Molecular Psychiatry最新文献

{"title":"Cell-type-specific genetic architecture reveals neuronal and immune contributions to neuropsychiatric disorders","authors":"Xinyue Wang, Lingxue Luo, Suhua Chang, Li Yang","doi":"10.1038/s41380-026-03606-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03606-3","url":null,"abstract":"Neuropsychiatric disorders exhibit complex polygenic architectures, yet the cell-type-specific mechanisms underlying most risk loci remain unclear. Here, we integrate single-cell expression quantitative trait locus (sc-eQTL) data from brain and blood tissues with genome-wide association studies (GWAS) of six neuropsychiatric disorders (schizophrenia (SCZ), Parkinson’s disease (PD), bipolar disorder (BP), major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD)) to systematically identify putative causal genes at cellular resolution. Employing summary-data-based Mendelian randomization (SMR) across diverse neuronal and immune cell types, we discovered 345 cell-type-specific risk genes for various diseases, including both replicated candidates (such as MAPT in astrocytes for SCZ and PD and FLOT1 in excitatory neurons and inhibitory neurons for SCZ, BP and MDD) and novel associations (such as APTX in microglia for SCZ). Cross-disorder analyses revealed shared pathways in synaptic function and immune regulation. In contrast, disease-specific and tissue-specific patterns were observed across different disorders. Strikingly, we found that brain-derived risk genes exhibited significantly higher cell-type specificity than those identified in blood, underscoring the more focused cellular context of genetic effects in the central nervous system. Our findings suggest that neuropsychiatric disorders arise from a combination of neuronal dysfunction and immune system dysregulation. The study demonstrates how cell-type-specific mapping uncovers etiological mechanisms obscured in bulk-tissue analyses, proving novel information for clarifying the biological mechanism of gene expression implicated in the development of the six neuropsychiatric disorders.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"1 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147734030","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 and disorder-specific prenatal and perinatal risk factors for neurodevelopmental disorders: a nationwide cohort study","authors":"Hugo Peyre, Paula Rios, Jérémie Botton, Philippe Herlemont, Valérie Olié, Sara Miranda, Mahmoud Zureik, Alain Weill, Rosemary Dray-Spira","doi":"10.1038/s41380-026-03607-2","DOIUrl":"https://doi.org/10.1038/s41380-026-03607-2","url":null,"abstract":"Neurodevelopmental disorders (NDDs) are common, frequently co-occur, and impose a substantial burden, yet the extent to which early-life risk factors differ across the spectrum of NDDs remains unclear. Using the EPI-MERES register, derived from the French National Health Data System, we conducted a nationwide cohort study of all 6.8 million children born in France between 2010 and 2018, followed until September 2024. We investigated prenatal and perinatal risk factors, including gestational age, small for gestational age (SGA), neonatal hypoxia, congenital malformations, parental age, maternal alcohol and tobacco exposure, maternal obesity, and socioeconomic disadvantage, in relation to five major NDDs: communication disorders, specific learning disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Models were estimated both with and without adjustment for co-occurring NDDs. Overall, 506,505 children (7.5%) were identified with at least one NDD over a median follow-up of 9.6 years. Co-occurrence was frequent, especially for ID (54.5%), ASD (52.2%), and ADHD (34.9%). In models not adjusted for NDD co-occurrence, several factors were common across disorders, including male sex, prematurity, SGA, congenital malformations, maternal obesity, prenatal alcohol and tobacco exposure, and young maternal age. In addition, some exposures showed disorder-specific associations, most notably with ID: extreme prematurity, SGA, congenital malformations, neonatal hypoxia, and advanced parental age. After adjustment for co-occurring NDDs, several associations were attenuated, indicating that some risk factors contribute simultaneously to multiple disorders; for example, the male predominance in ID and the association of extreme prematurity with ASD were substantially reduced. These findings delineate shared and disorder-specific prenatal and perinatal risk profiles and emphasize the importance of considering co-occurring diagnoses in understanding etiological pathways and informing early prevention strategies.