of the Dutch Hunger Winter demonstrated that maternal famine during early gestation increased...
Schizophrenia is a severe neurodevelopmental disorder whose etiology remains incompletely understood. Epidemiological studies of the Dutch Hunger Winter demonstrated that maternal famine during early gestation increased the risk of schizophrenia in offspring, implicating the Developmental Origins of Health and Disease (DOHaD) framework. However, the molecular mechanisms underlying this association remain unclear. Here, we developed a novel DOHaD-based schizophrenia model by subjecting pregnant mice to transient fasting restricted to the peri-implantation period, a critical window of global epigenomic reprogramming. Male offspring of fasted dams exhibited schizophrenia-related phenotypes, including impaired sensorimotor gating, abnormal behavioral patterns, and reduced dendritic spine density in the medial prefrontal cortex. Multi-omics profiling, integrating bulk RNA sequencing, Visium HD spatial transcriptomics, and DNA methylation arrays, revealed convergent alterations in synaptic organization, protein homeostasis, and oxidative stress pathways. These findings highlight how brief maternal fasting reprograms the epigenome and reshapes neural circuitry. Our work establishes the first animal model that directly mirrors early gestational famine exposure linked to schizophrenia risk, providing a unique platform for uncovering epigenetic mechanisms underlying the developmental origins of psychiatric disorders.
Predicting the geographical distribution of drug use disorder in Sweden from the geographical variation in social deprivation, genetic risk and urbanization.
Kendler KS, Zhao P, Mansourian A … +4 more , Ohlsson H, Sundquist J, Malmberg B, Sundquist K
Mol Psychiatry · 2026 May · PMID 42115367 · Publisher ↗
Drug use disorder (DUD) is distributed unevenly over geographical areas of Sweden. We explore, using geographically weighted regression, the proportion of this variation associated with community levels of genetic risk,...
Drug use disorder (DUD) is distributed unevenly over geographical areas of Sweden. We explore, using geographically weighted regression, the proportion of this variation associated with community levels of genetic risk, social deprivation and urbanicity. In the 5983 Demographic Statistical areas (DeSOs) within Sweden, we predict DeSO prevalence from mean genetic risk for DUD, measured by the family genetic risk score (FGRS), social deprivation (SD) and degree of urbanization. We first modeled results for genetic risk and SD only finding, in all of Sweden, the proportions of predicted variance (±95% CIs) in DeSO levels of DUD associated with genetic risk and SD were, respectively, 0.58 (0.58-0.59) and 0.42 (0.41-0.42). Similar results were obtained in the major cities: Stockholm, Gothenburg, and Malmö. Genetic effects were more predictive in males while levels of SD were more predictive in females. In maps of FGRS and SD prediction of DUD levels in DeSOs, we found results consistent with prior geographical patterns known in Sweden. Adding urbanicity to our model, only modestly predicted DeSO levels of DUD. To explore the potential origins of geographic variation in FGRS, we showed that young adults with high FGRS preferentially migrated to areas in Sweden with high levels of DUD. Our findings provide an initial tentative step toward clarifying the role of genetic and social-demographic factors in the geographical distribution of DUD within Sweden.
Comparison of the clinical efficacy, safety and EEG functional connectivity changes between 18-Hz rTMS and iTBS of accelerated dTMS treatment for major depressive disorder: a randomized controlled trial.
Yang L, Dai H, Zhu M … +12 more , Feng M, Li S, Wang J, Wang Z, Ren H, Zhang M, Gu S, Gu Y, Lu H, Zhang Z, Li J, Zhao Z
Mol Psychiatry · 2026 May · PMID 42115366 · Publisher ↗
Although the antidepressant efficacy of 18-Hz deep transcranial magnetic stimulation (dTMS) has been validated, its prolonged treatment duration has considerable limitations for treatment capacity and patient adherence....
