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Iwata K, Nakabayashi K, Ishiwata K, Nakamura K, Kameno Y, Hata K, Matsuzaki H. Genome-wide DNA methylation profiles in the raphe nuclei of patients with autism spectrum disorder. Psychiatry Clin Neurosci 2025. [PMID: 40272067 DOI: 10.1111/pcn.13830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 03/26/2025] [Accepted: 04/08/2025] [Indexed: 04/25/2025]
Abstract
AIM Autism spectrum disorder (ASD) has a strong genetic basis, yet its genetic complexities remain elusive. Current research highlights environmental factors and epigenetic processes, such as DNA methylation, as crucial in ASD development. This exploratory study addresses a gap in understanding epigenetic regulation in the dorsal raphe (DR)-a region regulating multiple neurotransmitters and implicated in ASD-by examining DNA methylation profiles in postmortem ASD and control brains. METHODS We comprehensively analyzed genome-wide DNA methylation profiles in the DR brain region (seven controls and five ASD) using the Infinium HumanMethylation450 BeadChip (Illumina). Additionally, quantitative polymerase chain reaction was used to measure messenger RNA levels of differentially methylated genes in ASD (11 controls and six ASD). RESULTS We identified differentially methylated regions (DMRs) between ASD and controls. These DMRs were located among various genomic regions, including promoters, gene bodies, and intergenic regions. Notably, we found hypermethylation in genes related to olfaction (e.g. OR2C3), which is regulated by serotonin. Additionally, we observed that the hypomethylation of promoter-associated CpG islands in RABGGTB, a gene related to autophagy and synaptic function, corresponded with its increased expression. CONCLUSIONS Our findings reveal extensive DNA methylation changes in critical genomic regions, shedding light on potential mechanisms underlying ASD. The identification of RABGGTB as a novel candidate gene, not listed in the SFARI database, underscores its significance and warrants further research to explore its role in ASD diagnosis. This study enhances our understanding of the epigenetic landscape in ASD, emphasizing the interplay between genetic and environmental factors in its pathophysiology.
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Affiliation(s)
- Keiko Iwata
- Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui, Japan
- Department of Functional Brain Activities, United Graduate School of Child Development, Hamamatsu University School of Medicine, Osaka University, Kanazawa University, Chiba University, and University of Fukui, Osaka, Japan
- Laboratory of Pharmacology, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
| | - Keisuke Ishiwata
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
| | - Kazuhiko Nakamura
- Department of Neuropsychiatry, Hirosaki University School of Medicine, Hirosaki, Japan
| | - Yosuke Kameno
- Department of Psychiatry, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
- Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hideo Matsuzaki
- Division of Development of Mental Functions, Research Center for Child Mental Development, University of Fukui, Fukui, Japan
- Department of Functional Brain Activities, United Graduate School of Child Development, Hamamatsu University School of Medicine, Osaka University, Kanazawa University, Chiba University, and University of Fukui, Osaka, Japan
- Life Science Innovation Center, University of Fukui, Fukui, Japan
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Liu P, Luo X, Cao L, Zhang Y, Ji J, Wang X, Wang K, Pan X, Yang R, Tan Z, Tan Y, Li CS, Guo X, Wang Z, Luo X. Phenome-wide association studies between SERINC2 and neuropsychiatric disorders. Front Psychiatry 2025; 15:1420395. [PMID: 39902246 PMCID: PMC11788846 DOI: 10.3389/fpsyt.2024.1420395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 11/29/2024] [Indexed: 02/05/2025] Open
Abstract
Objectives SERINC2 has been associated with alcoholism, bipolar disorder and autism, but the comparability and specificity issues of the findings remain unaddressed. The present study aimed to comprehensively analyze various neuropsychiatric disorders pinpoint the most reliable conditions predisposed by SERINC2. Methods A total of 2,187 imputed SNPs across SERINC2 were examined in 1,167,439 subjects from 72 independent cohorts with 18 different neuropsychiatric disorders. SNP-disease associations were tested and then meta-analyzed, followed by FDR correction, to identify significant disease-risk SNPs. Finally, functional studies on the differential SERINC2 mRNA expression in brains and the potential regulatory effects of disease-risk alleles on SERINC2 mRNA expression, gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA) and average thickness (TH) were conducted. Results In European descent, alcoholism was most significantly associated with SERINC2 variants (245 SNPs with 5.5×10-8≤p ≤ 0.049 and 4.9×10-5≤q ≤ 0.034) that were largely shared across cocaine dependence, marijuana dependence, nicotine dependence, polysubstance dependence, schizophrenia, OCD, and autism (8.2×10-8≤p ≤ 0.050 and 1.9×10-5≤q ≤ 0.049); in Chinese population, bipolar disorder was also significantly associated with SERINC2 variants (10 SNPs: 1.3×10-4≤p ≤ 4.7×10-4 and 0.025≤q ≤ 0.031). Furthermore, the disease-risk alleles had highly similar regulatory effects on mRNA expression (8.1×10-7≤p ≤ 0.046), subcortical GMVs (7.0×10-4≤p ≤ 0.048) and cortical TH and SA (1.3×10-3≤p ≤ 0.050) in brains across alcoholism, schizophrenia, OCD and autism. The bipolar disorder-risk alleles had these regulatory effects but with different effect patterns. Finally, SERINC2 mRNA was differentially expressed in several brain regions between alcoholism or schizophrenia and controls. Conclusion SERINC2 is primarily linked to substance use disorders, schizophrenia, OCD, autism and bipolar disorder, not only statistically but also biologically.
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Affiliation(s)
- Ping Liu
- Department of Psychosomatic Medicine, People’s Hospital of Deyang City, Deyang, Sichuan, China
| | - Xinqun Luo
- Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Liping Cao
- Department of Psychiatry, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yong Zhang
- Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China
| | - Jiawu Ji
- Department of Psychiatry, Fujian Medical University Affiliated Fuzhou Neuropsychiatric Hospital, Fuzhou, Fujian, China
| | - Xiaoping Wang
- Department of Neurology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Kesheng Wang
- Department of Biobehavioral Health and Nursing Science, College of Nursing, University of South Carolina, Columbia, SC, United States
| | - Xinghua Pan
- Precision Regenerative Medicine Research Centre, Medical Science Division, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macao SAR, China
| | - Ruilan Yang
- Department of Psychiatry, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zewen Tan
- Department of Psychiatry, Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yunlong Tan
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing, China
| | - Chiang-shan Li
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Xiaoyun Guo
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai,
China
| | - Zhiren Wang
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing, China
| | - Xingguang Luo
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing, China
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
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3
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Castro-Martínez JA, Vargas E, Díaz-Beltrán L, Esteban FJ. Enhancing Transcriptomic Insights into Neurological Disorders Through the Comparative Analysis of Shapley Values. Curr Issues Mol Biol 2024; 46:13583-13606. [PMID: 39727940 PMCID: PMC11726880 DOI: 10.3390/cimb46120812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/22/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
Neurological disorders such as Autism Spectrum Disorder (ASD), Schizophrenia (SCH), Bipolar Disorder (BD), and Major Depressive Disorder (MDD) affect millions of people worldwide, yet their molecular mechanisms remain poorly understood. This study describes the application of the Comparative Analysis of Shapley values (CASh) to transcriptomic data from nine datasets associated with these complex disorders, demonstrating its effectiveness in identifying differentially expressed genes (DEGs). CASh, which combines Game Theory with Bootstrap resampling, offers a robust alternative to traditional statistical methods by assessing the contribution of each gene in the broader context of the complete dataset. Unlike conventional approaches, CASh is highly effective at detecting subtle but meaningful molecular patterns that are often missed. These findings highlight the potential of CASh to enhance the precision of transcriptomic analysis, providing a deeper understanding of the molecular mechanisms underlying these disorders and establishing a solid basis to improve diagnostic techniques and developing more targeted therapeutic interventions.
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Affiliation(s)
- José A. Castro-Martínez
- Systems Biology Unit, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, 23071 Jaén, Spain; (J.A.C.-M.); (E.V.)
| | - Eva Vargas
- Systems Biology Unit, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, 23071 Jaén, Spain; (J.A.C.-M.); (E.V.)
| | - Leticia Díaz-Beltrán
- Systems Biology Unit, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, 23071 Jaén, Spain; (J.A.C.-M.); (E.V.)
- Clinical Research Unit, Department of Medical Oncology, University Hospital of Jaén, 23007 Jaén, Spain
| | - Francisco J. Esteban
- Systems Biology Unit, Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, 23071 Jaén, Spain; (J.A.C.-M.); (E.V.)
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Snelleksz M, Dean B. Higher levels of AKT-interacting protein in the frontal pole from people with schizophrenia are limited to a sub-group who have a marked deficit in cortical muscarinic M1 receptors. Psychiatry Res 2024; 341:116156. [PMID: 39236366 DOI: 10.1016/j.psychres.2024.116156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 06/29/2024] [Accepted: 07/03/2024] [Indexed: 09/07/2024]
Abstract
We are studying the molecular pathology of a sub-group within schizophrenia (∼ 25 %: termed Muscarinic Receptor Deficit subgroup of Schizophrenia (MRDS)) who can be separated because they have very low levels of cortical muscarinic M1 receptors (CHRM1). Based on our transcriptomic data from Brodmann's area ((BA) 9, 10 and 33 (controls, schizophrenia and mood disorders) and the cortex of the CHRM1-/- mouse (a molecular model of aberrant CHRM1 signaling), we predicted levels of AKT interacting protein (AKTIP), but not tubulin alpha 1b (TUBA1B) or AKT serine/threonine kinase 1 (AKT1) and pyruvate dehydrogenase kinase 1 (PDK1) (two AKTIP-functionally associated proteins), would be changed in MRDS. Hence, we used Western blotting to measure AKTIP (BA 10: controls, schizophrenia and mood disorders; BA 9: controls and schizophrenia) plus TUBA1B, AKT1 and PDK1 (BA 10: controls and schizophrenia) proteins. The only significant change with diagnosis was higher levels of AKTIP protein in BA 10 (Cohen's d = 0.73; p = 0.02) in schizophrenia compared to controls due to higher levels of AKTIP only in people with MRDS (Cohen's d = 0.80; p = 0.03). As AKTIP is involved in AKT1 signaling, our data suggests that signaling pathway is particularly disturbed in BA 10 in MRDS.
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Affiliation(s)
- Megan Snelleksz
- The Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
| | - Brian Dean
- The Molecular Psychiatry Laboratory, The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
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5
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Chen Z, Ge R, Wang C, Elazab A, Fu X, Min W, Qin F, Jia G, Fan X. Identification of important gene signatures in schizophrenia through feature fusion and genetic algorithm. Mamm Genome 2024; 35:241-255. [PMID: 38512459 DOI: 10.1007/s00335-024-10034-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/07/2024] [Indexed: 03/23/2024]
Abstract
Schizophrenia is a debilitating psychiatric disorder that can significantly affect a patient's quality of life and lead to permanent brain damage. Although medical research has identified certain genetic risk factors, the specific pathogenesis of the disorder remains unclear. Despite the prevalence of research employing magnetic resonance imaging, few studies have focused on the gene level and gene expression profile involving a large number of screened genes. However, the high dimensionality of genetic data presents a great challenge to accurately modeling the data. To tackle the current challenges, this study presents a novel feature selection strategy that utilizes heuristic feature fusion and a multi-objective optimization genetic algorithm. The goal is to improve classification performance and identify the key gene subset for schizophrenia diagnostics. Traditional gene screening techniques are inadequate for accurately determining the precise number of key genes associated with schizophrenia. Our innovative approach integrates a filter-based feature selection method to reduce data dimensionality and a multi-objective optimization genetic algorithm for improved classification tasks. By combining the filtering and wrapper methods, our strategy leverages their respective strengths in a deliberate manner, leading to superior classification accuracy and a more efficient selection of relevant genes. This approach has demonstrated significant improvements in classification results across 11 out of 14 relevant datasets. The performance on the remaining three datasets is comparable to the existing methods. Furthermore, visual and enrichment analyses have confirmed the practicality of our proposed method as a promising tool for the early detection of schizophrenia.
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Affiliation(s)
| | - Ruiquan Ge
- Hangzhou Dianzi University, Hangzhou, China.
- Hangzhou Institute of Advanced Technology, Hangzhou, China.