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"23 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147734032","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":"Re-evaluating the effectiveness of ultrabrief pulse ECT: the potential role of (In)appropriate seizure threshold titration.","authors":"Julia R Meijer, Chris Baeken, Sara De Witte, Eric van Exel","doi":"10.1038/s41380-026-03612-5","DOIUrl":"https://doi.org/10.1038/s41380-026-03612-5","url":null,"abstract":"","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776993","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":"Multimodal microglial and kynurenine pathway alterations across the affective-psychosis spectrum: a systematic review of patterns, heterogeneity, and dimensional implications.","authors":"Madeleine Nussbaumer, Paul C Guest, Kolja Schiltz, Leon Dudeck, Leila Shokati Asl, Gabriela Meyer-Lotz, Henrik Dobrowolny, Stefan Leucht, Hans-Gert Bernstein, Thomas Nickl-Jockschat, Brisa S Fernandes, Johann Steiner","doi":"10.1038/s41380-026-03614-3","DOIUrl":"https://doi.org/10.1038/s41380-026-03614-3","url":null,"abstract":"<p><p>Immune dysregulation is implicated in patient subgroups in major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ), but the role of microglia across affective and psychotic illnesses remains unclear. We propose an integrative framework linking systemic immune drivers to microglia-related circuit engagement, cellular phenotype, and kynurenine pathway (KP) branch balance. We systematically reviewed human TSPO-PET, cerebrospinal fluid (CSF) KP metabolite, and postmortem microglial and KP studies. Quantitative synthesis focused on MDD versus SCZ. BD was integrated descriptively due to limited data. MDD showed the most reproducible in vivo signal, with increased TSPO binding in frontolimbic regions (cingulate cortex, hippocampus, prefrontal cortex), and had lower heterogeneity and higher precision than SCZ. Postmortem MDD findings were largely null for diagnosis-level increases in microglial density or classical activation markers, but suggested subtle homeostatic shifts. KP findings were localized and regionally dissociated, including cingulate QUIN-related microglial signals and reduced hippocampal QUIN immunoreactivity in single cohorts. BD evidence was sparse as TSPO-PET comprised a single study reporting hippocampal increases, and postmortem microglial markers were mostly unchanged at the diagnosis level, with suicide or psychosis stratification revealing subgroup effects. Also, BD KP data suggested anterior cingulate upstream activation with a psychosis-linked downstream signal (reduced prefrontal KMO) in a subgroup. In SCZ, TSPO-PET findings were heterogeneous with small decreases or no change, and postmortem studies indicated either activation-marker increases or loss of homeostatic microglial signatures. In addition, the most consistent biochemical signal in SCZ was a shift toward the KYNA branch (increased CSF KYNA and cortical KYNA), consistent with KP-linked glutamatergic dysregulation. Overall, microglia-related alterations appear better explained by biological subgroups and symptom dimensions than by categorical diagnoses, motivating future transdiagnostic studies with dimensional phenotyping, subgroup stratification, longitudinal designs, and microglia-specific biomarkers. Limitations include the limited cellular specificity of TSPO-PET, small sample sizes, and postmortem studies focusing on few cortical/limbic regions rather than whole-brain coverage.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776995","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":"Genetic overlap and shared risk loci between autism spectrum disorder and cardiometabolic traits.","authors":"Gerard Muntané, Alexey Shadrin, M Guardiola-Ripoll, Kevin S O'Connell, Oleksandr Frei, Terje Naerland, Elisabet Vilella, Ole A Andreassen","doi":"10.1038/s41380-026-03563-x","DOIUrl":"https://doi.org/10.1038/s41380-026-03563-x","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting 2% of the global population. Beyond core symptoms such as social communication deficits and repetitive behaviors, individuals with ASD are at increased risk of cardiometabolic comorbidities, including obesity, diabetes, and cardiovascular disease. Here, we investigate the shared genetic architecture between ASD and cardiometabolic traits using large genome-wide association studies datasets and advanced statistical approaches: the bivariate causal mixture (MiXeR) model and pleiotropy-informed conditional false discovery rate (pleioFDR). Our results show significant polygenic overlap between ASD and several cardiometabolic phenotypes, despite almost negligible genetic correlation between the traits. Specifically, we observed positive genetic correlations within the shared component for ASD and metabolic traits, such as body mass index (rg=0.03), type 2 diabetes (rg=0.23), and total cholesterol (rg=0.78). In contrast, negative correlations emerged between ASD and cardiovascular traits, including diastolic and