Although the antidepressant efficacy of 18-Hz deep transcranial magnetic stimulation (dTMS) has been validated, its prolonged treatment duration has considerable limitations for treatment capacity and patient adherence. Therefore, novel short-course protocols such as accelerated dTMS and intermittent theta burst stimulation (iTBS) present promising alternative options. Here we addressed the question of whether iTBS of accelerated dTMS achieves comparable therapeutic and electrophysiological effects to accelerated dTMS with the conventional 18-Hz rTMS protocol in patients with major depressive disorder (MDD). In a randomized controlled trial (n = 73), participants received either 18-Hz rTMS of accelerated dTMS (rTMS-dTMS group), iTBS of accelerated dTMS (iTBS-dTMS group), or pharmacotherapy alone (drug group). Both dTMS protocols were administered twice daily for 10 days targeting the left lateral prefrontal cortex including the dorsolateral region. Results showed that Hamilton Depression Rating Scale (HAMD) score of the iTBS-dTMS group decreased significantly from 22.5 ± 3.7 before treatment to 8.2 ± 4.1 after treatment (t = 15.900, p < 0.001). HAMD score of the rTMS-dTMS group decreased significantly from 21.3 ± 2.9 before treatment to 8.0 ± 3.8 after treatment (t = 17.232, p < 0.001). The drug group also exhibited significantly improved patients' mood symptoms, and the HAMD score decreased from 24.7 ± 6.8 to 14.0 ± 5.0 (t = 6.363, p < 0.001). The treatment response rate was 85.7% in the iTBS-dTMS group and 76.9% in the rTMS-dTMS group, which was much higher than that of the drug group (42.1%). The remission rate was 50.0% in the iTBS-dTMS group and 42.3% in the rTMS-dTMS group, which was significantly higher than 10.5% of the drug group. We demonstrate here that both accelerated dTMS protocols significantly reduced HAMD scores, improved the response rates, and remission rates, outperforming pharmacotherapy alone. Resting-state EEG analysis further revealed unique frequency-specific functional connectivity (FC) modulation effects: the rTMS-dTMS group primarily exhibited weakened alpha-band functional connectivity within the fronto-occipital, fronto-temporal and fronto-central networks after treatment, whereas the iTBS-dTMS group predominantly demonstrated reduced theta-band functional connectivity within the fronto-parietal, fronto-occipital and fronto-temporal pathways after treatment. These findings indicate that iTBS of accelerated dTMS demonstrates comparable efficacy and tolerability to 18-Hz rTMS of accelerated dTMS, whilst inducing treatment-specific network-level neurophysiological alterations. In the rTMS-dTMS group, relative changes in FC between the frontal and temporal/precentral regions showed significant negative correlation with HAMD score reduction rates, while relative changes in FC between the frontal lobe and parietal lobe showed a significant positive correlation with the rate of HAMD score reduction for the iTBS-dTMS group. This study revealed novel mechanisms by which accelerated dTMS protocols modulate brain networks, providing evidence for the clinical application of accelerated iTBS-dTMS as an efficient, evidence-based treatment for MDD.
Integrating cell-type-specific gene expression and genome-wide associations identifies risk genes for schizophrenia.
Lou W, Dang X, Luo XJ
Mol Psychiatry · 2026 May · PMID 42106519 · Publisher ↗
Integrative studies such as transcriptome-wide association studies (TWAS) and Mendelian randomization (MR) have identified multiple risk genes whose expression level is associated with schizophrenia (SCZ). However, the v...
Integrative studies such as transcriptome-wide association studies (TWAS) and Mendelian randomization (MR) have identified multiple risk genes whose expression level is associated with schizophrenia (SCZ). However, the vast majority of integrative studies are based on quantitative trait loci (QTL) data from bulk brain tissues. Given that gene expression and genetic regulatory effects are highly dependent on cell types, it is important to conduct integrative studies using expression data from specific brain cell types. Here, we investigate the causality between cell-type-specific gene expression and SCZ. We first conducted MR by integrating four cell-type-specific expression quantitative trait loci (eQTL) datasets and genome-wide associations of SCZ separately. We then performed a meta-analysis to explore the causal relationships between gene expression in different human brain cell types and SCZ. We identified multiple genes whose cell-type-specific expression levels are causally associated with SCZ, including 148 significant genes in excitatory neurons, 71 in inhibitory neurons, 63 in astrocytes, 48 in microglia, 70 in oligodendrocytes, 39 in oligodendrocyte precursor cells, 20 in endothelial cells, and 7 in pericytes. We also performed MR using eQTL data from brain tissues and identified 206 genes whose expression levels are causally associated with SCZ. By integrating multiple lines of evidence, we prioritized the most plausible causal genes, including the MAU2 and PPP1R13B. Finally, we performed a drug target analysis to evaluate the therapeutic potential of these genes. Our study reveals the causal relationships between cell-type-specific gene expression and SCZ, providing promising targets for mechanistic investigation and therapeutic interventions.
Homozygous CHD8 mutation intensifies ASD phenotypes and attenuates sex differences.
Kim J, Lee S, Hwang E … +16 more , Jung H, Lee C, Choi SH, Lee S, Kim S, Moon H, Kim J, Lee G, Kim YG, Shin S, Kang H, Kim SJ, Gee HY, Kim SG, Lee E, Kim E
Mol Psychiatry · 2026 May · PMID 42106518 · Publisher ↗
CHD8 is a chromatin remodeler implicated in autism spectrum disorders (ASD) and multiple neurodevelopmental disorders, yet heterozygous Chd8-mutant mouse lines often exhibit only mild ASD-related phenotypes, leaving its...
