Molecular Psychiatry最新文献

{"title":"Molecular genetic influences on sustained attention and executive processes and their links with psychopathology in the AFFECT study.","authors":"Justin D Tubbs, Travis T Mallard, Maria Dalby, Yunxuan Jiang, Younga H Lee, Karmel W Choi, Tian Ge, Niels Plath, Lene Hammer-Helmich, Julie M Granka, Andrew D Grotzinger, David Hinds, Jordan W Smoller, Joshua W Buckholtz","doi":"10.1038/s41380-026-03712-2","DOIUrl":"10.1038/s41380-026-03712-2","url":null,"abstract":"<p><p>Both sustained attention (SA) and executive functioning (EF) are critical for adaptive behavior and compromised across a range of psychiatric disorders, yet their etiological relationships remain underexplored. Here, we report the first multivariate characterization of molecular genetic influences on SA (vigilance, lapse recovery cost, lapse propensity) and EF (processing speed, response selection, working memory). In collaboration with 23andMe, we report previously unpublished genome-wide association studies of these phenotypes in a single cohort of more than 20,000 individuals enriched for diagnoses of major depressive disorder and bipolar disorder. We used Genomic Structural Equation Modeling to formally model patterns of genetic covariance among these task-based measures of cognition, and their relationships with other cognitive, clinical, and imaging-derived phenotypes. We identified two distinct latent genetic factors: one influencing EF and one influencing SA. Both the EF and SA factors were genetically correlated with cognitive and clinical phenotypes, with each latent factor uniquely linked to liability for psychiatric disorders, including attention-deficit/hyperactivity disorder. However, genetic correlations with imaging-derived neuroanatomical phenotypes were modest and non-significant after correction for multiple comparisons. Collectively, these results provide an initial multivariate genetic characterization of SA and EF, though replication in larger and more diverse samples will be important. They suggest that genetic influences on sustained attention are generally distinct from those that influence executive function. The EF and SA factors show distinct patterns of genetic overlap with multiple cognitive and psychiatric outcomes, underscoring the need for more granular cognitive phenotyping to generate new insights into the genetic architecture of cognition and the etiology of psychopathology.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":"6422-6432"},"PeriodicalIF":10.4,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13668728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Neurophysiological signatures of Stanford Neuromodulation Therapy in treatment resistant depression.","authors":"Davide Momi, Derrick M Buchanan, Masataka Wada, Andrew D Geoly, Noriah J Johnson, Eleanor J Cole, Adi Maron-Katz, Claudia Tischler, Christopher C Cline, Diego A Pizzagalli, Manish Saggar, Daphne Voineskos, John D Griffiths, Camarin E Rolle, Corey J Keller, Nolan Williams","doi":"10.1038/s41380-026-03915-7","DOIUrl":"https://doi.org/10.1038/s41380-026-03915-7","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared cortical morphometry and molecular signatures across depression and physical diseases.","authors":"Chenguang Jiang, Hongliang Zhou, Yucheng Yuan, Wei Xu, Yue Zhou, Taipeng Sun, Linlin You, Suzhen Chen, Yingying Yin, Yingying Yue, Xiaoyun Liu, Guangwei Sun, Yubo Zhang, Jiacheng Tan, Ruihua Shi, Xiaoyan Xu, Zhi Xu, Zhenhe Zhou, Wenbin Guo, Wenhao Jiang, Yonggui Yuan","doi":"10.1038/s41380-026-03928-2","DOIUrl":"https://doi.org/10.1038/s41380-026-03928-2","url":null,"abstract":"<p><p>Major depressive disorder (MDD) is highly comorbid with physical diseases, suggesting shared neurobiological mechanisms. However, the common structural and molecular substrates underlying this comorbidity remain poorly understood. We analyzed multimodal MRI data from 577 patients (MDD, asthma, fibromyalgia, gastroesophageal reflux disease, type 2 diabetes) and 275 healthy controls, constructed individual morphometric similarity networks (MSN) to identify shared cortical alterations, and applied principal component analysis with multiscale molecular annotation (transcriptomic, cell-type, neurotransmitter, and cognitive mapping) to characterize underlying mechanisms. All patient groups exhibited regional MSN abnormalities. A shared MSN pattern emerged, featuring increased similarity in visual and somatomotor regions and decreased similarity in ventral attention, limbic, and default mode networks, and was replicated in independent cohorts. This pattern was significantly associated with spatial gene expression enriched for synaptic signaling, membrane potential regulation, and neuronal architecture, with predominant expression in excitatory/inhibitory neurons and astrocytes. It further mapped onto specific neurotransmitter systems, with exploratory cognitive decoding suggesting possible relevance to emotion and social cognition. Related genes overlapped with known risk loci for Alzheimer's disease and bipolar disorder. These findings identify a robust across diseases cortical MSN phenotype linked to convergent molecular and neurochemical correlates, offering a framework for studying shared vulnerability and transdiagnostic mechanisms across depression and physical diseases.