Brain, Behavior, and Immunity最新文献

{"title":"Early life behavioral deficits and microglia remodeling in the mesocorticolimbic system precede the emergence of Schizophrenia-like symptoms.","authors":"Ana C Rodrigues-Neves, Jéssica Monteiro, Bárbara Coimbra, Rita Gaspar, Verónica Domingues, Carina Soares-Cunha, Patrícia Patrício, Marta I Pereira, Ana L Cardoso, Luísa Pinto, João Bessa, Ana J Rodrigues, António F Ambrósio, Catarina A Gomes","doi":"10.1016/j.bbi.2025.06.009","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.06.009","url":null,"abstract":"<p><p>Microglia-mediated sensing, during development, dictates synapse formation/elimination and function. This depends on microglia morphology, in the sense their cellular processes adopt variable length/degree of ramification, in response to neuronal cues, in turn regulated by local microenvironmental conditions. In schizophrenia, two neuronal pathways of the mesocorticolimbic system are oppositely dysregulated, resulting in hypo- and hyper-dopaminergic tonus in target regions, prefrontal cortex (PFC) and nucleus accumbens (NAc). This bimodal tonus is associated with disease manifestations, including social symptoms. Although schizophrenia is a developmental disease, electrophysiological and behavioral preclinical data have been mainly obtained in adulthood and information about disease trajectory until adolescence (an important period of diagnosis) is very limited. The main goal of the present work is to characterize the morphological differentiation of microglia in PFC and NAc, in infancy and adolescence, using an experimental model of schizophrenia (rats prenatally exposed to methylazoxymethanol acetate, MAM) and to detect early manifestations of neurodevelopmental deficits. In infancy, MAM affects neurodevelopmental milestones and induces microglia hypertrophy in PFC and NAc, in both sexes. In adolescence, social behavior is affected (with subtle differences between sexes) and, notably, a region-specific microglia remodeling is observed: in PFC, there is a recovery of the physiological morphology, but an atrophic phenotype emerges in NAc. Although out of the scope of this work, in an attempt to validate the model in adult females, we screened for sex differences in behavior and (electro)physiology, aspects also discussed. This topic deserves a cautious analysis by the scientific community and reinforces the importance of performing preclinical studies in both sexes.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease severity across psychiatric disorders is linked to pro-inflammatory cytokines.","authors":"Pierre Solomon, Monika Budde, Mojtaba Oraki Kohshour, Kristina Adorja, Maria Heilbronner, Alba Navarro-Flores, Sergi Papiol, Daniela Reich-Erkelenz, Eva C Schulte, Fanny Senner, Thomas Vogl, Lalit Kaurani, Dennis M Krüger, Farahnaz Sananbenesi, Tonatiuh Pena, Susanne Burkhardt, Anna-Lena Schütz, Ion-George Anghelescu, Volker Arolt, Bernhardt T Baune, Udo Dannlowski, Detlef E Dietrich, Andreas J Fallgatter, Christian Figge, Georg Juckel, Carsten Konrad, Fabian U Lang, Jens Reimer, Eva Z Reininghaus, Max Schmauß, Carsten Spitzer, Jens Wiltfang, Jörg Zimmermann, André Fischer, Peter Falkai, Thomas G Schulze, Urs Heilbronner, Jeremie Poschmann","doi":"10.1016/j.bbi.2025.06.004","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.06.004","url":null,"abstract":"<p><strong>Importance: </strong>Numerous studies indicate that the traditional categorical classification of severe mental disorders (SMD), such as schizophrenia, bipolar disorders, and major depressive disorders, does not align with the underlying biology of those disorders as they frequently overlap in terms of symptoms and risk factors.</p><p><strong>Objective: </strong>This study aimed to identify transdiagnostic patient clusters based on disease severity and explore the underlying biological mechanisms independently of the traditional categorical classification.</p><p><strong>Design: </strong>We utilized data from 443 participants diagnosed with SMD of the PsyCourse Study, a longitudinal study with deep phenotyping across up to four visits. We performed longitudinal clustering to group patients based on symptom trajectories and cognitive performance. The resulting clusters were compared on cross-sectional variables, including independent measures of severity as well as polygenic risk scores, serum protein quantification, miRNA expression, and DNA methylation.