CHD8 is a chromatin remodeler implicated in autism spectrum disorders (ASD) and multiple neurodevelopmental disorders, yet heterozygous Chd8-mutant mouse lines often exhibit only mild ASD-related phenotypes, leaving its role unclear. Because a complete knockout of Chd8 causes embryonic lethality, we generated viable homozygous Chd8-mutant mice carrying the human CHD8-Asn2373LysfsX2 mutation using a hybrid (C57BL6/J × 129/Sv) genetic background. Compared to heterozygous Chd8 mice, the homozygous Chd8 mice showed more robust phenotypes, including increased ASD-related behaviors and brain volume, decreased cerebral blood volume/flow, brain rhythms, and synaptic transmission, and ASD-related transcriptomic changes. Notably, while Chd8 mice on a pure background predominantly displayed behavioral deficits in males, the homozygous mutants in the hybrid background exhibited more pronounced female phenotypes, suggesting the interaction of genetic background and mutation strength. A direct comparison of Chd8 and Chd8 mice on the same hybrid background across brain volume, cerebral blood flow, neuronal firing, synaptic transmission, and transcriptome revealed a gene dosage-dependent attenuation of sexual dimorphic phenotypes that varied by developmental stage and brain region. Transcriptomic analyses further implicated pathways related to synaptic function, RNA splicing, and mitochondrial activity in mediating differences in male-female protection and susceptibility. Thus, a homozygous Chd8 mutation not only intensifies ASD-related traits but can also diminish typical sex-specific severity patterns, uncovering a novel link between mutation strength and sexual dimorphism in ASD.
Spatial concordance metrics and related risk factors of brain-peripheral barrier axes: unveiling distinct concordance patterns for mental and neurological axes.
Cui Z
Mol Psychiatry · 2026 May · PMID 42104116 · Publisher ↗
Numerous studies have documented bidirectional interactions between the central nervous system and barrier organs (skin, gut, and lung). While genome-wide association studies have revealed shared genetic factors across b...
Numerous studies have documented bidirectional interactions between the central nervous system and barrier organs (skin, gut, and lung). While genome-wide association studies have revealed shared genetic factors across brain-peripheral barrier axes, investigating these connections from an environmental perspective in large populations remains difficult. Using data from the Global Burden of Disease (GBD) 2023, I extracted annual incidence rates for 56 diseases related to brain-peripheral barrier axes and exposure rates for the 70 most detailed risk factors across 204 countries and territories. By categorizing regional incidence rates into four quartiles for each disease, I pinpointed regions with concordance of these axes and constructed a spatial atlas of disease concordance within the brain-peripheral barrier axis from a macro-epidemiologic view. Subsequently, I calculated global spatial concordance percentages for each axis, which allowed the comparatively assessment of concordance patterns across different axes, specific diseases, and their variations over time, across the lifespan, and by gender. Finally, I applied machine learning models and Shapley additive explanations to identify risk factors related to the spatial concordance of each axis. From 1990 to 2023, the overall trend for most brain-peripheral barrier axis pairs remained stable. Spatial concordance patterns showed dynamic fluctuations across the lifespan, followed by a convergence toward stability in older age. Several risk factors are related to most brain-peripheral barrier axes. Notably, the mental and neurological axes exhibited distinct concordance patterns. Compared with neurological axes, concordance within mental axes showed a broader and more dispersed geographic distribution, with greater variation across sexes and over time. Furthermore, concordance percentages of mental and neurological axes exhibited opposing age-related trends, contrasting disease spectra for peripheral conditions, and inverse relationships with alcohol and sodium consumption. Those divergences suggest distinct mechanisms underlying the brain-peripheral barrier axes in mental and neurological diseases. Related risk factors offer population-based hypotheses for further investigation in individual-level studies.
Cocaine facilitates Ca fluctuations in prefrontal cortex astrocytes via norepinephrine transmission in awake mice.
Sun S, Wu X, Gao M … +13 more , Li J, Sun L, Wang L, Chen G, Wang Q, Xiong Y, Lu Y, Zhou B, Liu B, Zhang Q, Wang C, Zhu F, Zhou Z
Mol Psychiatry · 2026 May · PMID 42104115 · Publisher ↗
Astrocytic Ca activity is crucial for maintaining normal brain function. However, the pathophysiological role of astrocytes in the context of addictive drugs remains largely unknown. Taking advantage of two-photon Ca ima...