systolic blood pressure (rg = -0,22, for both), pulse pressure (rg = -0.25), and coronary artery disease (rg = -0.90). Finally, we identified 100 shared loci between ASD and cardiometabolic traits, mapping to 124 genes and suggesting shared biological mechanisms underlying these phenotypes and pointing to potential therapeutic targets. Shared loci between ASD and metabolic traits predominantly showed concordant effects, whereas those overlapping with cardiovascular traits-particularly blood pressure-related traits-tended to exhibit discordant effects. Together, these findings deepen our understanding of the biological connections between ASD and cardiometabolic comorbidities and may help inform more personalized strategies for managing ASD and its associated long-term health risks.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729393","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":"Single-cell transcriptomics of human brain disorders.","authors":"Keon Arbabi, Giuseppe Carito, Tain Luquez, Michael Wainberg","doi":"10.1038/s41380-026-03573-9","DOIUrl":"https://doi.org/10.1038/s41380-026-03573-9","url":null,"abstract":"<p><p>Brain disease is ultimately a disease of its constituent cells, and single-cell genomics has recently begun to illuminate the cellular pathologies underlying human brain disorders. In this review, we synthesize the key biological insights from recent single-cell studies of post-mortem human brain tissue across a range of neurological and psychiatric conditions. Organized by major central nervous system cell type, we detail the depletion of vulnerable cellular populations, the emergence of disease-associated states, the dysregulation of gene expression programs, and the interplay between these changes and genetic risk factors. Collectively, these studies mark a turning point in brain disease research, providing the first comprehensive maps of how neurological and psychiatric disorders manifest across the cellular landscape of the human brain.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":" ","pages":""},"PeriodicalIF":10.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729455","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":"GLP-1 receptor agonists and risk of suicide or suicide attempts – A nationwide cohort and self-controlled case series study","authors":"Christoffer Stanislaus, Matilde Winther-Jensen, Sharleny Stanislaus, Merete Osler, Klara Coello, Maj Vinberg","doi":"10.1038/s41380-026-03619-y","DOIUrl":"https://doi.org/10.1038/s41380-026-03619-y","url":null,"abstract":"The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have raised concerns about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicide or suicide attempts. We conducted two new-user, active comparator cohort studies. The GLP1-RAs vs sodium-glucose cotransporter-2 (SGLT-2) inhibitors cohort included new users of GLP-1 RAs (n = 83,464) or SGLT-2 inhibitors (n = 78,366), and the GLP1-RAs vs dipeptidyl peptidase-4 (DPP-4) inhibitors cohort included new users of GLP-1 RAs (n = 108,322) or DPP-4 inhibitors (n = 55,411). We also employed a self-controlled case series design to compare suicide, or suicide attempts before and after GLP-1 RA treatment initiation across three time periods. In the cohort analyses patients who initiated GLP-1 RAs did not differ in the hazard ratio (HR) for suicide or suicide attempts from SGLT-2 inhibitor users (HR: 0.93; 95% CI: 0.57–1.52), and GLP-1 RA users had a lower risk of suicide or suicide attempts compared with DPP-4 inhibitor users (HR: 0.58; 95% CI: 0.37–0.91). In the self-controlled case series design, use of GLP-1 RAs was associated with a lower incidence rate ratio (IRR) of suicide or suicide attempts one year after treatment initiation (IRR: 0.45; 95% CI: 0.10–0.50) and 13–24 months after treatment initiation compared with pretreatment. This study showed that use of GLP-1 RAs was not associated with increased incidence of suicide or suicide attempts in either the active comparator new-user design or in the self-controlled case series design.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"14 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709306","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":"Multiscale characterization of cortical signatures in positive and negative schizotypy: a worldwide ENIGMA study","authors":"Matthias Kirschner, Benazir Hodzic-Santor, Leda Kennedy, Justine Y. Hansen, Mathilde Antoniades, Igor Nenadić, Tilo Kircher, Axel Krug, Tina Meller, Udo Dannlowski, Dominik Grotegerd, Kira Flinkenflügel, Susanne Meinert, Tiana Borgers, Janik Goltermann, Tim Hahn, Joscha Böhnlein, Elisabeth J. Leehr, Carlotta Barkhau, Alex Fornito, Aurina Arnatkeviciute, Mark A. Bellgrove, Jeggan Tiego, Pamela DeRosse, Melissa Green, Yann Quidé, Christos Pantelis, Raymond C. K. Chan, Yi Wang, Ulrich Ettinger, Martin