</p><p><strong>Results: </strong>We identified two distinct clusters of patients that exhibited marked differences in illness severity but did not differ significantly in age, sex, or diagnostic proportions. We found 19 serum proteins significantly dysregulated between the two clusters. Functional enrichment pointed to a convergence of immune system dysregulation and neurodevelopmental processes.</p><p><strong>Conclusion: </strong>The observed differences in serum protein expression suggest that disease severity is associated with the convergence of immune system dysregulation and neurodevelopmental alterations, particularly involving pathways related to inflammation and brain plasticity. The identification of pro-inflammatory proteins among the differentially expressed markers underscores the potential role of systemic inflammation in the pathophysiology of SMD. These results highlight the importance of considering illness severity as a core dimension in psychiatric research and clinical practice and suggest that targeting immune-related mechanisms may offer promising new therapeutic avenues for patients with SMD.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring microglial replacement: From disease models to clinical translation","authors":"Kai Zhou ,&nbsp;Yafeng Wang ,&nbsp;Yiran Xu ,&nbsp;Yaodong Zhang ,&nbsp;Changlian Zhu","doi":"10.1016/j.bbi.2025.06.011","DOIUrl":"10.1016/j.bbi.2025.06.011","url":null,"abstract":"<div><div>Microglia, the resident immune cells of the central nervous system (CNS), play pivotal roles in immune surveillance, synaptic remodeling, and neuroinflammatory responses. Recent interest has focused on microglial replacement therapy to renew microglial populations, mitigate neuroinflammation, and deliver functional genes. This review synthesizes current research on the potential applications of microglial replacement therapy, highlighting preclinical studies employing diverse depletion models, the source of replaced microglia, and their impacts on CNS disorders. Moreover, challenges and considerations for the clinical translation of microglial replacement therapy are discussed. Overall, microglial replacement therapy holds promise for restoring CNS homeostasis and ameliorating neuroinflammation, offering new avenues for the development of disease-modifying treatments for CNS disorders.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 179-185"},"PeriodicalIF":8.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial SIRT2 deficiency aggravates cognitive decline and amyloid pathology in Alzheimer’s disease","authors":"Noemi Sola-Sevilla ,&nbsp;Maider Garmendia-Berges ,&nbsp;Mikel Aleixo ,&nbsp;MCarmen Mera-Delgado ,&nbsp;Maite Solas ,&nbsp;Rosa M. Tordera ,&nbsp;Lucía García-Carracedo ,&nbsp;Sara Expósito ,&nbsp;Elena Anaya-Cubero ,&nbsp;Joaquín Fernández-Irigoyen ,&nbsp;Elisabeth Guruceaga ,&nbsp;Enrique Santamaria ,&nbsp;Eduardo D. Martin ,&nbsp;Elena Puerta","doi":"10.1016/j.bbi.2025.06.016","DOIUrl":"10.1016/j.bbi.2025.06.016","url":null,"abstract":"<div><div>Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has been implicated in aging and neurodegenerative diseases such as Alzheimer’s disease (AD). While global SIRT2 inhibition has shown promise in reducing amyloid-beta pathology and cognitive deficits in different mouse models of AD, peripheral SIRT2 inhibition has been associated with adverse effects, such as increased inflammation. This suggests that targeted inhibition of specific cellular populations within the brain may represent a more precise and effective approach for the treatment of AD. To explore this hypothesis, we generated a conditional microglial SIRT2 knockout mouse model in the context of AD. Our results reveal that microglial SIRT2 reduction does not confer protective effects in the APP/PS1 model; rather, it aggravates cognitive decline, accelerates amyloid plaque deposition, and increases levels of pro-inflammatory cytokines at early stages of AD pathology. Transcriptomic analysis further indicates that SIRT2-deficient microglia exhibit altered expression of genes associated with aging and synaptic dysfunction. This phenotype was accompanied by increased phagocytosis of PSD95 and impaired long-term potentiation. These findings suggest that while SIRT2 inhibition in some contexts may be beneficial, targeted inhibition within microglia could accelerate AD progression, underscoring the need for cell-specific approaches when considering SIRT2 as a therapeutic target.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 223-243"},"PeriodicalIF":8.