- Key Laboratory of Discrete Industrial Internet of Things of Zhejiang Province, Hangzhou, China.
| | - Changmiao Wang
- Shenzhen Research Institute of Big Data, Shenzhen, China
| | - Ahmed Elazab
- Computer Science Department, Misr Higher Institute for Commerce and Computers, Mansoura, Egypt
| | - Xianjun Fu
- School of Artificial Intelligence, Zhejiang College of Security Technology, Wenzhou, China
| | - Wenwen Min
- School of Information Science and Engineering, Yunnan University, Kunming, China
| | - Feiwei Qin
- Hangzhou Dianzi University, Hangzhou, China
| | | | - Xiaopeng Fan
- Hangzhou Institute of Advanced Technology, Hangzhou, China
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6
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Burrack N, Yitzhaky A, Mizrahi L, Wang M, Stern S, Hertzberg L. Altered Expression of PDE4 Genes in Schizophrenia: Insights from a Brain and Blood Sample Meta-Analysis and iPSC-Derived Neurons. Genes (Basel) 2024; 15:609. [PMID: 38790238 PMCID: PMC11121586 DOI: 10.3390/genes15050609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 05/03/2024] [Accepted: 05/05/2024] [Indexed: 05/26/2024] Open
Abstract
Schizophrenia symptomatology includes negative symptoms and cognitive impairment. Several studies have linked schizophrenia with the PDE4 family of enzymes due to their genetic association and function in cognitive processes such as long-term potentiation. We conducted a systematic gene expression meta-analysis of four PDE4 genes (PDE4A-D) in 10 brain sample datasets (437 samples) and three blood sample datasets (300 samples). Subsequently, we measured mRNA levels in iPSC-derived hippocampal dentate gyrus neurons generated from fibroblasts of three groups: healthy controls, healthy monozygotic twins (MZ), and their MZ siblings with schizophrenia. We found downregulation of PDE4B in brain tissues, further validated by independent data of the CommonMind consortium (515 samples). Interestingly, the downregulation signal was present in a subgroup of the patients, while the others showed no differential expression or even upregulation. Notably, PDE4A, PDE4B, and PDE4D exhibited upregulation in iPSC-derived neurons compared to healthy controls, whereas in blood samples, PDE4B was found to be upregulated while PDE4A was downregulated. While the precise mechanism and direction of altered PDE4 expression necessitate further investigation, the observed multilevel differential expression across the brain, blood, and iPSC-derived neurons compellingly suggests the involvement of PDE4 genes in the pathophysiology of schizophrenia.
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Affiliation(s)
- Nitzan Burrack
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel;
- Clinical Research Center, Soroka University Medical Center, Beer-Sheva 84101, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Liron Mizrahi
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3103301, Israel
| | - Meiyan Wang
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Shani Stern
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 3103301, Israel
| | - Libi Hertzberg
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot 76100, Israel
- Shalvata Mental Health Center, Affiliated with the Faculty of Medicine, Tel-Aviv University, 13 Aliat Hanoar St., Hod Hasharon 45100, Israel
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7
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Fiorito AM, Fakra E, Sescousse G, Ibrahim EC, Rey R. Molecular mapping of a core transcriptional signature of microglia-specific genes in schizophrenia. Transl Psychiatry 2023; 13:386. [PMID: 38092734 PMCID: PMC10719376 DOI: 10.1038/s41398-023-02677-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 12/17/2023] Open
Abstract
Besides playing a central role in neuroinflammation, microglia regulate synaptic development and is involved in plasticity. Converging lines of evidence suggest that these different processes play a critical role in schizophrenia. Furthermore, previous studies reported altered transcription of microglia genes in schizophrenia, while microglia itself seems to be involved in the etiopathology of the disease. However, the regional specificity of these brain transcriptional abnormalities remains unclear. Moreover, it is unknown whether brain and peripheral expression of microglia genes are related. Thus, we investigated the expression of a pre-registered list of 10 genes from a core signature of human microglia both at brain and peripheral levels. We included 9 independent Gene Expression Omnibus datasets (764 samples obtained from 266 individuals with schizophrenia and 237 healthy controls) from 8 different brain regions and 3 peripheral tissues. We report evidence of a widespread transcriptional alteration of microglia genes both in brain tissues (we observed a decreased expression in the cerebellum, associative striatum, hippocampus, and parietal cortex of individuals with schizophrenia compared with healthy controls) and whole blood (characterized by a mixed altered expression pattern). Our results suggest that brain underexpression of microglia genes may represent a candidate transcriptional signature for schizophrenia. Moreover, the dual brain-whole blood transcriptional alterations of microglia/macrophage genes identified support the model of schizophrenia as a whole-body disorder and lend weight to the use of blood samples as a potential source of biological peripheral biomarkers.
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Affiliation(s)
- Anna M Fiorito
- Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, PSYR2 Team, University of Lyon, Lyon, France
- Centre Hospitalier Le Vinatier, Bron, France
| | - Eric Fakra
- Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, PSYR2 Team, University of Lyon, Lyon, France
- Department of Psychiatry, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Guillaume Sescousse
- Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, PSYR2 Team, University of Lyon, Lyon, France
- Centre Hospitalier Le Vinatier, Bron, France
| | - El Chérif Ibrahim
- Aix-Marseille Univ, CNRS, INT, Institut de Neurosciences de la Timone, Marseille, France
| | - Romain Rey
- Lyon Neuroscience Research Center, INSERM U1028, CNRS UMR 5292, PSYR2 Team, University of Lyon, Lyon, France.
- Centre Hospitalier Le Vinatier, Bron, France.
- Fondation FondaMental, Créteil, France.
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8
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Bartal G, Yitzhaky A, Segev A, Hertzberg L. Multiple genes encoding mitochondrial ribosomes are downregulated in brain and blood samples of individuals with schizophrenia. World J Biol Psychiatry 2023; 24:829-837. [PMID: 37158323 DOI: 10.1080/15622975.2023.2211653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/04/2023] [Indexed: 05/10/2023]
Abstract
OBJECTIVES Schizophrenia is a chronic, debilitating mental disorder whose pathophysiology is complex and not fully understood. Numerous studies suggest mitochondrial dysfunction may contribute to the development of schizophrenia. While mitochondrial ribosomes (mitoribosomes) are essential for proper mitochondrial functioning, their gene expression levels have not been studied yet in schizophrenia. METHODS We performed a systematic meta-analysis of the expression of 81 mitoribosomes subunits encoding genes, integrating ten brain samples datasets of patients with schizophrenia compared to healthy controls (overall 422 samples, 211 schizophrenia, and 211 controls). We also performed a meta-analysis of their expression in blood, integrating two blood sample datasets (overall 90 samples, 53 schizophrenia, and 37 controls). RESULTS Multiple mitoribosomes subunits were significantly downregulated in brain samples (18 genes) and in blood samples (11 genes) of individuals with schizophrenia, where two showed significant downregulation in both brain and blood, MRPL4 and MRPS7. CONCLUSIONS Our results support the accumulating evidence of impaired mitochondrial activity in schizophrenia. While further research is needed to validate mitoribosomes' role as biomarkers, this direction has the potential to promote patients' stratification and personalised treatment for schizophrenia.
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Affiliation(s)
- Gideon Bartal
- The Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Aviv Segev
- The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Shalvata Mental Health Center, Hod Hasharon, Israel
| | - Libi Hertzberg
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
- The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Shalvata Mental Health Center, Hod Hasharon, Israel
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Campos-Martin R, Bey K, Elsner B, Reuter B, Klawohn J, Philipsen A, Kathmann N, Wagner M, Ramirez A. Epigenome-wide analysis identifies methylome profiles linked to obsessive-compulsive disorder, disease severity, and treatment response. Mol Psychiatry 2023; 28:4321-4330. [PMID: 37587247 PMCID: PMC10827661 DOI: 10.1038/s41380-023-02219-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/27/2023] [Accepted: 08/04/2023] [Indexed: 08/18/2023]
Abstract
Obsessive-compulsive disorder (OCD) is a prevalent mental disorder affecting ~2-3% of the population. This disorder involves genetic and, possibly, epigenetic risk factors. The dynamic nature of epigenetics also presents a promising avenue for identifying biomarkers associated with symptom severity, clinical progression, and treatment response in OCD. We, therefore, conducted a comprehensive case-control investigation using Illumina MethylationEPIC BeadChip, encompassing 185 OCD patients and 199 controls recruited from two distinct sites in Germany. Rigorous clinical assessments were performed by trained raters employing the Structured Clinical Interview for DSM-IV (SCID-I). We performed a robust two-step epigenome-wide association study that led to the identification of 305 differentially methylated CpG positions. Next, we validated these findings by pinpointing the optimal set of CpGs that could effectively classify individuals into their respective groups. This approach identified a subset comprising 12 CpGs that overlapped with the 305 CpGs identified in our EWAS. These 12 CpGs are close to or in genes associated with the sweet-compulsive brain hypothesis which proposes that aberrant dopaminergic transmission in the striatum may impair insulin signaling sensitivity among OCD patients. We replicated three of the 12 CpGs signals from a recent independent study conducted on the Han Chinese population, underscoring also the cross-cultural relevance of our findings. In conclusion, our study further supports the involvement of epigenetic mechanisms in the pathogenesis of OCD. By elucidating the underlying molecular alterations associated with OCD, our study contributes to advancing our understanding of this complex disorder and may ultimately improve clinical outcomes for affected individuals.
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Affiliation(s)
- Rafael Campos-Martin
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937, Cologne, Germany
| | - Katharina Bey
- Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
| | - Björn Elsner
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Benedikt Reuter
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Medicine, MSB Medical School Berlin, Berlin, Germany
| | - Julia Klawohn
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Medicine, MSB Medical School Berlin, Berlin, Germany
| | - Alexandra Philipsen
- Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
| | - Norbert Kathmann
- Department of Psychology, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Michael Wagner
- Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
- Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
| | - Alfredo Ramirez
- Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937, Cologne, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
- Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany.
- Department of Psychiatry and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, San Antonio, TX, USA.
- Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, Cologne, Germany.
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Wang Z, Lin X, Luo X, Xiao J, Zhang Y, Xu J, Wang S, Zhao F, Wang H, Zheng H, Zhang W, Lin C, Tan Z, Cao L, Wang Z, Tan Y, Chen W, Cao Y, Guo X, Pittenger C, Luo X. Pleiotropic Association of CACNA1C Variants With Neuropsychiatric Disorders. Schizophr Bull 2023; 49:1174-1184. [PMID: 37306960 PMCID: PMC10483336 DOI: 10.1093/schbul/sbad073] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
BACKGROUND Neuropsychiatric disorders are highly heritable and have overlapping genetic underpinnings. Single nucleotide polymorphisms (SNPs) in the gene CACNA1C have been associated with several neuropsychiatric disorders, across multiple genome-wide association studies. METHOD A total of 70,711 subjects from 37 independent cohorts with 13 different neuropsychiatric disorders were meta-analyzed to identify overlap of disorder-associated SNPs within CACNA1C. The differential expression of CACNA1C mRNA in five independent postmortem brain cohorts was examined. Finally, the associations of disease-sharing risk alleles with total intracranial volume (ICV), gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA), and average cortical thickness (TH) were tested. RESULTS Eighteen SNPs within CACNA1C were nominally associated with more than one neuropsychiatric disorder (P < .05); the associations shared among schizophrenia, bipolar disorder, and alcohol use disorder survived false discovery rate correction (five SNPs with P < 7.3 × 10-4 and q < 0.05). CACNA1C mRNA was differentially expressed in brains from individuals with schizophrenia, bipolar disorder, and Parkinson's disease, relative to controls (three SNPs with P < .01). Risk alleles shared by schizophrenia, bipolar disorder, substance dependence, and Parkinson's disease were significantly associated with ICV, GMVs, SA, or TH (one SNP with P ≤ 7.1 × 10-3 and q < 0.05). CONCLUSION Integrating multiple levels of analyses, we identified CACNA1C variants associated with multiple psychiatric disorders, and schizophrenia and bipolar disorder were most strongly implicated. CACNA1C variants may contribute to shared risk and pathophysiology in these conditions.
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Affiliation(s)
- Zuxing Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
- Sichuan Provincial Center for Mental Health, The Center of Psychosomatic Medicine of Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China
| | - Xiandong Lin
- Laboratory of Radiation Oncology and Radiobiology, Fujian Provincial Cancer Hospital, the Teaching Hospital of Fujian Medical University, Fuzhou, Fujian 350014, China
| | - Xinqun Luo
- Department of Neurosurgery, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350001, China
| | - Jun Xiao
- Sichuan Provincial Center for Mental Health, The Center of Psychosomatic Medicine of Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China
| | - Yong Zhang
- Tianjin Mental Health Center, Tianjin 300180, China
| | - Jianying Xu
- Zhuhai Center for Maternal and Child Health Care, Zhuhai, Guangdong 519000, China
| | - Shibin Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
| | - Fen Zhao
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
| | - Huifen Wang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
| | - Hangxiao Zheng
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
| | - Wei Zhang
- Department of Pharmacology, Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, 050017, P. R. China
| | - Chen Lin
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing 100096, China
| | - Zewen Tan
- Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510370, China
| | - Liping Cao
- Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510370, China
| | - Zhiren Wang
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing 100096, China
| | - Yunlong Tan
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing 100096, China
| | - Wenzhong Chen
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
| | - Yuping Cao
- Department of Psychiatry, Second Xiangya Hospital, Central South University; China National Clinical Research Center on Mental Disorders, China National Technology Institute on Mental Disorders, Changsha, Hunan 410011, China
| | - Xiaoyun Guo
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of medicine, Shanghai 200030, China
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, US
| | - Christopher Pittenger
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, US
| | - Xingguang Luo
- Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing 100096, China
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11
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Shamir A, Yitzhaky A, Segev A, Haroutunian V, Katsel P, Hertzberg L. Up-Regulation of S100 Gene Family in Brain Samples of a Subgroup of Individuals with Schizophrenia: Meta-analysis. Neuromolecular Med 2023; 25:388-401. [PMID: 37005977 DOI: 10.1007/s12017-023-08743-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 03/12/2023] [Indexed: 04/04/2023]
Abstract
The S100 proteins family is known to affect neuroinflammation and astrocyte activation, which have been suggested to be contributors to the pathogenesis of schizophrenia. We conducted a systematic meta-analysis of S100 genes differential expression in postmortem samples of patients with schizophrenia vs. healthy controls, following the commonly used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Twelve microarray datasets met the inclusion criteria (overall 511 samples, 253 schizophrenia and 258 controls were analyzed). Nine out of 21 genes were significantly up-regulated or with tendency for up-regulation. A per-sample fold change analysis indicated that the S100 genes' up-regulation was concentrated in a subgroup of the patients. None of the genes have been found to be down-regulated. ANXA3, which encodes Annexin 3 protein and was associated with neuroinflammation, was up-regulated and positively correlated with the S100 genes' expression pattern. In addition, astrocytes and endothelial cell markers were significantly correlated with S100A8 expression. S100 correlation with ANXA3 and endothelial cell markers suggests that the up-regulation we detected reflects increased inflammation. However, it might also reflect astrocytes abundance or activation. The fact that S100 proteins were shown to be up-regulated in blood samples and other body fluids of patients with schizophrenia suggests a potential role as biomarkers, which might help disease subtyping, and the development of etiological treatments for immune dysregulation in schizophrenia.
