Genome-wide association studies (GWAS) and large-scale rare variant burden analyses have identified both common and rare loss-of-function variants associated with neuropsychiatric and neurodegenerative disorders. Yet, th...Genome-wide association studies (GWAS) and large-scale rare variant burden analyses have identified both common and rare loss-of-function variants associated with neuropsychiatric and neurodegenerative disorders. Yet, the shared biological processes influenced by both classes of variation remain poorly characterized. In this study, we utilized transcriptomic data from 933 post-mortem brain samples to identify genes that show convergent coexpression with GWAS and rare variant burden risk genes across six brain disorders. Despite largely distinct sets of significant risk genes from GWAS and rare variant burden studies, we found a significant overlap in their convergently coexpressed genes. These convergent genes showed enrichment for common and rare variant heritability and highlighted key biological pathways and cell-type markers impacted by both types of genetic variation. Compared to genes coexpressed with one variant class, shared convergent genes exhibited stronger evolutionary constraint and greater enrichment for known drug targets, underscoring their potential therapeutic relevance. Collectively, our results establish a systematic and generalizable framework for integrating coexpression data with genetic risk to reveal transcriptional programs supported by both common and rare variant evidence, offering mechanistic insights into neuropsychiatric diseases.
Biomarkers can potentially improve the diagnosis, monitoring, and treatment of posttraumatic stress disorder (PTSD). However, PTSD biomarkers that are scalable and easily integrated into real-world clinical settings have...Biomarkers can potentially improve the diagnosis, monitoring, and treatment of posttraumatic stress disorder (PTSD). However, PTSD biomarkers that are scalable and easily integrated into real-world clinical settings have not been identified. The analysis was conducted between June to November 2024 using genomic samples and laboratory test results recorded in the Mass General Brigham (MGB) Health System. The analysis included 23,743 European ancestry participants from the nested MGB Biobank study. The first exposure was polygenic risk score (PRS) for PTSD, calculated using the largest available European ancestry genome-wide association study (GWAS), employing a Bayesian polygenic scoring method. The second exposure was a clinical diagnosis of PTSD, determined by the presence of two or more instances of PTSD-related diagnostic codes in the longitudinal electronic health records (EHR). The primary outcomes were the inverse normal quantile transformed, median lab values of 241 laboratory traits with non-zero h estimates. Sixteen unique laboratory traits across the cardiometabolic, hematologic, hepatic, and immune systems were implicated in both genomic and phenotypic lab-wide association scans (LabWAS). Two-sample Mendelian randomization analyses provided evidence of potential unidirectional causal effects of PTSD liability on hepatic (decreased albumin and total bilirubin), cardiometabolic (decreased HDL cholesterol and increased VLDL cholesterol), and hematologic (decreased mean platelet volume) markers. These findings demonstrate the potential of a triangulation approach to uncover scalable and clinically relevant biomarkers for PTSD.
Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the underlying genetic factors has been challenging. Recent genome-wide association studies...Suicide is one of the leading causes of death worldwide. Although suicidal behaviors demonstrate high heritability, identifying the underlying genetic factors has been challenging. Recent genome-wide association studies for suicidal behavior identified a SNP on chromosome 7, rs62474683, which was the most significantly associated SNP. As this SNP is intergenic, the mechanism by which it may be related to suicidal behaviors is unclear. In order to determine the potential functional effects of the rs62474683 genotype, and how it may be related to suicidal behavior, we ascertained expression of genes within a 1.8Mbp region surrounding this SNP in two brain regions in individuals with depression who died by suicide, and investigated the relationship between genetic variation and gene expression. Additionally, we explored, at the single cell level, the effect of the variant on gene expression and chromatin accessibility. While we found several genes displaying differential expression, Forkhead box P2 (FOXP2) was the most consistently altered in brains of individuals who died by suicide and its expression was related to rs62474683 genotype. Furthermore, the association between FOXP2 expression and suicide appeared to be both brain region- and cell type-specific. Finally, we found evidence for an association between the region containing rs62474683 and FOXP2, and identified Homeobox family transcription factors as potential mediators of this relationship. In conclusion, our study provides evidence suggesting a potential functional association between the most significant suicide attempt-associated locus to date and genes displaying differential expression in individuals with depression who died by suicide.