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repetitive transcranial magnetic stimulation (rTMS) combined with antidepressant pharmacotherapy for depression: state-dependent mechanisms, clinical evidence, and translational challenges","authors":"Junwen Deng,Yingbo Shao,Lina Jiang,Baolin Wu,Neil Roberts,Qiang Wang,Zhiyun Jia","doi":"10.1038/s41380-026-03930-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03930-8","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"31 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A microglial basis for fragile X syndrome via impairment of FMRP-regulated lysosomal function","authors":"Heng Li,Jennifer Ja-Yoon Choi,Eric J. Huang,Baoji Xu","doi":"10.1038/s41380-026-03927-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03927-3","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"11 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attention deficit hyperactivity disorder: transition to psychotic disorders.","authors":"Anita Thapar, Charlotte A Dennison, Ali Kandeğer, Michael J Owen","doi":"10.1038/s41380-026-03926-4","DOIUrl":"https://doi.org/10.1038/s41380-026-03926-4","url":null,"abstract":"<p><p>It is well recognized that Attention-deficit/hyperactivity disorder (ADHD) is associated with heightened risk for common psychiatric disorders; early identification and treatment of ADHD may help reduce some of this risk. However, the substantially increased risk of bipolar disorder, psychosis, and schizophrenia (hereafter psychotic disorders) is often overlooked (odds ratios 4.7-8.9). Given how common ADHD is, there is growing pressure for greater involvement of primary care services, especially for less complex forms of ADHD. However, those at highest risk for transition to a psychotic disorder need to be prioritised for secondary care follow up. Currently it is unknown how to stratify ADHD according to risk or indeed why only some develop a psychotic disorder. This perspective examines key hypotheses that may explain why transition occurs only in a subset of individuals. One hypothesis is that features suggestive of ADHD may represent early manifestations of psychotic disorders, although direct support for this is limited. The potential role of ADHD treatment is also considered; current data indicate that therapeutic use of methylphenidate is not associated with increased risk of psychotic disorders, while uncertainty remains for amphetamines. The possible mediating roles of ADHD-evoked environmental exposures are discussed, but evidence for mediation is lacking. We also consider the evidence that ADHD and psychotic disorders result from shared underlying neurodevelopmental processes. We highlight key clinical implications for screening and monitoring individuals with ADHD for psychotic disorders and consider what factors may help in weighting risk. Finally, we identify important evidence gaps for future research.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: \"Increasing dopamine synthesis capacity in the dorsal striatum and tonic acetylcholine: implications for the new muscarinic agents in the treatment of schizophrenia\".","authors":"Darryl Eyles, Zilong Du, Xiaoying Cui, James P Kesby","doi":"10.1038/s41380-026-03923-7","DOIUrl":"10.1038/s41380-026-03923-7","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zebrafish behavioral phenomics reveals functional subtypes of autism risk genes","authors":"Karl Stuntzner-Gibson,Ping Zhang,Baixi He,Leonardo Diaz,Yijie Geng","doi":"10.1038/s41380-026-03922-8","DOIUrl":"https://doi.org/10.1038/s41380-026-03922-8","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"52 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149150187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of white matter microstructure in the association between childhood maltreatment and adult post-traumatic symptoms","authors":"Luisa Berger,Philine Rojczyk,Johanna Seitz-Holland,Fan Zhang,Lara Pankatz,Nico Sollmann,Elisabeth Kaufmann,Holly Carrington,Twishi Puri,Michael J. Coleman,Ofer Pasternak,Sylvain Bouix,Yogesh Rathi,Suheyla Cetin-Karayumak,Lauren J. O’Donnell,Peter Falkai,Mark S. George,Thomas W. McAllister,Ross Zafonte,Murray B. Stein,Martha E. Shenton,Inga K. Koerte","doi":"10.1038/s41380-026-03624-1","DOIUrl":"https://doi.org/10.1038/s41380-026-03624-1","url":null,"abstract":"Abstract Childhood maltreatment (CM) is a risk factor for adult post-traumatic symptoms and white matter (WM) alterations. It remains unknown how WM microstructure is affected alongside two common military conditions, post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI). Data from 299 participants (53% male, 35.69 ± 12.23 years of age) of the Injury and Traumatic Stress (INTRuST) clinical consortium was analyzed. The study included 56 individuals