Astrocytic Ca activity is crucial for maintaining normal brain function. However, the pathophysiological role of astrocytes in the context of addictive drugs remains largely unknown. Taking advantage of two-photon Ca imaging in awake mice, we show that a physiologically relevant level of cocaine induces synchronized and hyperactive Ca signals in frontal cortical astrocytes. Mechanistically, this process occurs primarily through the volume release of norepinephrine from locus coeruleus innervation, followed by the activation of Gq-coupled α1 adrenergic receptors in the prefrontal cortex and the subsequent IPR2-dependent store Ca release, thus causing hyperactive Ca fluctuations in astrocytes. Importantly, interrupting the hyperactive astrocytic Ca signals either by blocking store Ca release or by conditionally knocking out the astrocytic α1AR rescued FrA neuronal activity and aggravated cocaine-induced locomotor sensitization. These findings revealed that, in addition to neurons, astrocytes can be super-activated by cocaine through the crosstalk between norepinephrine nerves and glia, providing a new perspective for the understanding and clinical treatment of cocaine addiction.
Stable depression subtypes identified using functional connectome normative deviation models and their response to rTMS.
Chen C, Lin L, Liu Y … +6 more , Wang S, Wang J, Zang Y, Wang J, Qin W, Zhang B
Mol Psychiatry · 2026 May · PMID 42098265 · Publisher ↗
The heterogeneity of depression complicates treatment. Identifying stable biological subtypes could advance precision-targeted interventions. This study aims to identify stable depression subtypes using functional connec...
The heterogeneity of depression complicates treatment. Identifying stable biological subtypes could advance precision-targeted interventions. This study aims to identify stable depression subtypes using functional connectome normative deviation models and to assess their response to repetitive transcranial magnetic stimulation (rTMS). We analyzed 1204 patients spanning different states of depression, together with 1636 healthy controls. Functional connectome normative models were derived from healthy controls to generate individual deviation maps for patients with depression, which were clustered using k-means to identify biologically informed subtypes. Subtype-specific responses to dorsolateral prefrontal cortex rTMS were evaluated, and putative neurobiological mechanisms underlying differential rTMS responsiveness were investigated. Two reproducible subtypes emerged across various clinical and methodological conditions: subtype-1 exhibited hyperconnectivity in somatomotor and ventral attention networks and hypoconnectivity in frontoparietal and default mode networks, whereas subtype-2 showed the opposite pattern. Only subtype-2 showed significant improvement in anhedonia following rTMS treatment (SHAPS: z =- 2.92, P = 0.001, FDR), which was significantly greater than that of subtype-1 (SHAPS, subtype-1 vs. subtype-2 efficacy: z = -2.43, P = 0.046, FDR). Patients whose connectome deviation patterns more closely resembled subtype-2 had better anhedonia improvement (r = 0.48, P = 0.012), while those closer to subtype-1 had less improvement (r = -0.46, P = 0.016). Only the pattern of deviation changes in subtype-2 was positively correlated with the anhedonia-related functional connectivity network mapping (r = 0.43, P < 0.001). These preliminary findings highlight potential avenues for subtype-targeted interventions in depression and warrant validation in larger randomized controlled trials.
Physiological Age and Homeostatic Dysregulation Following Child Maltreatment in Youth.
Ye Q, Apsley AT, Etzel L … +10 more , Hastings WJ, Chiaro CR, Schreier HMC, Claus ED, Cohen AA, Fisher Z, Heim CM, Noll JG, Shenk CE, Shalev I
Mol Psychiatry · 2026 May · PMID 42098264 · Full text
Child maltreatment has been associated with biological hallmarks of aging, including telomere shortening and epigenetic instability; however, its influence on physiological age and homeostatic dysregulation in early life...
Child maltreatment has been associated with biological hallmarks of aging, including telomere shortening and epigenetic instability; however, its influence on physiological age and homeostatic dysregulation in early life remains unclear. The current study examined pediatric versions of physiological age and homeostatic dysregulation in children aged 8-13 with and without exposure to maltreatment. Maltreatment exposure was determined based on investigational records within 12 months prior to enrollment. Physiological measures were trained and validated utilizing external datasets - the National Health and Nutrition Examination Survey III and IV, respectively. Physiological age was computed using the Klemera-Doubal Method to indicate physiological developmental status. Homeostatic dysregulation level was computed as the Mahalanobis distance from an external reference group. 216 females and 245 males with a mean age of 11.4 years (SD 1.5) were included (76.6% White, 13.2% Black, and 13.0% Hispanic, 76.6% with maltreatment). Exposure to maltreatment was not associated with changes in physiological age but was associated with greater homeostatic dysregulation. Further analyses by maltreatment type and sex revealed that physical abuse was associated with greater homeostatic dysregulation, while sexual abuse was associated with delayed physiological development, specifically in males. Exposure to multiple types of maltreatment was associated with greater homeostatic dysregulation among males, but not among females. This study revealed that recent exposure to certain types of maltreatment may impair physiological development or regulation in children, with sex-specific patterns suggesting greater effects in males. Findings further indicate that physiological development composites in youth are sensitive to the impact of child maltreatment and can be incorporated in future work to evaluate the long-term sequelae of adverse exposures in pediatric populations. As the impact of maltreatment was only nominally significant after correction for multiple testing, validation work in other samples is needed.