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Affiliation(s)
- Anat Shamir
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Aviv Segev
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
- Shalvata Mental Health Center, 13 Aliat Hanoar St, 45100, Hod Hasharon, Israel
| | - Vahram Haroutunian
- Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry (MIRECC), James J Peters VA Medical Center, Bronx, NY, USA
| | - Pavel Katsel
- Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Libi Hertzberg
- The Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
- Shalvata Mental Health Center, 13 Aliat Hanoar St, 45100, Hod Hasharon, Israel.
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12
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Miyahara K, Hino M, Yu Z, Ono C, Nagaoka A, Hatano M, Shishido R, Yabe H, Tomita H, Kunii Y. The influence of tissue pH and RNA integrity number on gene expression of human postmortem brain. Front Psychiatry 2023; 14:1156524. [PMID: 37520228 PMCID: PMC10379646 DOI: 10.3389/fpsyt.2023.1156524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/26/2023] [Indexed: 08/01/2023] Open
Abstract
Background Evaluating and controlling confounders are necessary when investigating molecular pathogenesis using human postmortem brain tissue. Particularly, tissue pH and RNA integrity number (RIN) are valuable indicators for controlling confounders. However, the influences of these indicators on the expression of each gene in postmortem brain have not been fully investigated. Therefore, we aimed to assess these effects on gene expressions of human brain samples. Methods We isolated total RNA from occipital lobes of 13 patients with schizophrenia and measured the RIN and tissue pH. Gene expression was analyzed and gene sets affected by tissue pH and RIN were identified. Moreover, we examined the functions of these genes by enrichment analysis and upstream regulator analysis. Results We identified 2,043 genes (24.7%) whose expressions were highly correlated with pH; 3,004 genes (36.3%) whose expressions were highly correlated with RIN; and 1,293 genes (15.6%) whose expressions were highly correlated with both pH and RIN. Genes commonly affected by tissue pH and RIN were highly associated with energy production and the immune system. In addition, genes uniquely affected by tissue pH were highly associated with the cell cycle, whereas those uniquely affected by RIN were highly associated with RNA processing. Conclusion The current study elucidated the influence of pH and RIN on gene expression profiling and identified gene sets whose expressions were affected by tissue pH or RIN. These findings would be helpful in the control of confounders for future postmortem brain studies.
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Affiliation(s)
- Kazusa Miyahara
- Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
| | - Mizuki Hino
- Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Zhiqian Yu
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Chiaki Ono
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
| | - Atsuko Nagaoka
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Masataka Hatano
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Risa Shishido
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Hirooki Yabe
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan
| | - Hiroaki Tomita
- Department of Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan
- Department of Psychiatry, Tohoku University Hospital, Sendai, Miyagi, Japan
| | - Yasuto Kunii
- Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan
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13
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Asraf K, Zaidan H, Natoor B, Gaisler-Salomon I. Synergistic, long-term effects of glutamate dehydrogenase 1 deficiency and mild stress on cognitive function and mPFC gene and miRNA expression. Transl Psychiatry 2023; 13:248. [PMID: 37419882 DOI: 10.1038/s41398-023-02534-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 06/15/2023] [Accepted: 06/21/2023] [Indexed: 07/09/2023] Open
Abstract
Glutamate abnormalities in the medial prefrontal cortex (mPFC) are associated with cognitive deficits. We previously showed that homozygous deletion of CNS glutamate dehydrogenase 1 (Glud1), a metabolic enzyme critical for glutamate metabolism, leads to schizophrenia-like behavioral abnormalities and increased mPFC glutamate; mice heterozygous for CNS Glud1 deletion (C-Glud1+/- mice) showed no cognitive or molecular abnormalities. Here, we examined the protracted behavioral and molecular effects of mild injection stress on C-Glud1+/- mice. We found spatial and reversal learning deficits, as well as large-scale mPFC transcriptional changes in pathways associated with glutamate and GABA signaling, in stress-exposed C-Glud1+/- mice, but not in their stress-naïve or C-Glud1+/+ littermates. These effects were observed several weeks following stress exposure, and the expression levels of specific glutamatergic and GABAergic genes differentiated between high and low reversal learning performance. An increase in miR203-5p expression immediately following stress may provide a translational regulatory mechanism to account for the delayed effect of stress exposure on cognitive function. Our findings show that chronic glutamate abnormalities interact with acute stress to induce cognitive deficits, and resonate with gene x environment theories of schizophrenia. Stress-exposed C-Glud1+/- mice may model a schizophrenia high-risk population, which is uniquely sensitive to stress-related 'trigger' events.
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Affiliation(s)
- Kfir Asraf
- School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa, 3498838, Israel
- The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa, 3498838, Israel
| | - Hiba Zaidan
- School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa, 3498838, Israel
- The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa, 3498838, Israel
| | - Baylasan Natoor
- School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa, 3498838, Israel
- The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa, 3498838, Israel
| | - Inna Gaisler-Salomon
- School of Psychological Sciences, Department of Psychology, University of Haifa, Haifa, 3498838, Israel.
- The Integrated Brain and Behavior Research Center (IBBRC), University of Haifa, Haifa, 3498838, Israel.
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14
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Mekiten O, Yitzhaky A, Gould N, Rosenblum K, Hertzberg L. Ribosome subunits are upregulated in brain samples of a subgroup of individuals with schizophrenia: A systematic gene expression meta-analysis. J Psychiatr Res 2023; 164:372-381. [PMID: 37413782 DOI: 10.1016/j.jpsychires.2023.06.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 07/08/2023]
Abstract
One of the new theories accounting for the underlying pathophysiology of schizophrenia is excitation/inhibition imbalance. Interestingly, perturbation in protein synthesis machinery as well as oxidative stress can lead to excitation/inhibition imbalance. We thus performed a systematic meta-analysis of the expression of 79 ribosome subunit genes and two oxidative-stress related genes, HIF1A and NQO1, in brain samples of individuals with schizophrenia vs. healthy controls. We integrated 12 gene expression datasets, following the PRISMA guidelines (overall 511 samples, 253 schizophrenia and 258 controls). Five ribosome subunit genes were significantly upregulated in a subgroup of the patients with schizophrenia, while 24 (30%) showed a tendency for upregulation. HIF1A and NQO1 were also found to be significantly upregulated. Moreover, HIF1A and NQO1 showed positive correlation with the expression of the upregulated ribosome subunit genes. Our results, together with previous findings, suggest a possible role for altered mRNA translation in the pathogenesis of schizophrenia, in association with markers of increased oxidative stress in a subgroup of patients. Further studies should define whether the upregulation of ribosome subunits result in altered mRNA translation, which proteins are modulated and how it characterizes a subgroup of the patients with schizophrenia.
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Affiliation(s)
- Ori Mekiten
- Faculty of Medicine, Tel-Aviv University, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Nathaniel Gould
- Sagol Department of Neurobiology, University of Haifa, Haifa, Israel
| | - Kobi Rosenblum
- Sagol Department of Neurobiology, University of Haifa, Haifa, Israel; Center for Gene Manipulation in the Brain, University of Haifa, Haifa, Israel
| | - Libi Hertzberg
- Faculty of Medicine, Tel-Aviv University, Israel; Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; Shalvata Mental Health Center, Israel.
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15
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Medina AM, Hagenauer MH, Krolewski DM, Hughes E, Forrester LCT, Walsh DM, Waselus M, Richardson E, Turner CA, Sequeira PA, Cartagena PM, Thompson RC, Vawter MP, Bunney BG, Myers RM, Barchas JD, Lee FS, Schatzberg AF, Bunney WE, Akil H, Watson SJ. Neurotransmission-related gene expression in the frontal pole is altered in subjects with bipolar disorder and schizophrenia. Transl Psychiatry 2023; 13:118. [PMID: 37031222 PMCID: PMC10082811 DOI: 10.1038/s41398-023-02418-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/10/2023] Open
Abstract
The frontal pole (Brodmann area 10, BA10) is the largest cytoarchitectonic region of the human cortex, performing complex integrative functions. BA10 undergoes intensive adolescent grey matter pruning prior to the age of onset for bipolar disorder (BP) and schizophrenia (SCHIZ), and its dysfunction is likely to underly aspects of their shared symptomology. In this study, we investigated the role of BA10 neurotransmission-related gene expression in BP and SCHIZ. We performed qPCR to measure the expression of 115 neurotransmission-related targets in control, BP, and SCHIZ postmortem samples (n = 72). We chose this method for its high sensitivity to detect low-level expression. We then strengthened our findings by performing a meta-analysis of publicly released BA10 microarray data (n = 101) and identified sources of convergence with our qPCR results. To improve interpretation, we leveraged the unusually large database of clinical metadata accompanying our samples to explore the relationship between BA10 gene expression, therapeutics, substances of abuse, and symptom profiles, and validated these findings with publicly available datasets. Using these convergent sources of evidence, we identified 20 neurotransmission-related genes that were differentially expressed in BP and SCHIZ in BA10. These results included a large diagnosis-related decrease in two important therapeutic targets with low levels of expression, HTR2B and DRD4, as well as other findings related to dopaminergic, GABAergic and astrocytic function. We also observed that therapeutics may produce a differential expression that opposes diagnosis effects. In contrast, substances of abuse showed similar effects on BA10 gene expression as BP and SCHIZ, potentially amplifying diagnosis-related dysregulation.
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Affiliation(s)
- Adriana M Medina
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | | | - David M Krolewski
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - Evan Hughes
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | | | | | - Maria Waselus
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - Evelyn Richardson
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - Cortney A Turner
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | | | | | - Robert C Thompson
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | | | | | - Richard M Myers
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | | | | | | | | | - Huda Akil
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
| | - Stanley J Watson
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA
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16
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Wolf A, Yitzhaky A, Hertzberg L. SMAD genes are up-regulated in brain and blood samples of individuals with schizophrenia. J Neurosci Res 2023. [PMID: 36977612 DOI: 10.1002/jnr.25188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 03/04/2023] [Accepted: 03/08/2023] [Indexed: 03/30/2023]
Abstract
Schizophrenia is a severe psychiatric disorder, with heritability around 80%, but a not fully understood pathophysiology. Signal transduction through the mothers against decapentaplegic (SMADs) are eight different proteins involved in the regulation of inflammatory processes, cell cycle, and tissue patterning. The literature is not consistent regarding the differential expression of SMAD genes among subjects with schizophrenia. In this article, we performed a systematic meta-analysis of the expression of SMAD genes in 423 brain samples (211 schizophrenia vs. 212 healthy controls), integrating 10 datasets from two public repositories, following the PRISMA guidelines. We found a statistically significant up-regulation of SMAD1, SMAD4, SMAD5, and SMAD7, and a tendency for up-regulation of SMAD3 and SMAD9 in brain samples of patients with schizophrenia. Overall, six of the eight genes showed a tendency for up-regulation, and none of them was found to have a tendency for down-regulation. SMAD1 and SMAD4 were up-regulated also in blood samples of 13 individuals with schizophrenia versus eight healthy controls, suggesting the SMAD genes' potential role as biomarkers of schizophrenia. Furthermore, SMAD genes' expression levels were significantly correlated with those of Sphingosine-1-phosphate receptor-1 (S1PR1), which is known to regulate inflammatory processes. Our meta-analysis supports the involvement of SMAD genes in the pathophysiology of schizophrenia through their role in inflammatory processes, as well as demonstrates the importance of gene expression meta-analysis for improving our understanding of psychiatric diseases.