with PTSD (41 with comorbid mTBI), 107 with mTBI, and 136 controls (no PTSD and/or mTBI). Diffusion parameters (mean, axial, and radial diffusivity, MD, AD, RD; fractional anisotropy, FA) in major WM tracts were extracted from diffusion MRI. CM was assessed using the Childhood Trauma Questionnaire (CTQ). Multiple regression models examined associations between CM severity and WM diffusion. Moderation analyses assessed the effect of PTSD and/or mTBI on these associations. Mediation analyses examined how WM diffusion affects the associations between CM and both PTSD and post-concussive symptom severity. Greater CM severity was associated with lower MD and AD, independent of PTSD and/or mTBI. WM diffusion, particularly in the corpus callosum and the superior longitudinal fasciculus, mediated the associations between CM severity and both PTSD (MD b ab  = 0.022, AD b ab  = 0.019-0.034) and post-concussive symptoms (MD b ab  = 0.028-0.040, AD b ab  = 0.032-0.047). Findings suggest that WM alterations are more strongly associated with CM itself than with either PTSD and/or mTBI. Mediating effects in regions critical for sensory integration highlight the role of WM microstructure as a neurobiological pathway through which CM might predispose to post-traumatic symptoms.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"50 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149150189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the psychosis spectrum - imaging neurosubtypes from multiscale functional network connectivity.","authors":"Ram Ballem, Pablo Andrés-Camazón, Kyle M Jensen, Prerana Bajracharya, Covadonga M Díaz-Caneja, Juan R Bustillo, Jessica A Turner, Zening Fu, Carol A Tamminga, Brett A Clementz, Matcheri S Keshavan, Elliot S Gershon, Jennifer E McDowell, Sarah K Keedy, Elena I Ivleva, S Kristian Hill, Godfrey D Pearlson, Jiayu Chen, Vince D Calhoun, Armin Iraji","doi":"10.1038/s41380-026-03921-9","DOIUrl":"10.1038/s41380-026-03921-9","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Psychosis exhibits marked neurobiological heterogeneity that is not adequately captured by symptom-based diagnoses. Although prior efforts have identified subgroups, it remains unclear how latent disease variability manifests within the brain's multiscale intrinsic functional organization and whether these patterns can be leveraged to systematically identify biologically driven subtypes of psychosis. Here, we aim to identify Psychosis Imaging Neurosubtypes (PINs)-homogeneous subgroups defined solely from neurobiological features of brain function, independent of clinical or cognitive definitions, and whether these subgroups show meaningful phenotypic differentiation. Resting-state fMRI data from 2103 B-SNIP 1&2 participants were used to compute subject-specific multiscale functional network connectivity (msFNC). We then derived a low-dimensional neurobiological subspace, termed Latent Network Connectivity, which captured system-wide interconnected multiscale information across three components. Projections of probands msFNC onto this subspace revealed three PINs through unsupervised learning that spanned DSM diagnoses (Schizophrenia, Bipolar, Schizoaffective Disorder). Although defined purely from intrinsic neurobiology, PINs exhibited distinct cognitive, clinical, and connectivity profiles. PIN-1, the most cognitively impaired, showed Cerebellar-Subcortical and Visual-Sensorimotor hypoconnectivity, alongside Visual-Subcortical hyperconnectivity. Most cognitively preserved PIN-2 showed Visual-Subcortical, Subcortical-Sensorimotor, and Subcortical-Higher Cognition hypoconnectivity. PIN-3 exhibited intermediate cognition, showing Cerebellar-Subcortical hypoconnectivity alongside Cerebellar-Sensorimotor and Subcortical-Sensorimotor hyperconnectivity. Although covariate-adjusted analyses did not reveal significant clinical differences among PINs, exploratory analyses identified selective differences in YMDR, PANSS, and Age of Onset. Notably, 55% of relatives aligned with the same neurosubtype as their probands, a rate significantly higher than chance and than DSM-based alignment, suggesting potential heritability. Cognitive performance reliably aligns with distinct brain connectivity patterns, which are also evident in relatives, supporting their construct validity. Our PINs partially converged with previously reported BSNIP Biotypes with some correspondence (e.g. PIN1 with Biotype 1) but not with the other Biotypes, which were determined using integrated electrophysiological, cognitive, and oculomotor data, supporting convergent validity, while also indicating that intrinsic rsfMRI derived multiscale connectivity partitions psychosis heterogeneity somewhat differently from multimodal biomarker approaches. These findings underscore the limitations of DSM-based classifications in capturing the biological complexity of psychotic disorders and highlight the potential of imaging-based neurosubtypes to enhance our understanding of the psychosis spec","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}