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying sick people while sick yourself: a study of identification of facial cues and walking patterns of sick individuals during experimental endotoxemia.","authors":"L S Hansson, A Tognetti, E Tavakoli-Berg, J M Stache, M Kakeeto, J Melin, S Bredin, R Skarp, C Lensmar, R Demand, M J Olsson, D B Wilhelms, R Toll John, K B Jensen, M Lekander, J Lasselin","doi":"10.1016/j.bbi.2025.06.013","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.06.013","url":null,"abstract":"<p><p>Sick humans and other animals often withdraw from social interactions. It has been suggested that social withdrawal might enable avoidance of contagious individuals, but experimental evidence is lacking on how the state of sickness may affect perception of sick others. Here, we investigated if individuals were more likely to rate others as sick, while being sick themselves, compared to when healthy. Furthermore, we assessed if the intensity of the fever response and sickness behavior would predict changes in sickness detection. Thirty-four participants were experimentally made sick using an intravenous injection of the bacterial endotoxin lipopolysaccharide (LPS condition; dose of 1.0 ng/kg body weight) and completed a sickness detection task during the peak of the inflammatory and sickness response. Participants performed the same task when they were healthy (control condition, n = 32), in a randomized order before or after the main study day. In the sickness detection task, participants watched photos of individuals' faces as well as video recordings of the same individuals walking, and rated the individual on each stimulus as sick or healthy. The photos and video recordings were obtained from twenty-two individuals who participated in a previous study, and who were made sick with an intravenous injection of lipopolysaccharide (2.0 ng/kg body weight) on one occasion, and remained healthy after an intravenous injection of a placebo (0.9 % NaCl) on another occasion. Participants could detect sick individuals based on photos and walking patterns above chance level during both the LPS and the control condition. There was no significant difference in how often participants identified sick faces and sick walkers in the LPS condition - when they were sick themselves - compared to in the control condition. However, healthy walkers (but not healthy faces) were more often rated as sick by participants in the LPS condition compared to the control condition. Neither the fever response nor the intensity of sickness behavior predicted changes in sickness detection. The results do not indicate more accurate sickness detection in others during own sickness. Nevertheless, the data from walking patterns indicates that sick individuals may be more prone to categorize healthy individuals as sick. If replicated, this could in speculation be related to a need to reduce the risk of becoming infected while already fighting a pathogen.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variation in anti-SARS-CoV-2 spike antibody responses by variants in patients with severe mental illness after COVID-19 vaccination.","authors":"Chun-Yuan Lin, Ying-Chyi Song, Chin-Chou Yang, Po-Shou Yeh, Ya-Yan Yu, Chih-Chia Huang","doi":"10.1016/j.bbi.2025.06.015","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.06.015","url":null,"abstract":"<p><p>Research has shown that patients with psychiatric disorders are more susceptible to contracting SARS-CoV-2 and tend to experience worse outcomes from COVID-19. Therefore, vaccination is strongly suggested for these patients to enhance protection. However, there is limited research on how COVID-19 vaccines induce antibody responses, specifically in individuals with psychiatric conditions. Furthermore, the situation has become more complex with the emergence of variants of concern (VOCs), and the effectiveness of antibody responses against these variants is still poorly understood. To determine whether patients with severe mental illness (SMI) mount an adequate immune reaction to COVID-19 vaccination, we studied the immunization effect of two widely used vaccines, ChAdOx1-S (AstraZeneca) and mRNA-1273 (Moderna), in patients with SMI compared to healthy controls. We enrolled 163 patients with SMI (mainly schizophrenia) and 66 healthy controls, all of whom were negative for previous SARS-CoV-2 infection. We analyzed anti-SARS-CoV-2 spike antibody titers against wild-type (WT), Delta, and Omicron variants after full (two-dose) vaccination with either the ChAdOx1-S or mRNA-1273 COVID-19 vaccines. Patients with SMI exhibited significantly lower mean anti-SARS-CoV-2 spike antibody titers. These results were consistent across different vaccine types and VOCs. Vaccination with ChAdOx1-S consistently induced lower spike-binding antibodies against WT, Delta, and Omicron variants compared to the mRNA-1273 vaccine. While the antibody activities against Omicron are well preserved, they are weaker than those against the WT and Delta variants. Our findings explain why patients with SMI are particularly susceptible to SARS-CoV-2 infection, breakthrough infections, and poorer COVID-19 outcomes.