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Affiliation(s)
- Ammie Wolf
- The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Libi Hertzberg
- The Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
- Shalvata Mental Health Center, 13 Aliat Hanoar St., Hod Hasharon, 45100, Israel
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17
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Chen Z, Li X, Cui X, Zhang L, Liu Q, Lu Y, Wang X, Shi H, Ding M, Yang Y, Li W, Lv L. Association of CTNND2 gene polymorphism with schizophrenia: Two-sample case-control study in Chinese Han population. Int J Psychiatry Med 2023:912174231164669. [PMID: 36930964 DOI: 10.1177/00912174231164669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/19/2023]
Abstract
OBJECTIVES Genetic factors play an important role in the etiology of schizophrenia (SZ). Catenin Delta 2 (CTNND2) is one of the genes regulating neuronal development in the brain. It is unclear whether CTNND2 is involved in SZ. With the hypothesis that CTNND2 may be a risk gene for SZ, we performed a case-control association analysis to investigate if CTNND2 gene single nucleotide polymorphisms (SNPs) are implicated in SZ in a Han Chinese northern population. MATERIALS AND METHODS We recruited subjects from 2010 to 2022 from the Han population of northern Henan and divided them into two case-control samples, including a discovery sample (SZ = 528 and control = 528) and replication sample (SZ = 2458 and control = 6914). Twenty-one SNPs were genotyped on the Illumina BeadStation 500G platform using GoldenGate technology and analyzed by PLINK. Positive and Negative Syndrome Scale (PANSS) was used to assess clinical symptoms. RESULTS Rs16901943, rs7733427, and rs2168878 SNPs were associated with SZ (Chi2 = 7.484, 11.576, and 5.391, respectively, df = 1; p = 0.006, 0.00067, and 0.02, respectively) in two samples. Rs10058868 was associated with SZ in male patients in the discovery sample (Chi2 = 6.264, df = 1, p = .044). Only rs7733427 survived Bonferroni correction. Linkage disequilibrium block three haplotypes were associated with SZ in the discovery and total sample. PANSS analysis of the four SNPs implicated rs10058868 and rs2168878 with symptoms of depression and excitement, respectively, in the SZ patients. CONCLUSION Four SNPs were identified as being correlated with SZ. The CTNND2 gene may be involved in susceptibility to SZ.
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Affiliation(s)
- Zhaonian Chen
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Xiaojing Li
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Xiangzheng Cui
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Luwen Zhang
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Qing Liu
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yanli Lu
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Xiujuan Wang
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Han Shi
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Minli Ding
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yongfeng Yang
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Wenqiang Li
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Luxian Lv
- 34727The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
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18
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Meta-analysis of brain samples of individuals with schizophrenia detects down-regulation of multiple ATP synthase encoding genes in both females and males. J Psychiatr Res 2023; 158:350-359. [PMID: 36640659 DOI: 10.1016/j.jpsychires.2023.01.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 10/05/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023]
Abstract
Schizophrenia is a chronic and debilitating mental disorder, with unknown pathophysiology. Converging lines of evidence suggest that mitochondrial functioning may be compromised in schizophrenia. Postmortem brain samples of individuals with schizophrenia showed dysregulated expression levels of genes encoding enzyme complexes comprising the mitochondrial electron transport chain (ETC), including ATP synthase, the fifth ETC complex. However, there are inconsistencies regarding the direction of change, i.e., up- or down-regulation, and differences between female and male patients were hardly examined. We have performed a systematic meta-analysis of the expression of 16 ATP synthase encoding genes in postmortem brain samples of individuals with schizophrenia vs. healthy controls of three regions: Brodmann Area 10 (BA10), BA22/Superior Temporal Gyrus (STG) and the cerebellum. Eight independent datasets were integrated (overall 294brain samples, 145 of individuals with schizophrenia and 149 controls). The meta-analysis was applied to all individuals with schizophrenia vs. the controls, and also to female and male patients vs. age-matched controls, separately. A significant down-regulation of two ATP synthase encoding genes was detected in schizophrenia, ATP5A1 and ATP5H, and a trend towards down-regulation of five further ATP synthase genes. The down-regulation tendency was shown for both females and males with schizophrenia. Our findings support the hypothesis that schizophrenia is associated with reduced ATP synthesis via the oxidative phosphorylation system, which is caused by reduced cellular demand of ATP. Abnormal cellular energy metabolism can lead to alterations in neural function and brain circuitry, and thereby to the cognitive and behavioral aberrations characteristic of schizophrenia.
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19
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Chen Y, Dai J, Tang L, Mikhailova T, Liang Q, Li M, Zhou J, Kopp RF, Weickert C, Chen C, Liu C. Neuroimmune transcriptome changes in patient brains of psychiatric and neurological disorders. Mol Psychiatry 2023; 28:710-721. [PMID: 36424395 PMCID: PMC9911365 DOI: 10.1038/s41380-022-01854-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 10/07/2022] [Accepted: 10/21/2022] [Indexed: 11/25/2022]
Abstract
Neuroinflammation has been implicated in multiple brain disorders but the extent and the magnitude of change in immune-related genes (IRGs) across distinct brain disorders has not been directly compared. In this study, 1275 IRGs were curated and their expression changes investigated in 2467 postmortem brains of controls and patients with six major brain disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD). There were 865 IRGs present across all microarray and RNA-seq datasets. More than 60% of the IRGs had significantly altered expression in at least one of the six disorders. The differentially expressed immune-related genes (dIRGs) shared across disorders were mainly related to innate immunity. Moreover, sex, tissue, and putative cell type were systematically evaluated for immune alterations in different neuropsychiatric disorders. Co-expression networks revealed that transcripts of the neuroimmune systems interacted with neuronal-systems, both of which contribute to the pathology of brain disorders. However, only a few genes with expression changes were also identified as containing risk variants in genome-wide association studies. The transcriptome alterations at gene and network levels may clarify the immune-related pathophysiology and help to better define neuropsychiatric and neurological disorders.
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Affiliation(s)
- Yu Chen
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jiacheng Dai
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China
| | - Longfei Tang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tatiana Mikhailova
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Qiuman Liang
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Miao Li
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiaqi Zhou
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Richard F Kopp
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Cynthia Weickert
- Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA
- School of Psychiatry, UNSW, Sydney, NSW, Australia
| | - Chao Chen
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.
- Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, China.
| | - Chunyu Liu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, and Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.
- Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA.
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20
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Segev S, Yitzhaky A, Ben Shachar D, Hertzberg L. VDAC genes down-regulation in brain samples of individuals with schizophrenia is revealed by a systematic meta-analysis. Neurosci Res 2023:S0168-0102(23)00022-6. [PMID: 36717018 DOI: 10.1016/j.neures.2023.01.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 01/23/2023] [Accepted: 01/26/2023] [Indexed: 01/29/2023]
Abstract
Mitochondrial dysfunction was shown to be involved in schizophrenia pathophysiology. Abnormal energy states can lead to alterations in neural function and thereby to the cognitive and behavioral aberrations characteristics of schizophrenia. Voltage-dependent anion-selective channels (VDAC) are located in the outer mitochondrial membrane and are involved in mitochondrial energy production. Only few studies explored VDAC genes' expression in schizophrenia, and their results were not consistent. We conducted a systematic meta-analysis of ten brain samples gene expression datasets (overall 368 samples, 179 schizophrenia, 189 controls). In addition, we conducted a meta-analysis of three blood samples datasets (overall 300 samples, 167 schizophrenia, 133 controls). Pairwise correlation analysis was conducted between the VDAC and proteasome subunit genes' expression patterns. VDAC1, VDAC2 and VDAC3 showed significant down-regulation in brain samples of patients with schizophrenia. They also showed significant positive correlations with the proteasome subunit genes' expression levels. Our findings suggest that VDAC genes might play a role in mitochondrial dysfunction in schizophrenia. VDAC1 was down-regulated also in blood samples, which suggests its potential role as a biomarker for schizophrenia. The correlation with proteasome subunits, which were previously shown to be down-regulated in a subgroup of the patients, suggests that our findings might characterize a subgroup of the patients. This direction has the potential to lead to patients' stratification and more precisely-targeted therapy and necessitates further study.
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Affiliation(s)
- Shaked Segev
- Sackler School of Medicine, Tel-Aviv University, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Dorit Ben Shachar
- Psychobiology Research Lab, Department of Neuroscience, The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Israel
| | - Libi Hertzberg
- Sackler School of Medicine, Tel-Aviv University, Israel; Shalvata Mental Health Center, Israel; Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
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21
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Shriebman Y, Yitzhaky A, Kosloff M, Hertzberg L. Gene expression meta-analysis in patients with schizophrenia reveals up-regulation of RGS2 and RGS16 in Brodmann Area 10. Eur J Neurosci 2023; 57:360-372. [PMID: 36443250 DOI: 10.1111/ejn.15876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 09/10/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022]
Abstract
Regulator of G-protein signalling (RGS) proteins inhibit signalling by G-protein-coupled receptors (GPCRs). GPCRs mediate the functions of several important neurotransmitters and serve as targets of many anti-psychotics. RGS2, RGS4, RGS5 and RGS16 are located on chromosome 1q23.3-31, a locus found to be associated with schizophrenia. Although previous gene expression analysis detected down-regulation of RGS4 expression in brain samples of patients with schizophrenia, the results were not consistent. In the present study, we performed a systematic meta-analysis of differential RGS2, RGS4, RGS5 and RGS16 expression in Brodmann Area 10 (BA10) samples of patients with schizophrenia and from healthy controls. Two microarray datasets met the inclusion criteria (overall, 41 schizophrenia samples and 38 controls were analysed). RGS2 and RGS16 were found to be up-regulated in BA10 samples of individuals with schizophrenia, whereas no differential expression of RGS4 and RGS5 was detected. Analysis of dorso-lateral prefrontal cortex samples of the CommonMind Consortium (258 schizophrenia samples vs. 279 controls) further validated the results. Given their central role in inactivating G-protein-coupled signalling pathways, our results suggest that differential gene expression might lead to enhanced inactivation of G-protein signalling in schizophrenia. This, in turn, suggests that additional studies are needed to further explore the consequences of the differential expression we detected, this time at the protein and functional levels.
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Affiliation(s)
- Yaen Shriebman
- Shalvata Mental Health Center, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Mickey Kosloff
- Department of Human Biology, University of Haifa, Haifa, Israel
| | - Libi Hertzberg
- Shalvata Mental Health Center, affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
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22
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Ardesch DJ, Libedinsky I, Scholtens LH, Wei Y, van den Heuvel MP. Convergence of brain transcriptomic and neuroimaging patterns in schizophrenia, bipolar disorder, autism spectrum disorder and major depression disorder. BIOLOGICAL PSYCHIATRY: COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2023. [DOI: 10.1016/j.bpsc.2022.12.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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23
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Jelen LA, Green MS, King S, Morris AG, Zhang X, Lythgoe DJ, Young AH, De Belleroche J, Stone JM. Variants in the zinc transporter-3 encoding gene (SLC30A3) in schizophrenia and bipolar disorder: Effects on brain glutamate-A pilot study. Front Psychiatry 2022; 13:929306. [PMID: 36203844 PMCID: PMC9531870 DOI: 10.3389/fpsyt.2022.929306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 08/23/2022] [Indexed: 11/25/2022] Open
Abstract
Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and cognitive activity in patients with schizophrenia and bipolar affective disorder. Fifteen patients with schizophrenia (SCZ), 15 with bipolar affective disorder type 2 (BD), and 14 healthy volunteers (HV) were genotyped for two SLC30A3 single nucleotide polymorphisms (rs11126936 and rs11126929). They also underwent structural and functional MRI (n-back) imaging as well as static (PRESS) and functional magnetic resonance spectroscopy (n-back) on a 3 Tesla MRI system. SCZ with at least one copy of the minor allele showed reductions in dorsal anterior cingulate cortex glutamate during the n-back task, whereas SCZ without the minor allele showed an increase in glutamate. BD with the minor allele had reduced glutamate in the anterior cingulate cortex (p < 0.05). There was no effect of SLC30A3 genotype on BOLD activation during n-back or on cortical brain volume. This study supports the further investigation of SLC30A3 and its role in glutamatergic neurotransmission and in the neuropathology of mental illness.
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Affiliation(s)
- Luke A. Jelen
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, United Kingdom
| | - Mark S. Green
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Sinead King
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- Department of Psychiatry and Behavioural Sciences, Stanford University, Palo Alto, CA, United States
- Centre for Neuroimaging and Cognitive Genomics, National University of Ireland, Galway, Ireland
| | - Alex G. Morris
- Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
| | - Xinyuan Zhang
- Imperial College London, Hammersmith Hospital Campus, London, United Kingdom
| | - David J. Lythgoe
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
| | - Allan H. Young
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, United Kingdom
| | | | - James M. Stone
- Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
- South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, United Kingdom
- Psychiatry, Department of Neuroscience, Brighton and Sussex Medical School (BSMS), University of Sussex, Brighton, United Kingdom
- Department of Psychiatry, Sussex Partnership Foundation Trust, Eastbourne DGH, Eastbourne, United Kingdom
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24
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Du Y, Gao Y, Wu G, Li Z, Du X, Li J, Li X, Liu Z, Xu Y, Liu S. Exploration of the relationship between hippocampus and immune system in schizophrenia based on immune infiltration analysis. Front Immunol 2022; 13:878997. [PMID: 35983039 PMCID: PMC9380889 DOI: 10.3389/fimmu.2022.878997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 07/11/2022] [Indexed: 11/23/2022] Open
Abstract
Immune dysfunction has been implicated in the pathogenesis of schizophrenia (SZ). Despite previous studies showing a broad link between immune dysregulation and the central nervous system of SZ, the exact relationship has not been completely elucidated. With immune infiltration analysis as an entry point, this study aimed to explore the relationship between schizophrenia and the immune system in more detail from brain regions, immune cells, genes, and pathways. Here, we comprehensively analyzed the hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR) between SZ and control groups. Differentially expressed genes (DEGs) and functional enrichment analysis showed that three brain regions were closely related to the immune system. Compared with PFC and STR, there were 20 immune-related genes (IRGs) and 42 immune pathways in HPC. The results of immune infiltration analysis showed that the differential immune cells in HPC were effector memory T (Tem) cells. The correlation of immune-related DEGs (IDEGs) and immune cells further analysis showed that NPY, BLNK, OXTR, and FGF12, were moderately correlated with Tem cells. Functional pathway analysis indicated that these four genes might affect Tem by regulating the PI3K-AKT pathway and the neuroactive ligand-receptor interaction pathway. The receiver operating characteristic curve (ROC) analysis results indicated that these four genes had a high diagnostic ability (AUC=95.19%). Finally, the disease animal model was successfully replicated, and further validation was conducted using the real-time PCR and the western blot. These results showed that these gene expression changes were consistent with our previous expression profiling. In conclusion, our findings suggested that HPC in SZ may be more closely related to immune disorders and modulate immune function through Tem, PI3K-Akt pathway, and neuroactive ligand-binding receptor interactions. To the best of our knowledge, the Immucell AI tool has been applied for the first time to analyze immune infiltration in SZ, contributing to a better understanding of the role of immune dysfunction in SZ from a new perspective.