ASD mutations in the ciliary gene CEP41 impact development of projection neurons and interneurons in a human cortical organoid model.
Hasenpusch-Theil K, Lesayova A, Kozić Z … +5 more , Beltran M, Wilson G, Henderson NC, Dando O, Theil T
Mol Psychiatry · 2026 May · PMID 42082754 · Publisher ↗
Primary cilia control cell-cell signalling and their dysfunction has been implicated in Autism Spectrum Disorders (ASD) but their roles in the ASD aetiology remain largely unexplored. Here, we analysed the impact of ASD...
Primary cilia control cell-cell signalling and their dysfunction has been implicated in Autism Spectrum Disorders (ASD) but their roles in the ASD aetiology remain largely unexplored. Here, we analysed the impact of ASD mutations in CEP41 using human cortical organoids. CEP41 encodes a centrosomal protein located at the basal body and the ciliary axoneme and is mutated in ASD individuals and in Joubert syndrome, a ciliopathy with high incidence of ASD. To gain insights into CEP41's role in ASD aetiology, we characterised human cortical organoids carrying the CEP41 R242H point mutations found in ASD individuals. This mutation did not interfere with CEP41's ciliary localisation but cilia were shorter and had lower levels of tubulin polyglutamylation, which is indicative of altered cilia stability and signalling. Moreover, scRNAseq analyses revealed that the expression of several transcription factors with critical roles in interneuron development was altered in mutant interneurons and their progenitors. The CEP41 mutation also caused an augmented formation of upper layer cortical neurons. Taken together, these findings indicate that CEP41 controls excitatory and inhibitory neuron differentiation, alterations in which might lead to an excitation/inhibition imbalance that is widely recognized as a convergent mechanism underlying neurodevelopmental disorders.
Heterogeneous functional state dynamics and its structural substrates in male individuals with autism spectrum disorder.
Liu T, Chen X, Zheng X … +7 more , Ren H, Xie Y, Fu Z, Zhao Y, Yang L, He Y, Liao X
Mol Psychiatry · 2026 May · PMID 42069873 · Publisher ↗
Neuroimaging studies have revealed altered functional connectome dynamics in autism spectrum disorder (ASD) and linked these alterations to clinical symptoms. However, most studies have emphasized population-level contra...
Neuroimaging studies have revealed altered functional connectome dynamics in autism spectrum disorder (ASD) and linked these alterations to clinical symptoms. However, most studies have emphasized population-level contrasts, leaving interindividual variability in connectome dynamics and its structural underpinnings poorly understood. To address this gap, we analyzed resting-state functional and structural MRI data from 939 male participants (440 with ASD, 499 typically developing controls) across 18 sites in the Autism Brain Imaging Data Exchange (ABIDE). Whole-brain functional state dynamics was characterized using five leading activity modes and their expressions via eigen-microstate analysis. Age-related trajectories of mode expressions were constructed for typically developing controls using normative modeling, enabling quantification of individual-level deviations in functional dynamics. Compared with controls, ASD individuals showed greater interindividual variability in functional deviation profiles. Unsupervised clustering of these profiles identified two robust ASD subtypes with distinct mode-specific dysfunctions. One subtype primarily involved the visual, default-mode, frontoparietal, and dorsal attention networks, whereas the other subtype primarily involved the somatomotor, visual, frontoparietal, and ventral attention networks. These subtypes were clinically dissociable, differing in restricted and repetitive behaviors and social impairments, and exhibited mode-specific brain-symptom associations. Furthermore, the subtypes exhibited distinct cortical thickness alterations, and individual subtype membership was predicted with high accuracy (83%) using a random forest classifier based on cortical thickness. The main findings were replicated in an independent cohort outside ABIDE. This study delineates two reproducible and clinically dissociable ASD subtypes and links functional connectome dynamics to structural substrates, offering novel insights into the neurobiological basis behind ASD heterogeneity.
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