Chronic stress can trigger major depressive disorder through peripheral immune factors. Enhanced circulating levels of complement component 3 (C3), a key innate immunity molecule that is predominantly produced by the liv...Chronic stress can trigger major depressive disorder through peripheral immune factors. Enhanced circulating levels of complement component 3 (C3), a key innate immunity molecule that is predominantly produced by the liver, have been observed in depressed patients. However, the role of liver-derived C3 in the regulation of behavior under chronic stress remains ambiguous. Here, we found that liver-derived C3 critically contributes to stress susceptibility and blood-brain barrier (BBB) impairment in the nucleus accumbens (NAc) by inhibiting endothelial cell claudin-5, a pivotal tight junction protein for BBB integrity. In three mouse models of depression, hepatic C3 expression was notably increased in mice, with no comparable changes in other peripheral organs. Genetic ablation of C3 ameliorated chronic social defeat stress (CSDS)-induced increases in NAc BBB permeability and depressive-like behavior, and this amelioration was reversed upon re-expression of hepatic C3. Consistently, knockdown of hepatic C3 similarly improved these deleterious effects induced by CSDS. Furthermore, overexpression of hepatic C3 was sufficient to induce depressive-like behavior following subthreshold social stress. Hepatic C3 manipulation bidirectionally regulated expression of claudin-5 in NAc endothelial cells. Mechanistically, the liver-derived C3 suppressed claudin-5 expression in brain endothelial cells and increased stress susceptibility in mice through the C3a receptor-CCAAT/enhancer-binding protein-α signaling pathway in the NAc. Moreover, corticosterone upregulated hepatic C3 release by activation of nuclear factor-κB (NF-κB). Taken together, these results demonstrate that liver-derived C3 promotes susceptibility to depression by increasing BBB permeability under chronic stress, and propose targeting hepatic C3 as a promising therapeutic strategy for depression.
Neuroinflammation is a pivotal feature of neuropsychiatric conditions, yet the brain-intrinsic epigenetic mechanisms initiating this response are not fully understood. In this study, we show that loss of the histone H3K9...Neuroinflammation is a pivotal feature of neuropsychiatric conditions, yet the brain-intrinsic epigenetic mechanisms initiating this response are not fully understood. In this study, we show that loss of the histone H3K9me3 methyltransferase SETDB1 in excitatory neurons (Setdb1-CK-cKO) triggers endogenous retrovirus (ERV) activation and neuroinflammation in the mouse cortex. ERV activation occurs in both neurons and astrocytes, leading to the emergence of a distinct reactive astrocyte population with increased expression of inflammatory chemokines and cytokines. Mechanistically, we identify the purinergic receptor gene P2rx7 as a direct target of SETDB1. We characterize a novel enhancer in the P2rx7 first intron that is epigenetically silenced by SETDB1; loss of SETDB1 results in increased chromatin accessibility and aberrant P2rx7 overexpression. This epigenetic regulatory mechanism is conserved between mouse and human. Moreover, genetic ablation of P2rx7 in Setdb1-CK-cKO mice partially reverses ERV activation and inflammatory gene dysregulation, and attenuates synaptic dysfunction. These findings provide new mechanistic insight into the epigenetic regulation of P2X7R signaling in controlling endogenous neuroinflammatory responses in the central nervous system.