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal opioid exposure and maternal HCV infection impair microglia development and function: A patient-specific in vitro model","authors":"Heather E. True ,&nbsp;Hami Hemati ,&nbsp;Rebecca Geron ,&nbsp;Brianna M. Doratt ,&nbsp;Delphine C. Malherbe ,&nbsp;Cynthia Cockerham ,&nbsp;John O’Brien ,&nbsp;Ilhem Messaoudi","doi":"10.1016/j.bbi.2025.06.010","DOIUrl":"10.1016/j.bbi.2025.06.010","url":null,"abstract":"<div><div>Opioids are a class of pain-relieving drugs known to cross the placental and blood brain barriers, exposing the fetus <em>in utero</em>. Rates of opioid use disorder amongst pregnant individuals in the United States are on the rise, and intravenous routes of opioid administration are highly associated with hepatitis C (HCV) infection. Newborns with prenatal opioid exposure (POE) are more likely to be small for gestational age and have increased rates of neurodevelopmental delay. Microglia are brain-resident macrophages that originate from yolk-sac precursors that play critical role in neurodevelopment. However, our understanding of the impact of POE on microglia maturation and function remains limited due to the scarcity of adequate models. Here, we leveraged a model of induced microglia-like cells (iMGL) derived from umbilical cord blood mononuclear cells to uncover the mechanisms underlying the impact of POE ± maternal HCV infection on microglia morphology, phenotype, function, and transcriptional profiles. Our study revealed that iMGL are closely related to primary microglia. iMGL derived from pregnancies with POE and maternal HCV infection exhibited an ameboid-like phenotype, characterized by smaller area/perimeter and diminished ramifications. This was accompanied by dysregulated expression of key microglia markers, impaired phagocytic capacity, but increased secretion of inflammatory mediators. Finally, transcriptional analysis of iMGL with and without stimulation by LPS revealed that POE ± maternal HCV infection desensitized iMGL to LPS stimulation. This immune tolerance of iMGL in utero was reflected by altered expression of genes important for neurological and fetal development, phagocytosis, and antimicrobial responses with POE ± maternal HCV infection. Overall, these findings highlight the utility of iMGLs as an accessible patient-specific model to study preconditioning and development of fetal microglia and provide insight into mechanisms underlying adverse neurodevelopmental outcomes in newborns with POE in presence and absence of maternal HCV infection.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 206-220"},"PeriodicalIF":8.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to comment on: A critical analysis of the application of ML145 as a GPR35 antagonist in mice","authors":"Xu Kang ,&nbsp;Xian Wu","doi":"10.1016/j.bbi.2025.06.012","DOIUrl":"10.1016/j.bbi.2025.06.012","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 221-222"},"PeriodicalIF":8.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-VGLUT2 autoantibodies in neurological diseases.","authors":"Merle Corty, Friederike A Arlt, Kathrin Borowski, Stephanie Wernick, Madeleine Scharf, Fabian A Piecha, Claudia Steen, Philipp Oehler, Maria Buthut, Moritz Krill, Johann-Philipp Zöllner, Tammo Krafft, Robert Markewitz, Christiane Radzimski, Yvonne Denno, Christian Probst, Bianca Teegen, Christian Grefkes, Susanne Knake, Karsten Witt, Carsten Finke, Georg Hagemann, Jana Becker, Markus Kraemer, Torsten Witte, Lars Komorowski, Klaus-Peter Wandinger, Harald Prüss, Nico Melzer, Ramona Miske","doi":"10.1016/j.bbi.2025.06.014","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.06.014","url":null,"abstract":"<p><p>Autoantibodies are important biomarkers for the diagnosis of autoimmune diseases that help to determine treatment strategies and to understand disease pathology. Despite the increasing numbers of neuronal autoantibody discoveries, there are still patients presenting with neurological autoimmune diseases and so far uncharacterized autoantibodies. Between 