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Affiliation(s)
- Yanhong Du
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yao Gao
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Guangxian Wu
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
- Department of Physiology, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan, China
| | - Zexuan Li
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinzhe Du
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Junxia Li
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Xinrong Li
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhifen Liu
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Yong Xu
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Department of Mental Health, Shanxi Medical University, Taiyuan, China
- *Correspondence: Sha Liu, ; Yong Xu,
| | - Sha Liu
- Department of Psychiatry, First Hospital/First Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Sha Liu, ; Yong Xu,
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25
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Li Z, Li X, Jin M, Liu Y, He Y, Jia N, Cui X, Liu Y, Hu G, Yu Q. Identification of potential biomarkers and their correlation with immune infiltration cells in schizophrenia using combinative bioinformatics strategy. Psychiatry Res 2022; 314:114658. [PMID: 35660966 DOI: 10.1016/j.psychres.2022.114658] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 05/17/2022] [Accepted: 05/29/2022] [Indexed: 10/18/2022]
Abstract
Many studies have identified changes in gene expression in brains of schizophrenia patients and their altered molecular processes, but the findings in different datasets were inconsistent and diverse. Here we performed the most comprehensive analysis of gene expression patterns to explore the underlying mechanisms and the potential biomarkers for early diagnosis in schizophrenia. We focused on 10 gene expression datasets in post-mortem human brain samples of schizophrenia downloaded from gene expression omnibus (GEO) database using the integrated bioinformatics analyses including robust rank aggregation (RRA) algorithm, Weighted gene co-expression network analysis (WGCNA) and CIBERSORT. Machine learning algorithm was used to construct the risk prediction model for early diagnosis of schizophrenia. We identified 15 key genes (SLC1A3, AQP4, GJA1, ALDH1L1, SOX9, SLC4A4, EGR1, NOTCH2, PVALB, ID4, ABCG2, METTL7A, ARC, F3 and EMX2) in schizophrenia by performing multiple bioinformatics analysis algorithms. Moreover, the interesting part of the study is that there is a correlation between the expression of hub genes and the immune infiltrating cells estimated by CIBERSORT. Besides, the risk prediction model was constructed by using both these genes and the immune cells with a high accuracy of 0.83 in the training set, and achieved a high AUC of 0.77 for the test set. Our study identified several potential biomarkers for diagnosis of SCZ based on multiple bioinformatics algorithms, and the constructed risk prediction model using these biomarkers achieved high accuracy. The results provide evidence for an improved understanding of the molecular mechanism of schizophrenia.
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Affiliation(s)
- Zhijun Li
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Xinwei Li
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Mengdi Jin
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Yang Liu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Yang He
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Ningning Jia
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Xingyao Cui
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Yane Liu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Guoyan Hu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China
| | - Qiong Yu
- Department of Epidemiology and Biostatistics, School of public health, Jilin University, Changchun, 130021, China.
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26
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Li J, Pinto-Duarte A, Zander M, Cuoco MS, Lai CY, Osteen J, Fang L, Luo C, Lucero JD, Gomez-Castanon R, Nery JR, Silva-Garcia I, Pang Y, Sejnowski TJ, Powell SB, Ecker JR, Mukamel EA, Behrens MM. Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3. eLife 2022; 11:e66909. [PMID: 35604009 PMCID: PMC9170249 DOI: 10.7554/elife.66909] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/22/2022] [Indexed: 11/13/2022] Open
Abstract
Two epigenetic pathways of transcriptional repression, DNA methylation and polycomb repressive complex 2 (PRC2), are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.
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Affiliation(s)
- Junhao Li
- Department of Cognitive Science, University of California, San DiegoLa JollaUnited States
| | - Antonio Pinto-Duarte
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Mark Zander
- Genomic Analysis Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Michael S Cuoco
- Bioinformatics and Systems Biology Graduate Program, University of California, San DiegoLa JollaUnited States
| | - Chi-Yu Lai
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Julia Osteen
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Linjing Fang
- Waitt Advanced Biophotonics Core, Salk Institute for Biological StudiesLa JollaUnited States
| | - Chongyuan Luo
- Genomic Analysis Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
- Howard Hughes Medical Institute, Salk Institute for Biological StudiesLa JollaUnited States
| | - Jacinta D Lucero
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Rosa Gomez-Castanon
- Genomic Analysis Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Joseph R Nery
- Genomic Analysis Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
- Howard Hughes Medical Institute, Salk Institute for Biological StudiesLa JollaUnited States
| | - Isai Silva-Garcia
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Yan Pang
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Terrence J Sejnowski
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Susan B Powell
- Department of Psychiatry, University of California, San DiegoLa JollaUnited States
| | - Joseph R Ecker
- Genomic Analysis Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
| | - Eran A Mukamel
- Department of Cognitive Science, University of California, San DiegoLa JollaUnited States
| | - M Margarita Behrens
- Computational Neurobiology Laboratory, Salk Institute for Biological StudiesLa JollaUnited States
- Department of Psychiatry, University of California, San DiegoLa JollaUnited States
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27
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Bioinformatics and Network-based Approaches for Determining Pathways, Signature Molecules, and Drug Substances connected to Genetic Basis of Schizophrenia etiology. Brain Res 2022; 1785:147889. [PMID: 35339428 DOI: 10.1016/j.brainres.2022.147889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/28/2022] [Accepted: 03/21/2022] [Indexed: 12/12/2022]
Abstract
Knowledge of heterogeneous etiology and pathophysiology of schizophrenia (SZP) is reasonably inadequate and non-deterministic due to its inherent complexity and underlying vast dynamics related to genetic mechanisms. The evolution of large-scale transcriptome-wide datasets and subsequent development of relevant, robust technologies for their analyses show promises toward elucidating the genetic basis of disease pathogenesis, its early risk prediction, and predicting drug molecule targets for therapeutic intervention. In this research, we have scrutinized the genetic basis of SZP through functional annotation and network-based system biology approaches. We have determined 96 overlapping differentially expressed genes (DEGs) from 2 microarray datasets and subsequently identified their interconnecting networks to reveal transcriptome signatures like hub proteins (FYN, RAD51, SOCS3, XIAP, AKAP13, PIK3C2A, CBX5, GATA3, EIF3K, and CDKN2B), transcription factors and miRNAs. In addition, we have employed gene set enrichment to highlight significant gene ontology (e.g., positive regulation of microglial cell activation) and relevant pathways (such as axon guidance and focal adhesion) interconnected to the genes associated with SZP. Finally, we have suggested candidate drug substances like Luteolin HL60 UP as a possible therapeutic target based on these key molecular signatures.
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28
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Sandoval KC, Thackray SE, Wong A, Niewinski N, Chipak C, Rehal S, Dyck RH. Lack of Vesicular Zinc Does Not Affect the Behavioral Phenotype of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation Mice. Front Behav Neurosci 2022; 16:769322. [PMID: 35273483 PMCID: PMC8902171 DOI: 10.3389/fnbeh.2022.769322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/24/2022] [Indexed: 11/13/2022] Open
Abstract
Zinc is important in neural and synaptic development and neuronal transmission. Within the brain, zinc transporter 3 (ZnT3) is essential for zinc uptake into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder (NDD)-like behavior, such as decreased social interaction and increased anxiety- and repetitive-like behavior. Maternal immune activation (MIA) has been identified as an environmental factor for NDDs, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother’s immune system reacts to the exposure to viruses or infectious diseases. In this study, we investigated the interaction effect of a genetic factor [ZnT3 knockout (KO) mice] and an environmental factor (MIA). We induced MIA in pregnant female (dams) mice during mid-gestation, using polyinosinic:polycytidylic acid (polyI:C), which mimics a viral infection. Male and female ZnT3 KO and wild-type (WT) offspring were tested in five behavioral paradigms: Ultrasonic Vocalizations (USVs) at postnatal day 9 (P9), Open Field Test, Marble Burying Test, three-Chamber Social Test, and Pre-pulse Inhibition (PPI) in adulthood (P60–75). Our results indicate that loss of vesicular zinc does not result in enhanced ASD- and SZ-like phenotype compared to WT, nor does it show a more pronounced phenotype in male ZnT3 KO compared to female ZnT3 KO. Finally, MIA offspring demonstrated an ASD- and SZ-like phenotype only in specific behavioral tests: increased calls emitted in USVs and fewer marbles buried. Our results suggest that there is no interaction between the loss of vesicular zinc and MIA induction in the susceptibility to developing an ASD- and SZ-like phenotype.
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Affiliation(s)
- Katy Celina Sandoval
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
| | - Sarah E. Thackray
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
| | - Alison Wong
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
| | - Nicole Niewinski
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
| | - Colten Chipak
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
| | - Suhkjinder Rehal
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
| | - Richard H. Dyck
- Department of Psychology, University of Calgary, Calgary, AB, Canada
- Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, AB, Canada
- Alberta Children’s Hospital Research Institute (ACHRI), University of Calgary, Calgary, AB, Canada
- Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada
- *Correspondence: Richard H. Dyck,
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29
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Sabaie H, Gholipour M, Asadi MR, Abed S, Sharifi-Bonab M, Taheri M, Hussen BM, Brand S, Neishabouri SM, Rezazadeh M. Identification of key long non-coding RNA-associated competing endogenous RNA axes in Brodmann Area 10 brain region of schizophrenia patients. Front Psychiatry 2022; 13:1010977. [PMID: 36405929 PMCID: PMC9671706 DOI: 10.3389/fpsyt.2022.1010977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022] Open
Abstract
Schizophrenia (SCZ) is a serious mental condition with an unknown cause. According to the reports, Brodmann Area 10 (BA10) is linked to the pathology and cortical dysfunction of SCZ, which demonstrates a number of replicated findings related to research on SCZ and the dysfunction in tasks requiring cognitive control in particular. Genetics' role in the pathophysiology of SCZ is still unclear. Therefore, it may be helpful to understand the effects of these changes on the onset and progression of SCZ to find novel mechanisms involved in the regulation of gene transcription. In order to determine the molecular regulatory mechanisms affecting the SCZ, the long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) axes in the BA10 area were determined using a bioinformatics approach in the present work. A microarray dataset (GSE17612) consisted of brain post-mortem tissues of the BA10 area from SCZ patients and matched healthy subjects was downloaded from the Gene Expression Omnibus (GEO) database. This dataset included probes for both lncRNAs and mRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also discovered using the DIANA-LncBase and miRTarBase databases. In the ceRNA network, positive correlations between DEmRNAs and DElncRNAs were evaluated using the Pearson correlation coefficient. Finally, lncRNA-associated ceRNA axes were built by using the co-expression and DElncRNA-miRNA-DEmRNA connections. We identified the DElncRNA-miRNA-DEmRNA axes, which included two key lncRNAs (PEG3-AS1, MIR570HG), seven key miRNAs (hsa-miR-124-3p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-29b-3p), and eight key mRNAs (EGR1, ETV1, DUSP6, PLOD2, CD93, SERPINB9, ANGPTL4, TGFB2). Furthermore, DEmRNAs were found to be enriched in the "AGE-RAGE signaling pathway in diabetic complications", "Amoebiasis", "Transcriptional misregulation in cancer", "Human T-cell leukemia virus 1 infection", and "MAPK signaling pathway". This study offers research targets for examining significant molecular pathways connected to the pathogenesis of SCZ, even though the function of these ceRNA axes still needs to be investigated.
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Affiliation(s)
- Hani Sabaie
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Gholipour
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Asadi
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Samin Abed
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mirmohsen Sharifi-Bonab
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taheri
- Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Institute of Human Genetics, Jena University Hospital, Jena, Germany
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Iraq
| | - Serge Brand
- Center for Affective, Stress and Sleep Disorders, Psychiatric Clinics of the University of Basel, Basel, Switzerland
| | | | - Maryam Rezazadeh
- Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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30
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Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia. Mol Psychiatry 2022; 27:3247-3261. [PMID: 35618883 PMCID: PMC9708553 DOI: 10.1038/s41380-022-01554-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 11/08/2022]
Abstract
Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2-3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF-A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.