The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not full...The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not fully understood. Here we show that the activity of IL layer 5 pyramidal neurons projecting to the NAc shell (IL-NAcSh neurons) suppresses cocaine-associated memories. Following repeated cocaine exposures in a conditioned place preference paradigm, IL-NAcSh neurons anatomically traced by fluorescent Retrobeads undergo prolonged decrease of membrane excitability, lasting for at least 15 days after cocaine withdrawal. This persistent IL-NAcSh neuron hypoexcitability is accompanied by an increase in the rheobase, a decrease in the membrane input resistance, and an increase in the afterhyperpolarization potential. This cocaine induced maladapation in intrinsic excitability is not observed in prelimibic cortex neurons projecting to the NAc core (PL-NAcCo neurons), a separate descending circuit thought to promote cue-triggered drug seeking. Chemogenetic restoration of IL-NAcSh neuron activity reduces both the short-term and long-term retentions of cocaine conditioned place preference memories. Importantly, pharmacological activation or inhibition of the Kv7/KCNQ/M K+ channels bidirectionally regulates the rheobase and firing rate of IL-NAcSh pyramidal neurons, and local infusion of a Kv7 inhibitor in the IL attenuates cocaine place preference memories, suggesting a potential mechanism-based therapeutic. Our results provide direct support for the notion that the IL-NAcSh circuit serves to attenuate drug associated memories and restoring drug impaired IL-NAcSh neuron intrinsic excitability has the potential to mitigate drug-cue association memories and drug seeking.
Yang X, Agartz I, Andreassen O
… +73 more, Bachman P, Baeza I, Bartholomeusz C, Borgwardt S, Choi S, Colibazzi T, Cooper R, Corcoran C, de la Fuente-Sandoval C, Ebdrup B, Fortea A, Glenthøj BY, Glenthøj LB, Haas S, Hamilton H, Hayes R, He Y, Heekeren K, Ten Velden Hegelstad W, Hooker C, Kaess M, Kasai K, Katagiri N, Kim M, Kindler J, Koike S, Kristensen T, Kwon JS, Lawrie S, Lee J, Lin A, Loewy R, Mathalon D, McGorry P, Michel C, Møller P, Nemoto T, Pena M, Raghava J, Reyes-Madrigal F, Rivera-Chávez L, Rössler W, Sasabayashi D, Schall U, Schmidt A, Smigielski L, Sørensen M, Sugranyes G, Takahashi T, Tamnes C, Tang J, Theodoridou A, Tor J, Uhlhaas P, Værnes T, Via E, Vinogradov S, Waltz J, Westlye L, Wood S, Yamasue H, Yung A, Zhou J, Fusar-Poli P, Mizrahi R, Cropley V, Thompson P, van Amelsvoort T, Jalbrzikowski M, Becker B, Linden DEJ, Hernaus D, ENIGMA Clinical High Risk for Psychosis Working Group
The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we...The Clinical High Risk (CHR) state for psychosis is consistently associated with widespread cortical thinning. However, the underlying mechanisms driving this neuroanatomical phenotype remain poorly understood. Here, we integrated the ENIGMA CHR Working Group's large pooled dataset (N = 1782 CHR, N = 1333 healthy controls) with an open-source PET molecular atlas to identify, for the first time, potential neurochemical drivers of cortical thinning associated with psychosis risk, transition, and its core symptoms. Using multilinear model analysis, we show that local chemoarchitecture significantly explains CT differences associated with CHR case-control status, the severity of negative symptoms, and future psychosis transition after excluding medication confounds. PET-based maps of dopamine, GABA, glutamate, serotonin, and norepinephrine consistently emerged as the strongest predictors of lower CT in CHR and psychosis transition (total dominance range: 62-69% and 58-87%, respectively), with contributions of monoamine systems being especially sensitive to medication exposure (8-23% change in dominance range). Negative symptom-associated cortical thinning was best explained by PET-based maps of dopamine, histamine, serotonin and opioid systems (total dominance range: 60-81%), with contributions of histamine being sensitive to medication exposure (9-19% change in dominance range). Combined, these results uniquely identify specific neurochemical systems - particularly monoaminergic, glutamatergic, and GABAergic pathways - as key molecular mechanisms associated with cortical thinning in people at high risk of developing psychosis.
Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimer's disease (AD). As major regulators of epigenetic processes,...Epigenetic regulation is a key determinant of the aging process, and its dysregulation contributes to cognitive aging and increased vulnerability to Alzheimer's disease (AD). As major regulators of epigenetic processes, histone deacetylases (HDACs) have emerged as potential therapeutic targets for cognitive enhancement in neurodegenerative diseases. However, the distinct roles of individual HDAC isoforms remain to be defined. Here, we report that HDAC9 is specifically expressed in neurons of human and mouse brains, and its expression declines with age. HDAC9 deficiency impairs cognitive function and synaptic plasticity in young mice. Selective deletion of HDAC9 in hippocampal CA1 neurons also induces cognitive impairment. In contrast, overexpression of HDAC9 in forebrain glutamatergic neurons preserves cognitive function in aged mice. Moreover, HDAC9 is also downregulated in the brain of AD mouse models, whereas neuronal overexpression of HDAC9 alleviates AD-related cognitive and synaptic deficits and reduces Aβ deposition. Together, these findings suggest neuronal HDAC9 is necessary and sufficient for maintaining cognitive and synaptic functions in the context of aging and AD.
Gene by treatment (GxT) interactions likely contribute to variability in clinical response, but are difficult to identify in population studies. Here, we applied psychiatric and neurological disorder treatments to a geno...Gene by treatment (GxT) interactions likely contribute to variability in clinical response, but are difficult to identify in population studies. Here, we applied psychiatric and neurological disorder treatments to a genotyped population of human neural progenitors (n = 83 donors) and measured molecular responses on chromatin accessibility and gene expression. Gene regulatory responses to valproic acid (VPA), which is also a prenatal risk factor for autism, and lithium were highly enriched in genetic risk for psychiatric disorders, demonstrating the convergence of environmental and genetic factors. Genetic variation impacted molecular response to these drugs at over 1000 loci, a subset of which modulated the impacts of psychiatric risk variants. Finally, transcriptome-wide association conducted in the context of VPA revealed genes involved with folate metabolism associated with cognitive ability. As previous work has shown that folate supplementation can alleviate VPA-induced teratogenic effects, this approach identified a validated treatment pathway supporting its broad utility.
The epigenetic modification N6-methyladenosine (mA) is critical for neurodevelopment. However, its interplay with histone modifications during cerebellar development remains poorly understood. Ythdf2 is a core mA reader...The epigenetic modification N6-methyladenosine (mA) is critical for neurodevelopment. However, its interplay with histone modifications during cerebellar development remains poorly understood. Ythdf2 is a core mA reader that promotes selective degradation of methylated transcripts to shape gene expression dynamics. However, whether Ythdf2 also coordinates epitranscriptomic regulation with chromatin remodeling during cerebellar development is unknown. Here, we generated a Ythdf2 knockout (Ythdf2) mouse model and examined cerebellar development at embryonic day 13.5 (E13.5) and postnatal day 3 (P3). Ythdf2 mice developed overt cerebellar ataxia, manifested by tremors and abnormal gait. At the molecular level, loss of Ythdf2 disrupted neural progenitor maintenance and induced premature neuronal differentiation. The expression of progenitor markers, including Sox2, Nestin and Pax6 were markedly reduced, whereas markers of neuronal differentiation such as Tuj1 and Skor2 were increased. In contrast, genes associated with neuronal maturation, including Map2 and Calb1, and astrocytic marker Gfap were downregulated. m⁶A RIP seq analysis demonstrated that Ythdf2 caused a global reduction in m⁶A levels, with the differentially expressed m⁶A modified genes enriched for histone modification and chromatin stability. Furthermore, Ythdf2 loss suppressed transcriptional activity by altering H3K4me3 deposition, thereby reducing chromatin accessibility within neuronal developmental pathways. Co-immunoprecipitation revealed a specific interaction between YTHDF2 and the H3K4 methyltransferase SETD1B, but not CXXC1 or SETD1A, and Setd1b knockdown rescued the neural self-renewal and differentiation defects caused by Ythdf2 deletion. Together, these results establish a mechanistic link in which Ythdf2 connects mA-modified transcripts to Setd1b-mediated H3K4me3 deposition, thereby sustaining chromatin accessibility and transcriptional programs required for proper cerebellar development.