Debbané, Melodie Derome, Christian Gaser, Bianca Besteher, Kelly Diederen, Tom J. Spencer, Josselin Houenou, Edith Pomarol-Clotet, Raymond Salvador, Wulf Rössler, Lukasz Smigielski, Veena Kumari, Preethi Premkumar, Haeme R. P. Park, Kristina Wiebels, Imke Jansen, James Gilleen, Paul Allen, Jan-Bernard Marsman","doi":"10.1038/s41380-026-03547-x","DOIUrl":"https://doi.org/10.1038/s41380-026-03547-x","url":null,"abstract":"Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"224 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709309","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":"Rapid rescue of despair behaviors by sonogenetic neuromodulation of the mPFC-DRN pathway","authors":"Ting Lei, Quanxiang Xian, Danni Li, Min Su, Yong Wu, Xuandi Hou, Jianing Jing, Yizhou Jiang, Xiaohui Huang, Kin Fung Wong, Jiejun Zhu, Jinghui Guo, Zhihai Qiu, Lei Sun","doi":"10.1038/s41380-026-03616-1","DOIUrl":"https://doi.org/10.1038/s41380-026-03616-1","url":null,"abstract":"Sonogenetics combines genetic tools and low-intensity ultrasound to non-invasively modulate specific neuronal populations and circuits, exhibiting potential for treating brain diseases. This study examines sonogenetics’ potential in a mouse depression model, targeting excitatory medial prefrontal cortex (mPFC) neurons projecting to the dorsal raphe nucleus (DRN). Projecting neurons were induced to express a mechanosensitive ion channel (MscL-G22S), and alterations in patterns of neuronal activation and despair-like behaviors upon sonication were evaluated. Sonogenetics selectively activated targeted excitatory mPFC neurons projecting to the DRN, enhancing real-time DRN neuronal activity and serotonin release, with no observed tissue damage or astrocytic/microglial activation. Tail suspension and forced swim tests revealed that sonogenetically activating this pathway rapidly reversed despair-like behaviors in stressed mice, whereas effects observed upon mPFC sonication were abrogated by functionally silencing downstream DRN neurons, and this effect is fully recapitulated by selective inhibition of DRN serotonergic neurons alone. Collectively, this study constitutes the first demonstration of the potential for a circuit-targeted sonogenetic therapeutic approach for relieving despair behaviors.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"243 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709308","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":"Ceruloplasmin deficiency drives a fusiform-centric lipid–myelin pathology underlying a visual subtype in autism","authors":"Ya‑Yin Deng, Shuang‑Shuang Zhong, Shi-Huan Wang, Bo-Ya Yin, Xiang Zhou, Feng‑Yun Zou, Jia-Yuan Zhao, Yu-Xuan Ni, Xiao‑Wen Luo, Li‑Shan Shen, Jia-Lu Zhang, Zhi-Ping Lin, Wen-Ying Zhou, Hong-Zhu Deng, Ruo‑Mi Guo","doi":"10.1038/s41380-026-03613-4","DOIUrl":"https://doi.org/10.1038/s41380-026-03613-4","url":null,"abstract":"Atypical visual processing (AVP) commonly occurs in autism spectrum disorder (ASD) and contributes to social impairments, yet its neurobiological basis remains poorly characterized. To investigate potential lipid and myelin mechanisms, this study integrated multimodal MRI, quantifying lipid (proton density fat fraction) and myelin content (synthetic MRI) of 74 nuclei or brain regions, with serum profiling of iron, lead, and ceruloplasmin in 288 children, including 90 ASD with atypical visual processing (ASD‑AVP), 89 ASD without atypical visual processing (ASD‑AVP), and 109 typically developing (TD). The ASD-AVP subgroup exhibited a distinct co-pathology of elevated lipid and myelin centered on the fusiform gyrus (FG), accompanied by a unique positive lipid-myelin correlation (left: r = 0.47, right: r = 0.41). Serum analyses revealed decreased iron and ceruloplasmin and increased lead in ASD-AVP, and mediation analysis indicated that ceruloplasmin deficiency influences FG myelination via lipid pathways (35%–55%). Crucially, BTBR AVP-like mice recapitulated this phenotype with disorganized hypermyelination, whereas nAVP-like mice showed hypomyelination. A combined FG lipid-myelin signature strongly distinguished ASD-AVP from TD (AUC = 0.93) and ASD-nAVP (AUC = 0.87). Preliminary longitudinal follow-up in a subset of patients revealed that improvement in serum ceruloplasmin was associated with a reduction in FG lipid content and stabilization of myelin, paralleling clinical improvement. These findings identify a ceruloplasmin-driven, FG-centric lipid-myelin co-pathology, representing a maladaptive “inflammatory pseudo-compensation” mechanism specific to a visual ASD subtype, and offer novel biomarkers for biological subtyping and targeted interventions.","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"8 1","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709307","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}