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31
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Bernstein HG, Keilhoff G, Laube G, Dobrowolny H, Steiner J. Polyamines and polyamine-metabolizing enzymes in schizophrenia: Current knowledge and concepts of therapy. World J Psychiatry 2021; 11:1177-1190. [PMID: 35070769 PMCID: PMC8717027 DOI: 10.5498/wjp.v11.i12.1177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/30/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Polyamines play preeminent roles in a variety of cellular functions in the central nervous system and other organs. A large body of evidence suggests that the polyamine pathway is prominently involved in the etiology and pathology of schizophrenia. Alterations in the expression and activity of polyamine metabolizing enzymes, as well as changes in the levels of the individual polyamines, their precursors and derivatives, have been measured in schizophrenia and animal models of the disease. Additionally, neuroleptic treatment has been shown to influence polyamine concentrations in brain and blood of individuals with schizophrenia. Thus, the polyamine system may appear to be a promising target for neuropharmacological treatment of schizophrenia. However, for a number of practical reasons there is currently only limited hope for a polyamine-based schizophrenia therapy.
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Affiliation(s)
- Hans-Gert Bernstein
- Department of Psychiatry, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
| | - Gerburg Keilhoff
- Institute of Biochemistry and Cell Biology, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
| | - Gregor Laube
- Department of Anatomy, Charite, Berlin D-10117, Germany
| | - Henrik Dobrowolny
- Department of Psychiatry, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
| | - Johann Steiner
- Department of Psychiatry, University of Magdeburg, Magdeburg D-39116, Saxony-Anhalt, Germany
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32
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Davarinejad O, Najafi S, Zhaleh H, Golmohammadi F, Radmehr F, Alikhani M, Moghadam RH, Rahmati Y. MiR-574-5P, miR-1827, and miR-4429 as Potential Biomarkers for Schizophrenia. J Mol Neurosci 2021; 72:226-238. [PMID: 34811713 DOI: 10.1007/s12031-021-01945-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 11/06/2021] [Indexed: 01/02/2023]
Abstract
Schizophrenia is a severe chronic debilitating disorder with millions of affected individuals. Diagnosis is based on clinical presentations, which are made when the progressive disease has appeared. Early diagnosis may help improve the clinical outcomes and response to treatments. Lack of a reliable molecular diagnostic invokes the identification of novel biomarkers. To elucidate the molecular basis of the disease, in this study we used two mRNA expression arrays, including GSE93987 and GSE38485, and one miRNA array, GSE54914, and meta-analysis was conducted for evaluation of mRNA expression arrays via metaDE package. Using WGCNA package, we performed network analysis for both mRNA expression arrays separately. Then, we constructed protein-protein interaction network for significant modules. Limma package was employed to analyze the miRNA array for identification of dysregulated miRNAs (DEMs). Using genes of significant modules and DEMs, a mRNA-miRNA network was constructed and hub genes and miRNAs were identified. To confirm the dysregulated genes, expression values were evaluated through available datasets including GSE62333, GSE93987, and GSE38485. The ability of the detected hub miRNAs to discriminate schizophrenia from healthy controls was evaluated by assessing the receiver-operating curve. Finally, the expression levels of genes and miRNAs were evaluated in 40 schizophrenia patients compared with healthy controls via Real-Time PCR. The results confirmed dysregulation of hsa-miR-574-5P, hsa-miR-1827, hsa-miR-4429, CREBRF, ARPP19, TGFBR2, and YWHAZ in blood samples of schizophrenia patients. In conclusion, three miRNAs including hsa-miR-574-5P, hsa-miR-1827, and hsa-miR-4429 are suggested as potential biomarkers for diagnosis of schizophrenia.
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Affiliation(s)
- Omran Davarinejad
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Najafi
- Student Research Committee, Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hossein Zhaleh
- Substance Abuse Prevention Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farzaneh Golmohammadi
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farnaz Radmehr
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mostafa Alikhani
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Heidari Moghadam
- Cardiovascular Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Yazdan Rahmati
- Clinical Research Development Center, Imam Khomeini and Mohammad Kermanshahi and Farabi Hospitals, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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33
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Li Q, Wang Z, Zong L, Ye L, Ye J, Ou H, Jiang T, Guo B, Yang Q, Liang W, Zhang J, Long Y, Zheng X, Hou Y, Wu F, Zhou L, Li S, Huang X, Zhao C. Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function. Mol Psychiatry 2021; 26:6630-6642. [PMID: 33963283 DOI: 10.1038/s41380-021-01126-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 04/01/2021] [Accepted: 04/13/2021] [Indexed: 12/26/2022]
Abstract
The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.
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Affiliation(s)
- Qiyang Li
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhongju Wang
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Lu Zong
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Reproductive and Genetic Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Linyan Ye
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Junping Ye
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Haiyan Ou
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China
| | - Tingyun Jiang
- The Third People's Hospital of Zhongshan, Zhongshan, Guangdong, China
| | - Bo Guo
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Yang
- Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China
| | - Wenquan Liang
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Zhang
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China
| | - Yong Long
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China
| | - Xianzhen Zheng
- Guangdong General Hospital, Guangdong Academy of Medical Science and Guangdong Mental Health Center, Guangzhou, China
| | - Yu Hou
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China
| | - Fengchun Wu
- Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China
| | - Lin Zhou
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China
| | - Shufen Li
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China.,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China
| | - Xingbing Huang
- Department of Psychiatry, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong, China
| | - Cunyou Zhao
- Department of Medical Genetics, School of Basic Medical Sciences, and Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, Southern Medical University, Guangzhou, Guangdong, China. .,Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, and Guangdong Province Key Laboratory of Psychiatric Disorders, Southern Medical University, Guangzhou, Guangdong, China.
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34
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Verkerke M, Hol EM, Middeldorp J. Physiological and Pathological Ageing of Astrocytes in the Human Brain. Neurochem Res 2021; 46:2662-2675. [PMID: 33559106 PMCID: PMC8437874 DOI: 10.1007/s11064-021-03256-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/18/2021] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
Ageing is the greatest risk factor for dementia, although physiological ageing by itself does not lead to cognitive decline. In addition to ageing, APOE ε4 is genetically the strongest risk factor for Alzheimer's disease and is highly expressed in astrocytes. There are indications that human astrocytes change with age and upon expression of APOE4. As these glial cells maintain water and ion homeostasis in the brain and regulate neuronal transmission, it is likely that age- and APOE4-related changes in astrocytes have a major impact on brain functioning and play a role in age-related diseases. In this review, we will discuss the molecular and morphological changes of human astrocytes in ageing and the contribution of APOE4. We conclude this review with a discussion on technical issues, innovations, and future perspectives on how to gain more knowledge on astrocytes in the human ageing brain.
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Affiliation(s)
- Marloes Verkerke
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
| | - Elly M Hol
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.
| | - Jinte Middeldorp
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands
- Department of Immunobiology, Biomedical Primate Research Centre (BPRC), P.O. Box 3306, 2280 GH, Rijswijk, The Netherlands
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35
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Snelleksz M, Dean B. Lower levels of tubulin alpha 1b in the frontal pole in schizophrenia supports a role for changed cytoskeletal dynamics in the aetiology of the disorder. Psychiatry Res 2021; 303:114096. [PMID: 34274903 DOI: 10.1016/j.psychres.2021.114096] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/30/2021] [Accepted: 07/03/2021] [Indexed: 11/26/2022]
Abstract
Our transcriptomic study suggested there were markedly lower levels of tubulin alpha 1b (TUBA1B) expression in BA 10, but not BA 9, from patients with schizophrenia. We now use Western blotting to compare levels of TUBA1B protein in BA 9 and 10 from patients with schizophrenia and BA 10 from patients with mood disorders to controls as well as in the frontal cortex from rats after treatment with haloperidol, chlorpromazine or vehicle for 28 days. Levels of TUBA1B were significantly lower (- 18.6%) in BA 10, but not BA 9, from patients with schizophrenia. Levels of TUBA1B did not differ significantly from controls in BA 10 from patients with mood disorders or in the cortex of rats after antipsychotic drug treatments. Levels of TUBA1B were significantly lower (- 30%) in BA 10 from patients with schizophrenia who were not being treated with antipsychotic drugs close to death compared to those who were treated close to death. These data suggest that lower levels of TUBA1B, a cytoskeletal protein, in BA 10 from patients with schizophrenia are not a simple drug effect and therefore add to the hypothesis that a breakdown in cytoskeletal homoeostasis may be contributing to the genesis of the symptoms of the disorder.
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Affiliation(s)
- Megan Snelleksz
- The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia; The Florey Department of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Brian Dean
- The Molecular Psychiatry Laboratory, The Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia; The Florey Department of Neuroscience and Mental Health, Parkville, Victoria, Australia.
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Downregulation by CNNM2 of ATP5MD expression in the 10q24.32 schizophrenia-associated locus involved in impaired ATP production and neurodevelopment. NPJ SCHIZOPHRENIA 2021; 7:27. [PMID: 34021155 PMCID: PMC8139961 DOI: 10.1038/s41537-021-00159-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/21/2021] [Indexed: 12/11/2022]
Abstract
Genome-wide association studies (GWAS) have accelerated the discovery of numerous genetic variants associated with schizophrenia. However, most risk variants show a small effect size (odds ratio (OR) <1.2), suggesting that more functional risk variants remain to be identified. Here, we employed region-based multi-marker analysis of genomic annotation (MAGMA) to identify additional risk loci containing variants with large OR value from Psychiatry Genomics Consortium (PGC2) schizophrenia GWAS data and then employed summary-data-based mendelian randomization (SMR) to prioritize schizophrenia susceptibility genes. The top-ranked susceptibility gene ATP5MD, encoding an ATP synthase membrane subunit, is observed to be downregulated in schizophrenia by the risk allele of CNNM2-rs1926032 in the schizophrenia-associated 10q24.32 locus. The Atp5md knockout (KO) in mice was associated with abnormal startle reflex and gait, and ATP5MD knockdown (KD) in human induced pluripotent stem cell-derived neurons disrupted the neural development and mitochondrial respiration and ATP production. Moreover, CNNM2-rs1926032 KO could induce downregulation of ATP5MD expression and disruptions of mitochondrial respiration and ATP production. This study constitutes an important mechanistic component that links schizophrenia-associated CNNM2 regions to disruption in energy adenosine system modulation and neuronal function by long-distance chromatin domain downregulation of ATP5MD. This pathogenic mechanism provides therapeutic implications for schizophrenia.
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37
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Hertzberg L, Maggio N, Muler I, Yitzhaky A, Majer M, Haroutunian V, Zuk O, Katsel P, Domany E, Weiser M. Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia. Schizophr Bull 2021; 47:785-795. [PMID: 33141894 PMCID: PMC8084431 DOI: 10.1093/schbul/sbaa160] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they have not been identified yet. We performed comprehensive gene expression analysis to search for molecular signals that differentiate schizophrenia patients from healthy controls and examined whether an identified signal was concentrated in a subgroup of the patients. METHODS Transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI) was performed. Differential expression and pathway enrichment analysis results were compared to an independent cohort. Replicability was tested on 6 additional independent datasets. RESULTS The 2 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunit genes in schizophrenia. The signal of proteasome subunits down-regulation was replicated in 6 additional datasets (overall 8 cohorts with 267 schizophrenia and 266 control samples, from 5 brain regions). The signal was concentrated in a subgroup of patients with schizophrenia. CONCLUSIONS We detected global down-regulation of proteasome subunits in a subgroup of patients with schizophrenia. We hypothesize that the down-regulation of proteasome subunits leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins, which has been recently detected in a subgroup of schizophrenia patients. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.
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Affiliation(s)
- Libi Hertzberg
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
- Shalvata Mental Health Center, Affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nicola Maggio
- Department of Neurology, The Chaim Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
- Department of Neurology and Neurosurgery, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Inna Muler
- Childhood Leukemia Research Institute and the Department of Pediatric Hemato-Oncology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
- Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Michael Majer
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Vahram Haroutunian
- Departments of Psychiatry and Neuroscience, The Mount Sinai School of Medicine, New York, NY
- Department of Psychiatry, James J Peters VA Medical Center, Bronx, NY
| | - Or Zuk
- Department of Statistics, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Pavel Katsel
- Departments of Psychiatry and Neuroscience, The Mount Sinai School of Medicine, New York, NY
| | - Eytan Domany
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel
| | - Mark Weiser
- Department of Psychiatry, Chaim Sheba Medical Center, Ramat-Gan and the Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
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Yu H, Guo Y, Chen J, Chen X, Jia P, Zhao Z. Rewired Pathways and Disrupted Pathway Crosstalk in Schizophrenia Transcriptomes by Multiple Differential Coexpression Methods. Genes (Basel) 2021; 12:665. [PMID: 33946654 PMCID: PMC8146818 DOI: 10.3390/genes12050665] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/16/2021] [Accepted: 04/27/2021] [Indexed: 02/03/2023] Open
Abstract
Transcriptomic studies of mental disorders using the human brain tissues have been limited, and gene expression signatures in schizophrenia (SCZ) remain elusive. In this study, we applied three differential co-expression methods to analyze five transcriptomic datasets (three RNA-Seq and two microarray datasets) derived from SCZ and matched normal postmortem brain samples. We aimed to uncover biological pathways where internal correlation structure was rewired or inter-coordination was disrupted in SCZ. In total, we identified 60 rewired pathways, many of which were related to neurotransmitter, synapse, immune, and cell adhesion. We found the hub genes, which were on the center of rewired pathways, were highly mutually consistent among the five datasets. The combinatory list of 92 hub genes was generally multi-functional, suggesting their complex and dynamic roles in SCZ pathophysiology. In our constructed pathway crosstalk network, we found "Clostridium neurotoxicity" and "signaling events mediated by focal adhesion kinase" had the highest interactions. We further identified disconnected gene links underlying the disrupted pathway crosstalk. Among them, four gene pairs (PAK1:SYT1, PAK1:RFC5, DCTN1:STX1A, and GRIA1:MAP2K4) were normally correlated in universal contexts. In summary, we systematically identified rewired pathways, disrupted pathway crosstalk circuits, and critical genes and gene links in schizophrenia transcriptomes.