Aging is a complex biological process, and biological aging can be quantified by epigenetic clocks. Depression and anxiety are highly prevalent among older adults and are established risk factors for adverse health outco...Aging is a complex biological process, and biological aging can be quantified by epigenetic clocks. Depression and anxiety are highly prevalent among older adults and are established risk factors for adverse health outcomes. However, their relationships with epigenetic age acceleration (EAA) remain unclear, particularly in Asian populations. Using data from the Diet and Healthy Aging cohort, the present study examined the associations between depressive and anxiety symptoms and EAA within community-dwelling older adults (aged ≥ 60 years, n = 672). Depressive symptoms were assessed using the Geriatric Depression Scale (GDS), and anxiety symptoms were measured using the Geriatric Anxiety Inventory (GAI). Linear mixed-effects models were fitted to all available observations to account for within-person clustering, with additional within-person change analysis conducted among participants with repeated DNA methylation profiles (n = 116). These were followed by rigorous sensitivity analyses to inspect robustness. We found that depressive symptoms, but not anxiety, were robustly associated with higher EAA, primarily indexed by PCPhenoEAA. In fully adjusted models, each standard deviation (SD) increase in depressive symptoms corresponded to a 0.087 SD increase in PCPhenoEAA (β = 0.087, 95% CI [0.023, 0.151], p = 0.008). Participants screening positive for depression (GDS ≥ 5) exhibited, on average, 0.244 SD higher PCPhenoEAA compared with those without depression (β = 0.244, 95% CI [0.027, 0.461], p = 0.030). Despite relatively stable EAA across the follow-up period, within-person change in depressive symptoms was associated with a concomitant increase in PCPhenoEAA. Our findings highlight depression as an important and potentially modifiable factor in delaying biological aging among older Asian adults, highlighting the need for timely screening and interventions to promote healthy aging.
Anorexia nervosa (AN) is a complex psychiatric disorder with both psychiatric and metabolic underpinnings. This study aims to explore the genetic architecture of AN and the interplay between its psychiatric and metabolic...Anorexia nervosa (AN) is a complex psychiatric disorder with both psychiatric and metabolic underpinnings. This study aims to explore the genetic architecture of AN and the interplay between its psychiatric and metabolic components. Through a meta-analysis of AN GWAS data from European and Finnish populations, we identified a novel genome-wide significant locus near the SOX5 gene. Genetic correlation and Mendelian randomization analyses revealed shared and potentially causal relationships between AN and multiple psychiatric and metabolic traits. Local genetic correlation analysis identified 185 significant genomic regions contributing to shared heritability between AN and correlated phenotypes, with 100 loci demonstrating pleiotropic effects across multiple traits. The MTAG analyses identified 86 significant loci (34 overlapping with local genetic correlation results), including 25 novel loci such as brain-relevant VAMP2 (17p13.1) and metabolic-neurological hubs LPL (8p21.3) and BDNF (11p14.1). Gene Co-expression Network Analysis (WGCNA) further identified key gene modules associated with both metabolic and neurological pathways, particularly highlighting synaptic signaling and lipid metabolism. Single-cell transcriptomic analysis further resolved this genetic risk to the cellular level, confirming its concentration in limbic and striatal GABAergic neurons and extending the implicated circuitry to include cortical regions involved in motor function. These findings collectively demonstrate the intricate genetic interplay between psychiatric and metabolic pathways in AN, underscoring the necessity of an integrated approach to understanding its pathogenesis.