12/2016 and 06/2024, we collected sera of 314 patients with a distinct uncharacterized IgG pattern in neuronal tissue indirect immunofluorescence assay (IIFA). By immunoprecipitation and mass spectrometry we identified vesicular glutamate transporter 2 (VGLUT2) as the autoantibody target and confirmed it in sera of 285/314 patients by recombinant IIFA with VGLUT2-expressing HEK293 cells, competitive inhibition assays and colocalization studies with a commercial antibody. The main diagnoses available of 87/285 patients (mean age 58, range 1-92) were encephalitis 25/87, dementia/cognitive impairment 17/87 and polyneuropathy 16/87. Detailed clinical data of 18 patients were collected retrospectively. The major symptoms of those index patients (mean age 56, range 2-78) involved cognitive changes (10/18) including memory impairment, aphasia and disorientation as well as sensorimotor disturbances (9/18) and gait abnormalities (9/18), accompanied by visual impairments (8/18). (Poly)neuropathy was observed in 10/18 cases. The majority of the anti-VGLUT2 index patients had coexisting diabetes mellitus type 2 or other chronic multisystem disorders. In 8/12 index patients, immunotherapy had beneficial effects, although only slight improvements could be obtained in most of the cases. All 17 analyzed index patient sera recognized a cytoplasmic epitope between amino acid 520-564 of VGLUT2, determined by immunoblot with recombinant antigen fragments. Anti-VGLUT2 autoantibody-associated neurological diseases may represent a new type of autoimmune disorders that might benefit from immunomodulatory treatment and predominantly manifests with encephalitis, cognitive deficits and neuropathy.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic overlap of severe psychiatric disorders with lung function and asthma suggests shared biological mechanisms.","authors":"Zheng-An Lu, Alexander Ploner, Piotr Jaholkowski, Alexey A Shadrin, Bronwyn K Brew, Ole A Andreassen, Sarah E Bergen","doi":"10.1016/j.bbi.2025.06.003","DOIUrl":"https://doi.org/10.1016/j.bbi.2025.06.003","url":null,"abstract":"<p><strong>Background: </strong>Severe psychiatric disorders are frequently comorbid with lung function decline and asthma. Despite their considerable heritability, the genetic relationships between them are unclear.</p><p><strong>Methods: </strong>We investigated the shared genetic architecture for three severe psychiatric disorders (schizophrenia, bipolar disorder, and anorexia nervosa) with lung function and asthma using results from genome-wide association studies. We performed MiXeR analyses to quantify their genetic overlap. A conditional/conjunctional false discovery rate (cond/conjFDR) approach was employed to detect shared genomic loci. Gene-based enrichment analyses were adopted to explore the shared biological mechanisms. Transcriptome analyses results were incorporated to prioritize biologically plausible shared genes in relevant tissues.</p><p><strong>Findings: </strong>MiXeR analyses demonstrated consistent moderate polygenic overlap (∼400 to 800 shared variants) across all pairs of psychiatric and respiratory phenotypes. The cond/conjFDR analyses found that lung function shared 227 loci with SCZ, 83 loci with BIP and 13 loci with AN, whereas asthma shared 132 loci with SCZ, 25 loci with BIP and 2 loci with AN, among which there were 268 novel loci for psychiatric disorders and 244 novel loci for the respiratory phenotypes. Gene-based enrichment analyses demonstrated that genes shared with psychiatric disorders for lung function were enriched for less specific non-immune GO terms (i.e. muscle organ development, mitochondrial matrix and cellular response to ion zinc), whereas genes shared with asthma were mostly enriched for GO term categories involving immune mechanisms (i.e. lymphocyte activation, immune response, metabolism, protein metabolism and regulation of JAK-STAT cascade), indicating divergent shared etiology. A total of 55 shared genes were prioritized as biologically plausible in tissues including brain, lung, whole blood and adrenal gland.</p><p><strong>Interpretation: </strong>This study elucidates a complex shared genetic architecture for three severe psychiatric disorders with lung function and asthma and implicates overlapping immune and non-immune mechanisms. Our findings present novel evidence and putative mechanisms for a lung-brain axis underlying psychiatric disorders and lung diseases, which may inspire the development of novel treatments.</p>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}