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Affiliation(s)
- Hui Yu
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA; (H.Y.); (Y.G.)
| | - Yan Guo
- Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA; (H.Y.); (Y.G.)
| | - Jingchun Chen
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV 89154, USA; (J.C.); (X.C.)
| | - Xiangning Chen
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV 89154, USA; (J.C.); (X.C.)
| | - Peilin Jia
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Zhongming Zhao
- Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
- Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37203, USA
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Pathak GA, Wendt FR, Levey DF, Mecca AP, van Dyck CH, Gelernter J, Polimanti R. Pleiotropic effects of telomere length loci with brain morphology and brain tissue expression. Hum Mol Genet 2021; 30:1360-1370. [PMID: 33831179 PMCID: PMC8255129 DOI: 10.1093/hmg/ddab102] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/09/2021] [Accepted: 03/29/2021] [Indexed: 12/21/2022] Open
Abstract
Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10-6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10-7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B-show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug-gene interactions, we identified process 'transmission across chemical synapses' (P < 2.78 × 10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.
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Affiliation(s)
- Gita A Pathak
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06551, USA,Veteran Affairs Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Frank R Wendt
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06551, USA,Veteran Affairs Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Daniel F Levey
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06551, USA,Veteran Affairs Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Adam P Mecca
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06551, USA,Alzheimer’s Disease Research Unit, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Christopher H van Dyck
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06551, USA,Alzheimer’s Disease Research Unit, Yale University School of Medicine, New Haven, CT 06511, USA,Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA,Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, USA
| | - Joel Gelernter
- Department of Psychiatry, Yale School of Medicine, Yale University, New Haven, CT 06551, USA,Veteran Affairs Connecticut Healthcare System, West Haven, CT 06516, USA
| | - Renato Polimanti
- To whom correspondence should be addressed at: VA CT 116A2, 950 Campbell Avenue, West Haven, CT 06516, USA. Tel: +1 2039375711 ext. 5745; Fax: +1 2039373897;
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Dai J, Chen Y, Dai R, Jiang Y, Tian J, Liu S, Xu M, Li M, Zhou J, Liu C, Chen C. Agonal Factors Distort Gene-Expression Patterns in Human Postmortem Brains. Front Neurosci 2021; 15:614142. [PMID: 33841074 PMCID: PMC8027124 DOI: 10.3389/fnins.2021.614142] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 02/16/2021] [Indexed: 01/01/2023] Open
Abstract
Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Our study used gene expression data of 262 samples from ROSMAP with the detailed terminal state recorded for each donor, such as fever, infection, and unconsciousness. Fever and infection were the primary contributors to brain gene expression changes, brain cell-type-specific gene expression, and cell proportion changes. Furthermore, we also found that previous studies of gene expression in postmortem brains were confounded by agonal factors. Therefore, correction for agonal factors is important in the step of data preprocessing. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.
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Affiliation(s)
- Jiacheng Dai
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, and School of Life Sciences, Fudan University, Shanghai, China
| | - Yu Chen
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Rujia Dai
- Upstate Medical University, Syracuse, NY, United States
| | - Yi Jiang
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jianghua Tian
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Sihan Liu
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Meng Xu
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Miao Li
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiaqi Zhou
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chunyu Liu
- Department of Psychiatry, Upstate Medical University, Syracuse, NY, United States
| | - Chao Chen
- Center for Medical Genetics, Department of Psychiatry, School of Life Sciences, National Clinical Research Center on Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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Probing Synaptic Signaling with Optogenetic Stimulation and Genetically Encoded Calcium Reporters. Methods Mol Biol 2021. [PMID: 32865742 DOI: 10.1007/978-1-0716-0830-2_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2023]
Abstract
Optogenetics provides a powerful approach for investigating neuronal electrophysiology at the scale required for drug discovery applications. Probing synaptic function with high throughput using optogenetics requires robust tools that enable both precise stimulation of and facile readout of synaptic activity. Here we describe two functional assays to achieve this end: (1) a pre-synaptic calcium assay that utilizes the channelrhodopsin, CheRiff, patterned optogenetic stimulus, and the pre-synaptically targeted calcium reporter jRGECO1a to monitor pre-synaptic changes in calcium influx and (2) a synaptic transmission assay in which CheRiff and cytosolic jRGECO1a are expressed in non-overlapping sets of neurons, enabling pre-synaptic stimulation and post-synaptic readout of activity. This chapter describes the methodology and practical considerations for implementation of these two assays.
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Liu L, Zhao J, Chen Y, Feng R. Metabolomics strategy assisted by transcriptomics analysis to identify biomarkers associated with schizophrenia. Anal Chim Acta 2020; 1140:18-29. [PMID: 33218480 DOI: 10.1016/j.aca.2020.09.054] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/16/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Metabolomics strategy was perform to identify the novel serum biomarkers linked to schizophrenia with the assistance of transcriptomics analysis. METHODS Two analytical platforms, UPLC-Q-TOF MS/MS and 1H NMR, were used to acquire the serum fingerprinting profiles from a total of 112 participants (57 healthy controls and 55 schizophrenia patients). The differential metabolites were primarily selected after statistical analyses. Meanwhile, GSE17612 dataset downloaded from GEO database was implemented WGCNA analysis to discover crucial genes and corresponding biological processes. Based on metabolomics analysis, the metabolic distinctions were explored under the aid of transcriptomics. Then using Boruta algorithm identified the biomarkers, and LASSO regression analysis and Random Forest algorithm were used to evaluate the performance of the diagnostic model constructed by biomarkers selected. RESULTS A total of four metabolites (α-CEHC, neuraminic acid, glyceraldehyde and asparagine) were selected as the biomarkers to establish diagnosis model. The performance of this model showed a higher accuracy rate to distinguish schizophrenia patients from healthy controls (area under the receive operating characteristic curve, 0.992; precision recall curve, 1.000, the mean accuracy of random forest algorithm, 95.00%). CONCLUSIONS A four-biomarker model (α-CEHC, neuraminic acid, glyceraldehyde and asparagine) seems to be a good model for diagnosing schizophrenia patients. It might be helpful to guide the future studies on permitting early intervention designed to prevent disease progression.
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Affiliation(s)
- Liyan Liu
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Jinhui Zhao
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Yang Chen
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China
| | - Rennan Feng
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, Harbin, PR China.
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Maas DA, Martens MB, Priovoulos N, Zuure WA, Homberg JR, Nait-Oumesmar B, Martens GJM. Key role for lipids in cognitive symptoms of schizophrenia. Transl Psychiatry 2020; 10:399. [PMID: 33184259 PMCID: PMC7665187 DOI: 10.1038/s41398-020-01084-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 10/02/2020] [Accepted: 10/26/2020] [Indexed: 12/19/2022] Open
Abstract
Schizophrenia (SZ) is a psychiatric disorder with a convoluted etiology that includes cognitive symptoms, which arise from among others a dysfunctional dorsolateral prefrontal cortex (dlPFC). In our search for the molecular underpinnings of the cognitive deficits in SZ, we here performed RNA sequencing of gray matter from the dlPFC of SZ patients and controls. We found that the differentially expressed RNAs were enriched for mRNAs involved in the Liver X Receptor/Retinoid X Receptor (LXR/RXR) lipid metabolism pathway. Components of the LXR/RXR pathway were upregulated in gray matter but not in white matter of SZ dlPFC. Intriguingly, an analysis for shared genetic etiology, using two SZ genome-wide association studies (GWASs) and GWAS data for 514 metabolites, revealed genetic overlap between SZ and acylcarnitines, VLDL lipids, and fatty acid metabolites, which are all linked to the LXR/RXR signaling pathway. Furthermore, analysis of structural T1-weighted magnetic resonance imaging in combination with cognitive behavioral data showed that the lipid content of dlPFC gray matter is lower in SZ patients than in controls and correlates with a tendency towards reduced accuracy in the dlPFC-dependent task-switching test. We conclude that aberrations in LXR/RXR-regulated lipid metabolism lead to a decreased lipid content in SZ dlPFC that correlates with reduced cognitive performance.
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Affiliation(s)
- Dorien A. Maas
- grid.5590.90000000122931605Faculty of Science, Centre for Neuroscience, Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Geert Grooteplein Zuid 26-28, 6525 GA Nijmegen, The Netherlands ,Sorbonne Université, Paris Brain Institute – ICM, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, France ,Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands
| | - Marijn B. Martens
- NeuroDrug Research Ltd, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
| | - Nikos Priovoulos
- grid.458380.20000 0004 0368 8664Spinoza Centre for Neuroimaging, Meibergdreef 75, Amsterdam-Zuidoost, 1105 BK Amsterdam, The Netherlands
| | - Wieteke A. Zuure
- grid.5590.90000000122931605Faculty of Science, Centre for Neuroscience, Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Geert Grooteplein Zuid 26-28, 6525 GA Nijmegen, The Netherlands
| | - Judith R. Homberg
- Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Donders Centre for Medical Neuroscience, Radboud University Medical Center, Kapittelweg 29, 6525 EN Nijmegen, The Netherlands
| | - Brahim Nait-Oumesmar
- Sorbonne Université, Paris Brain Institute – ICM, Inserm U1127, CNRS UMR 7225, Hôpital Pitié-Salpêtrière, Paris, France
| | - Gerard J. M. Martens
- grid.5590.90000000122931605Faculty of Science, Centre for Neuroscience, Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Geert Grooteplein Zuid 26-28, 6525 GA Nijmegen, The Netherlands ,NeuroDrug Research Ltd, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
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Widespread transcriptional disruption of the microRNA biogenesis machinery in brain and peripheral tissues of individuals with schizophrenia. Transl Psychiatry 2020; 10:376. [PMID: 33149139 PMCID: PMC7642431 DOI: 10.1038/s41398-020-01052-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 09/16/2020] [Accepted: 10/01/2020] [Indexed: 12/17/2022] Open
Abstract
In schizophrenia, altered transcription in brain and peripheral tissues may be due to altered expression of the microRNA biogenesis machinery genes. In this study, we explore the expression of these genes both at the cerebral and peripheral levels. We used shinyGEO application to analyze gene expression from ten Gene Expression Omnibus datasets, in order to perform differential expression analyses for eight genes encoding the microRNA biogenesis machinery. First, we compared expression of the candidate genes between control subjects and individuals with schizophrenia in postmortem cerebral samples from seven different brain regions. Then, we compared the expression of the candidate genes between control subjects and individuals with schizophrenia in three peripheral tissues. In brain and peripheral tissues of individuals with schizophrenia, we report distinct altered expression patterns of the microRNA biogenesis machinery genes. In the dorsolateral prefrontal cortex, associative striatum and cerebellum of individuals with schizophrenia, we observed an overexpression pattern of some candidate genes suggesting a heightened miRNA production in these brain regions. Additionally, mixed transcriptional abnormalities were identified in the hippocampus. Moreover, in the blood and olfactory epithelium of individuals with schizophrenia, we observed distinct aberrant transcription patterns of the candidate genes. Remarkably, in individuals with schizophrenia, we report DICER1 overexpression in the dorsolateral prefrontal cortex, hippocampus and cerebellum as well as a congruent DICER1 upregulation in the blood compartment suggesting that it may represent a peripheral marker. Transcriptional disruption of the miRNA biogenesis machinery may contribute to schizophrenia pathogenesis both in brain and peripheral tissues.
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Rey R, Suaud-Chagny MF, Bohec AL, Dorey JM, d'Amato T, Tamouza R, Leboyer M. Overexpression of complement component C4 in the dorsolateral prefrontal cortex, parietal cortex, superior temporal gyrus and associative striatum of patients with schizophrenia. Brain Behav Immun 2020; 90:216-225. [PMID: 32827700 DOI: 10.1016/j.bbi.2020.08.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 08/10/2020] [Accepted: 08/17/2020] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND In schizophrenia, abnormal synaptic pruning during adolescence may be due to altered expression of the Complement component 4 (C4). Overexpression of C4 genes has been identified in the total cerebral cortex and in 6 different brain regions of schizophrenic patients compared to controls. These alterations should be replicated and extended to other brain regions relevant to schizophrenia. Moreover, it remains unknown whether cerebral and peripheral C4 expression levels are related. METHODS We explored C4 genes expression both at the cerebral and peripheral levels. Using shinyGEO application we analyzed C4 expression from eight Gene Expression Omnibus datasets obtained from 196 schizophrenic patients and 182 control subjects. First, we compared C4 expression between schizophrenic patients and controls in postmortem cerebral samples from 7 different brain regions. Then, we compared C4 expression between schizophrenic patients and controls in 4 peripheral tissues. RESULTS At the cerebral level, we provide further evidence of C4 overexpression in schizophrenic patients. Consistently with a previous report, we found C4 overexpression in the dorsolateral prefrontal cortex and in the parietal cortex of schizophrenic patients. The observation of C4 overexpression was further extended to the superior temporal cortex and the associative striatum of schizophrenic patients. Conversely, no significant alteration of C4 expression was observed in peripheral tissues. CONCLUSIONS Our results support the hypothesis of an excessive Complement activity in various brain regions of schizophrenic patients which may disrupt the synaptic pruning process occurring during adolescence. C4 overexpression may be specific to the cerebral tissue while other alterations of the Complement system may be detected at the systemic level.