Major depressive disorder is a prevalent mental condition and the second most disabling disease. Transcranial direct current stimulation (tDCS), with advantages such as affordability, home-use application, and mild side...Major depressive disorder is a prevalent mental condition and the second most disabling disease. Transcranial direct current stimulation (tDCS), with advantages such as affordability, home-use application, and mild side effects, has been proposed for treating depression. Yet, its clinical efficacy is not established. Optimizing tDCS interventions for more effective and feasible clinical application is a need and topic of ongoing research. This randomized, sham‑controlled trial compares the efficacy of computationally optimized multichannel tDCS (4 mA), a less source-demanding alternative for personalized tDCS, vs conventional tDCS (2 mA) for treating unipolar depression. Seventy-one patients were randomly assigned to the optimized multichannel tDCS, conventional tDCS, and sham tDCS arms, of whom 60 provided endpoint data. In the optimized multichannel tDCS, electrical current was delivered via 7 small electrodes (max 1.65 mA per electrode; total injected current per polarity ≈ 4 mA [precisely 3.99 mA]) while in the conventional (2 mA per electrode) and sham tDCS, two 35 cm² sponge electrodes were used. Intervention efficacy and treatment response were evaluated before the intervention, at weeks 2, 4, 6, and 1- and 3-month post-intervention, and cognitive functions and brain connectivity changes were assessed before and after the intervention. Both active tDCS interventions significantly reduced depressive symptoms compared to the sham group after the intervention. The optimized multichannel tDCS demonstrated earlier and stronger symptom alleviation than conventional tDCS. It additionally improved cognitive control and modulated functional connectivity markers associated with depression pathophysiology. The mean change in the primary clinical outcome from baseline to the study endpoint was 6.30 in the sham group and 13.50 and 21.50 in the conventional and multichannel tDCS groups, with corresponding response rate (≥50% symptom reduction) of 20% (4/20), 45% (9/20), and 75% (15/20), respectively. Blinding was unsuccessful only in the optimized multichannel arm, likely due to more intense stimulation-related sensations, however, this did not impact clinical outcomes. The optimized multichannel 4 mA tDCS shows clinical efficacy for treating depression, warranting further investigations in the future. Trial Registration Identifier: NCT06165445 / IRCT20210517051330N1.
Large-scale mega-analyses of worldwide combined Magnetic Resonance Imaging (MRI) studies have demonstrated brain differences between individuals with mental disorders and controls. However, the potential of large-scale o...Large-scale mega-analyses of worldwide combined Magnetic Resonance Imaging (MRI) studies have demonstrated brain differences between individuals with mental disorders and controls. However, the potential of large-scale observational studies using population-based clinical MRI data remains unexplored. We analyzed clinical MRI data from 23,545 patients in the Eastern half of Denmark (Capital Region of Denmark and Region Zealand). 2774 patients with mental disorders and 2062 non-psychiatric controls fulfilled our inclusion and exclusion criteria. Patients with mental disorders exhibited smaller thalamic (d = -0.298) and amygdala volumes (d = -0.250), with larger ventricles (d = 0.272), and thinner insula (d = -0.177), all p < 0.0001. Analysis across all ROIs revealed a widespread pattern of thinner cortex (d = -0.180), especially in the temporal pole (d = -0.234) and superior frontal (d = -0.212) regions, and increased extracerebral cerebrospinal fluid (d = 0.264). For volumetric measurements, findings were consistent across different inclusion and exclusion criteria but varied for cortical thickness measurements. Utilizing this currently largest population-based MRI cohort for mental disorders, we demonstrate that clinical MRI scans can detect brain structural differences among patients with mental disorders in real-world clinical settings, aiding in the stratification of patients without mental disorders. Cross-disorder analyses reveal shared neuroanatomical changes, including globally smaller brain volumes and thinner cortex. Integrating large-scale clinical MRI data with electronic health records holds promise for improved patient stratification and tracking of disease progression for future longitudinal cross-disorder studies, bridging real-world MRI data with clinical trajectories for further biological subgrouping.
Impulsivity is a core symptom across multiple addictive disorders, including internet gaming disorder (IGD), yet its multidimensional nature-particularly the neural basis of state and trait impulsivity in IGD-remains poo...Impulsivity is a core symptom across multiple addictive disorders, including internet gaming disorder (IGD), yet its multidimensional nature-particularly the neural basis of state and trait impulsivity in IGD-remains poorly understood. We aimed to elucidate the neural correlates of both impulsivity dimensions and uncover how IGD interacts with the heightened impulsive tendencies. Here we conducted a fMRI study with 87 college students at risk for IGD, employing a modified card-guessing task to capture state impulsivity under a loss decision framework. Modified card-guessing paradigm was applied to assess subjects' state-impulsivity via the loss chasing behavior-the tendency to increase wagers to recover previous losses. Trait impulsivity was assessed using the UPPS-P scale. Another independent cohort (n = 84) with similar IGD profiles was further to validate our finding. Behavioral modelling indicated that state impulsivity, manifesting as the loss chasing behavior (i.e., higher wagers under the loss decision framework), dynamically increased as a function of the loss streaks. Neuroimaging analyses identified key brain regions-such as the right middle frontal gyrus, superior frontal gyrus, striatum, and insula-whose activation during loss feedback predicted subsequent impulsive decisions. These neural signatures of state impulsivity successfully distinguished high-risk IGD individuals. Crucially, resting-state functional connectivity (rs-FC) within these regions not only identified IGD risk but also predicted trait impulsivity. Mediation analysis further demonstrated that IGD's influence on trait impulsivity was indirectly mediated by rs-FC patterns linked to state impulsivity. Our findings elucidate the distinct yet interconnected neural representations of state and trait impulsivity in IGD, underscoring the neurobehavioral continuum linking transient impulsive states to enduring impulsive traits in IGD.
Genome-wide association studies (GWAS) have identified over 300 risk loci for schizophrenia (SCZ). However, given the vast majority of risk variants identified from GWAS are localized in non-coding regions, identificatio...Genome-wide association studies (GWAS) have identified over 300 risk loci for schizophrenia (SCZ). However, given the vast majority of risk variants identified from GWAS are localized in non-coding regions, identification of functional risk variants from the risk loci and elucidating their molecular regulatory mechanisms remain major challenges. Here, we leverage a functional genomics approach to systematically identify functional variants from the reported risk loci. By integrating chromatin immunoprecipitation sequencing (ChIP-Seq) and position weight matrix (PWM) data, we identified 249 functional variants (located in 99 loci) that affect the binding of transcription factors (TFs). Expression quantitative trait loci (eQTL) annotation showed that 207 TF binding-affecting SNPs are significantly associated with gene expression in the human brain. For 92 loci where functional variants have not been identified by functional genomics, we conducted fine-mapping and applied motifbreakR to identify potential causal or functional variants. Notably, regulatory effects of 35 identified functional variants were validated by the published massively parallel reporter assays (MPRAs). Expression analysis showed dysregulation of genes whose expression levels are associated with functional variants in SCZ cases compared with controls. Our study identifies the functional variants from the reported risk loci and elucidates the molecular regulatory mechanisms of SCZ-associated functional non-coding variants, providing an important starting point to translate the genetic findings into disease biology and potential therapeutic targets.