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Affiliation(s)
- Romain Rey
- INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Psychiatric Disorders: from Resistance to Response Team, Lyon F-69000, France; University Lyon 1, Villeurbanne F-69000, France; Schizophrenia Expert Centre, Le Vinatier Hospital, Bron, France; Fondation FondaMental, Créteil, France.
| | - Marie-Françoise Suaud-Chagny
- INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Psychiatric Disorders: from Resistance to Response Team, Lyon F-69000, France; University Lyon 1, Villeurbanne F-69000, France
| | - Anne-Lise Bohec
- INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Psychiatric Disorders: from Resistance to Response Team, Lyon F-69000, France; University Lyon 1, Villeurbanne F-69000, France; Schizophrenia Expert Centre, Le Vinatier Hospital, Bron, France; Fondation FondaMental, Créteil, France
| | - Jean-Michel Dorey
- University Lyon 1, Villeurbanne F-69000, France; Department of Old Age Psychiatry, Le Vinatier Hospital, Bron, France
| | - Thierry d'Amato
- INSERM, U1028, CNRS, UMR5292, Lyon Neuroscience Research Center, Psychiatric Disorders: from Resistance to Response Team, Lyon F-69000, France; University Lyon 1, Villeurbanne F-69000, France; Schizophrenia Expert Centre, Le Vinatier Hospital, Bron, France; Fondation FondaMental, Créteil, France
| | - Ryad Tamouza
- Fondation FondaMental, Créteil, France; Department of Psychiatry and Addictology, Mondor University Hospital, AP-HP, DMU IMPACT, France; University Paris-Est-Créteil, UPEC, Créteil, France; Inserm U955, Mondor Institute for Biomedical Research, IMRB, Translational Neuropsychiatry Team, Créteil, France
| | - Marion Leboyer
- Fondation FondaMental, Créteil, France; Department of Psychiatry and Addictology, Mondor University Hospital, AP-HP, DMU IMPACT, France; University Paris-Est-Créteil, UPEC, Créteil, France; Inserm U955, Mondor Institute for Biomedical Research, IMRB, Translational Neuropsychiatry Team, Créteil, France
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Zaharija B, Samardžija B, Bradshaw NJ. The TRIOBP Isoforms and Their Distinct Roles in Actin Stabilization, Deafness, Mental Illness, and Cancer. Molecules 2020; 25:molecules25214967. [PMID: 33121024 PMCID: PMC7663296 DOI: 10.3390/molecules25214967] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 10/22/2020] [Accepted: 10/26/2020] [Indexed: 12/16/2022] Open
Abstract
The TRIOBP (TRIO and F-actin Binding Protein) gene encodes multiple proteins, which together play crucial roles in modulating the assembly of the actin cytoskeleton. Splicing of the TRIOBP gene is complex, with the two most studied TRIOBP protein isoforms sharing no overlapping amino acid sequence with each other. TRIOBP-1 (also known as TARA or TAP68) is a mainly structured protein that is ubiquitously expressed and binds to F-actin, preventing its depolymerization. It has been shown to be important for many processes including in the cell cycle, adhesion junctions, and neuronal differentiation. TRIOBP-1 has been implicated in schizophrenia through the formation of protein aggregates in the brain. In contrast, TRIOBP-4 is an entirely disordered protein with a highly specialized expression pattern. It is known to be crucial for the bundling of actin in the stereocilia of the inner ear, with mutations in it causing severe or profound hearing loss. Both of these isoforms are implicated in cancer. Additional longer isoforms of TRIOBP exist, which overlap with both TRIOBP-1 and 4. These appear to participate in the functions of both shorter isoforms, while also possessing unique functions in the inner ear. In this review, the structures and functions of all of these isoforms are discussed, with a view to understanding how they operate, both alone and in combination, to modulate actin and their consequences for human illness.
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Ohayon S, Yitzhaky A, Hertzberg L. Gene expression meta-analysis reveals the up-regulation of CREB1 and CREBBP in Brodmann Area 10 of patients with schizophrenia. Psychiatry Res 2020; 292:113311. [PMID: 32712449 DOI: 10.1016/j.psychres.2020.113311] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 01/26/2023]
Abstract
Cognitive impairments characterize individuals with schizophrenia, and are correlated to the patients' functional outcome. The transcription factor Cyclic AMP-responsive element-binding protein-1 (CREB1) is involved in learning and memory processes. CREB1 and both CREB-binding protein (CREBBP) and E1A Binding Protein P300 (EP300), co-activators of CREB1, have been associated with schizophrenia. We performed a systematic meta-analysis of CREB1, CREBBP and EP300 differential expression in post mortem Brodmann Area 10 (BA10) samples of patients with schizophrenia vs. healthy controls, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Two microarray datasets met the inclusion criteria (overall 41 schizophrenia samples and 38 controls were analyzed). We detect up-regulation of CREB1 and CREBBP in BA10 samples of patients with schizophrenia, while EP300 wasn't differentially expressed. The integration of two independent datasets and the positive correlation between the expression patterns of CREB1 and CREBBP increase the validity of the results. The up-regulation of CREB1 and its co-activator CREBBP might relate to BA10 altered activation that has been shown in schizophrenia. As BA10 was shown to be involved in the cognitive impairments associated with schizophrenia, this suggests involvement of CREB1 and CREBBP in the cognitive symptoms that characterize the disease.
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Affiliation(s)
- Shay Ohayon
- Department of Psychology, Bar-Ilan University, Ramat-Gan, Israel
| | - Assif Yitzhaky
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
| | - Libi Hertzberg
- Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; Shalvata Mental Health Center, affiliated with the Sackler School of Medicine, Tel-Aviv University, 13 Aliat Hanoar St. Hod Hasharon 45100, Israel.
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Moolamalla STR, Vinod PK. Genome-scale metabolic modelling predicts biomarkers and therapeutic targets for neuropsychiatric disorders. Comput Biol Med 2020; 125:103994. [PMID: 32980779 DOI: 10.1016/j.compbiomed.2020.103994] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/06/2020] [Accepted: 09/07/2020] [Indexed: 01/06/2023]
Abstract
Distinguishing neuropsychiatric disorders is challenging due to the overlap in symptoms and genetic risk factors. People suffering from these disorders face personal and professional challenges. Understanding the dysregulation of brain metabolism under disease condition can aid in effective diagnosis and in developing treatment strategies based on the metabolism. In this study, we reconstructed the metabolic network of three major neuropsychiatric disorders, schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) using transcriptomic data and constrained based modelling approach. We integrated brain transcriptomic data from six independent studies with a recent comprehensive genome-scale metabolic model Recon3D. The analysis of the reconstructed network revealed the flux-level alterations in the peroxisome-mitochondria-golgi axis in neuropsychiatric disorders. We also extracted reporter metabolites and pathways that distinguish these three neuropsychiatric disorders. We found differences with respect to fatty acid oxidation, aromatic and branched chain amino acid metabolism, bile acid synthesis, glycosaminoglycans synthesis and modifications, and phospholipid metabolism. Further, we predicted network perturbations that transform the disease metabolic state to a healthy metabolic state for each disorder. These analyses provide local and global views of the metabolic changes in SCZ, BD and MDD, which may have clinical implications.
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Affiliation(s)
- S T R Moolamalla
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, 500032, India
| | - P K Vinod
- Center for Computational Natural Sciences and Bioinformatics, International Institute of Information Technology, Hyderabad, 500032, India.
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Karunakaran KB, Chaparala S, Lo CW, Ganapathiraju MK. Cilia interactome with predicted protein-protein interactions reveals connections to Alzheimer's disease, aging and other neuropsychiatric processes. Sci Rep 2020; 10:15629. [PMID: 32973177 PMCID: PMC7515907 DOI: 10.1038/s41598-020-72024-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Cilia are dynamic microtubule-based organelles present on the surface of many eukaryotic cell types and can be motile or non-motile primary cilia. Cilia defects underlie a growing list of human disorders, collectively called ciliopathies, with overlapping phenotypes such as developmental delays and cognitive and memory deficits. Consistent with this, cilia play an important role in brain development, particularly in neurogenesis and neuronal migration. These findings suggest that a deeper systems-level understanding of how ciliary proteins function together may provide new mechanistic insights into the molecular etiologies of nervous system defects. Towards this end, we performed a protein-protein interaction (PPI) network analysis of known intraflagellar transport, BBSome, transition zone, ciliary membrane and motile cilia proteins. Known PPIs of ciliary proteins were assembled from online databases. Novel PPIs were predicted for each ciliary protein using a computational method we developed, called High-precision PPI Prediction (HiPPIP) model. The resulting cilia "interactome" consists of 165 ciliary proteins, 1,011 known PPIs, and 765 novel PPIs. The cilia interactome revealed interconnections between ciliary proteins, and their relation to several pathways related to neuropsychiatric processes, and to drug targets. Approximately 184 genes in the cilia interactome are targeted by 548 currently approved drugs, of which 103 are used to treat various diseases of nervous system origin. Taken together, the cilia interactome presented here provides novel insights into the relationship between ciliary protein dysfunction and neuropsychiatric disorders, for e.g. interconnections of Alzheimer's disease, aging and cilia genes. These results provide the framework for the rational design of new therapeutic agents for treatment of ciliopathies and neuropsychiatric disorders.
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Affiliation(s)
- Kalyani B Karunakaran
- Supercomputer Education and Research Centre, Indian Institute of Science, Bangalore, India
| | - Srilakshmi Chaparala
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
- Health Sciences Library System, University of Pittsburgh, Pittsburgh, PA, USA
| | - Cecilia W Lo
- Department of Developmental Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Madhavi K Ganapathiraju
- Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA.
- Intelligent Systems Program, School of Computing and Information, University of Pittsburgh, Pittsburgh, PA, USA.
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Troudet R, Ali WBH, Bacq-Daian D, Rossum IWV, Boland-Auge A, Battail C, Barau C, Rujescu D, McGuire P, Kahn RS, Deleuze JF, Leboyer M, Jamain S. Gene expression and response prediction to amisulpride in the OPTiMiSE first episode psychoses. Neuropsychopharmacology 2020; 45:1637-1644. [PMID: 32450569 PMCID: PMC7421408 DOI: 10.1038/s41386-020-0703-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/26/2020] [Accepted: 04/29/2020] [Indexed: 01/22/2023]
Abstract
A fundamental shortcoming in the current treatment of schizophrenia is the lack of valid criteria to predict who will respond to antipsychotic treatment. The identification of blood-based biological markers of the therapeutic response would enable clinicians to identify the subgroup of patients in whom conventional antipsychotic treatment is ineffective and offer alternative treatments. As part of the Optimisation of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) programme, we conducted an RNA-Seq analysis on 188 subjects with first episode psychosis, all of whom were subsequently treated with amisulpride for 4 weeks. We compared gene expression on total RNA from patients' blood before and after treatment and identified 32 genes for which the expression changed after treatment in good responders only. These findings were replicated in an independent sample of 24 patients with first episode psychosis. Six genes showed a significant difference in expression level between good and poor responders before starting treatment, allowing to predict treatment outcome with a predictive value of 93.8% when combined with clinical features. Collectively, these findings identified new mechanisms to explain symptom improvement after amisulpride medication and highlight the potential of combining gene expression profiling with clinical data to predict treatment response in first episode psychoses.
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Affiliation(s)
- Réjane Troudet
- Inserm U955, Psychiatrie Translationnelle, Créteil, France
- Université Paris Est, Faculté de Médecine, Créteil, France
- Fondation FondaMental, Créteil, France
| | - Wafa Bel Haj Ali
- Inserm U955, Psychiatrie Translationnelle, Créteil, France
- Université Paris Est, Faculté de Médecine, Créteil, France
- Fondation FondaMental, Créteil, France
| | - Delphine Bacq-Daian
- Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France
| | | | - Anne Boland-Auge
- Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France
| | - Christophe Battail
- Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France
| | - Caroline Barau
- AP-HP, Hôpital H. Mondor-A. Chenevier, Plateforme de Ressources Biologiques, Créteil, France
| | - Dan Rujescu
- Department of Psychiatry, University Hospital Halle, Halle, Germany
| | - Philip McGuire
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - René S Kahn
- Department of Psychiatry, Brain Center Rudolf Magnus, Utrecht, Netherlands
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-François Deleuze
- Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Université Paris-Saclay, Evry, France
| | - Marion Leboyer
- Inserm U955, Psychiatrie Translationnelle, Créteil, France
- Université Paris Est, Faculté de Médecine, Créteil, France
- Fondation FondaMental, Créteil, France
- AP-HP, DHU Pe-PSY, Pôle de psychiatrie et d'addictologie des Hôpitaux Universitaires Henri Mondor, Créteil, France
| | - Stéphane Jamain
- Inserm U955, Psychiatrie Translationnelle, Créteil, France.
- Université Paris Est, Faculté de Médecine, Créteil, France.
- Fondation FondaMental, Créteil, France.
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