Tanaka R, Liao J, Liu Y
… +16 more, Zhu W, Fukuzawa K, Kondo M, Sawahata M, Mori D, Mouri A, Kubota H, Tachibana D, Kobayashi Y, Matsuzaki T, Nagai T, Nabeshima T, Kaibuchi K, Ozaki N, Mizoguchi H, Yamada K
Copy number variations in the ARHGAP10 gene encoding Rho GTPase-activating protein 10 are significantly associated with schizophrenia. ARHGAP10 negatively regulates RhoA/Rho-kinase (ROCK) signaling. We previously demonst...Copy number variations in the ARHGAP10 gene encoding Rho GTPase-activating protein 10 are significantly associated with schizophrenia. ARHGAP10 negatively regulates RhoA/Rho-kinase (ROCK) signaling. We previously demonstrated that fasudil, a non-selective ROCK inhibitor, exhibited antipsychotic-like effects in several mouse models of schizophrenia. ROCK has two subtypes, ROCK1 and ROCK2. ROCK1 is mainly expressed in the thymus and blood, while ROCK2 is predominantly expressed in the brain. Therefore, it is expected that like fasudil, selective ROCK2 inhibitors will exhibit antipsychotic-like effects, accompanied by a lower incidence of adverse effects due to ROCK1 inhibition. Here, we used genetic and pharmacological models of schizophrenia to investigate whether the selective ROCK2 inhibitor KD025 would show antipsychotic-like effects with a favorable adverse effect profile. Oral administration of KD025 suppressed the abnormal increase in the phosphorylation level of myosin phosphatase-targeting subunit 1, a substrate of ROCK, and ameliorated the decreased spine density of layer 2/3 pyramidal neurons in the medial prefrontal cortex of Arhgap10 S490P/NHEJ mice. Furthermore, KD025 mitigated the methamphetamine-induced impairment of visual discrimination (VD) in Arhgap10 S490P/NHEJ and wild-type mice. KD025 also reduced MK-801-induced impairments of VD, novel object recognition, and hyperlocomotion. Regarding side effects that are commonly seen with typical antipsychotics, KD025 did not affect systolic blood pressure and did not induce extrapyramidal symptoms, hyperprolactinemia, or hyperglycemia at the effective dosage in naïve wild-type mice. Taken together, KD025 shows antipsychotic-like effects with a favorable adverse effect profile in genetic and pharmacological mouse models of schizophrenia.
While sex differences in the prevalence of depression are consistently observed in adolescence, sex-specific endophenotypes associated with depression appear earlier in childhood. Our study examined whether neurodevelopm...While sex differences in the prevalence of depression are consistently observed in adolescence, sex-specific endophenotypes associated with depression appear earlier in childhood. Our study examined whether neurodevelopmental changes in childhood associated with depressive symptoms in adolescence show sex-specificity. Longitudinal multi-modal neuroimaging data were collected at ages 4.5, 6.0, and 7.5 years. Neurodevelopment was measured by structure-function coupling (SC-FC), the correlation between structural and functional connectivity, derived for 114 cortical regions and averaged across the whole cortex. Depressive symptoms were self-reported at age 13 years with the Child Depression Inventory (CDI), Youth Self Report (YSR), and Multidimensional Anxiety Scale for Children. Partial least squares correlation was used to identify latent variables that maximized covariance between the 28 CDI items and 114 cortical regions. Females reported significantly higher depressive symptoms than males at age 13 years (N = 636, p < 0.001). Whole cortex SC-FC showed sex-specific trajectories across childhood (N = 549, 917 scans). Females showed a steeper decrease in SC-FC relative to males in the pre-school phase (ages 4.5 to 6.0, p = 0.019) but not during mid-childhood (ages 6.0 to 7.5, p = 0.340). For both childhood phases (Pre-school: N = 97, Mid-childhood: N = 162), sex-specific models better explained the data than full cohort ("All") models. Items/regions with significant contributions to their respective latent variables were distinct in males and females and between childhood phases. Sex-specific cortical changes improved regression models predicting YSR Depressive Problems. We provide evidence for sex-specific childhood neurodevelopmental pathways to depressive symptoms in adolescence that could guide the timing for more effective intervention programs.