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Chen X, Lu Y, Cue JM, Han MV, Nimgaonkar VL, Weinberger DR, Han S, Zhao Z, Chen J. Classification of schizophrenia, bipolar disorder and major depressive disorder with comorbid traits and deep learning algorithms. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2025; 11:14. [PMID: 39910091 PMCID: PMC11799204 DOI: 10.1038/s41537-025-00564-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 01/17/2025] [Indexed: 02/07/2025]
Abstract
Many psychiatric disorders share genetic liabilities, but whether these shared liabilities can be utilized to classify and differentiate psychiatric disorders remains unclear. In this study, we use polygenic risk scores (PRSs) of 42 traits comorbid with schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) to evaluate their utilities. We found that combining target specific PRS with PRSs of comorbid traits can improve the classification of the target disorders. Importantly, without inclusion of PRSs from targeted disorders, we can still classify SCZ (accuracy 0.710 ± 0.008, AUC 0.789 ± 0.011), BIP (accuracy 0.782 ± 0.006, AUC 0.852 ± 0.004), and MDD (accuracy 0.753 ± 0.019, AUC 0.822 ± 0.010). Furthermore, PRSs from comorbid traits alone can effectively differentiate unaffected controls and patients with SCZ, BIP, and MDD (accuracy 0.861 ± 0.003, AUC 0.961 ± 0.041). Our results demonstrate that shared liabilities can be used effectively to improve the classification and differentiation of these disorders. The finding that PRSs from comorbid traits alone can classify and differentiate SCZ, BIP and MDD reasonably well implies that a majority of the risk variants composing target PRSs are shared with comorbid traits. Overall, our results suggest that a data-driven approach may be feasible to classify and differentiate these disorders.
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Affiliation(s)
- Xiangning Chen
- Center for Precision Medicine, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
- Department of Bioinformatics and Systems Medicine, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houton, Houston, Texas, USA.
| | - Yimei Lu
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Joan Manuel Cue
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV, USA
| | - Mira V Han
- School of Life Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA
| | | | - Daniel R Weinberger
- Lieber Institute for Brain Development, Baltimore, MD, USA
- Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Shizhong Han
- Lieber Institute for Brain Development, Baltimore, MD, USA
- Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Zhongming Zhao
- Center for Precision Medicine, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, Texas, USA.
- Department of Bioinformatics and Systems Medicine, McWilliams School of Biomedical Informatics, University of Texas Health Science Center at Houton, Houston, Texas, USA.
| | - Jingchun Chen
- Nevada Institute of Personalized Medicine, University of Nevada Las Vegas, Las Vegas, NV, USA.
- School of Life Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
- Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas (UNLV), Las Vegas, NV, USA.
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Mundorf A, Freund N. Effects of Early Stress Exposure on Anxiety-like Behavior and MORC1 Expression in Rats. Biomolecules 2024; 14:1587. [PMID: 39766294 PMCID: PMC11674774 DOI: 10.3390/biom14121587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 12/06/2024] [Accepted: 12/10/2024] [Indexed: 01/11/2025] Open
Abstract
Exposure to stress during early and late childhood can lead to long-lasting neurobiological and behavioral impairments. Although sensitive periods for stress exposure are well established, less is known about the trajectory of induced alterations throughout development. In this study, we investigated the impact of maternal separation (MS), social isolation, and their combination on anxiety-like behavior and gene expression across developmental stages. Sprague Dawley rats were exposed to one or both stressors and later assessed for anxiety-like behavior in juvenility, adolescence, and adulthood. mRNA levels of Morc1, a gene linked to early-life stress and depression, were measured in the medial prefrontal cortex to assess developmental changes. The results showed that MS had age- and sex-dependent effects on anxiety-like behavior. Juveniles exhibited less anxiety after MS, while adolescents showed more pronounced behavioral changes following social isolation. No behavioral changes were observed in adults. Males exhibited greater anxiety-like behavior than females in adolescence and adulthood, but not in juvenility. Female adults exposed to both MS and social isolation had significantly lower Morc1 expression compared to controls. These findings highlight the dynamic effects of early stress across the lifespan, underscoring the critical role of adolescence and differential stress susceptibility by age and sex.
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Affiliation(s)
- Annakarina Mundorf
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, 44801 Bochum, Germany
- Institute for Systems Medicine and Department of Human Medicine, MSH Medical School, 20457 Hamburg, Germany
| | - Nadja Freund
- Division of Experimental and Molecular Psychiatry, Department of Psychiatry, Psychotherapy and Preventive Medicine, LWL University Hospital, Ruhr University Bochum, 44801 Bochum, Germany
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Zarazúa-Guzmán S, Vicente-Martínez JG, Pinos-Rodríguez JM, Arevalo-Villalobos JI. An overview of major depression disorder: The endocannabinoid system as a potential target for therapy. Basic Clin Pharmacol Toxicol 2024; 135:669-684. [PMID: 39370369 DOI: 10.1111/bcpt.14089] [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: 03/29/2024] [Revised: 09/07/2024] [Accepted: 09/15/2024] [Indexed: 10/08/2024]
Abstract
Major depressive disorder is the psychiatric disease with the highest global prevalence, impacting social functioning and decreasing the quality of life. The partial pathophysiological knowledge of the disease, the economic burden and the low remission rates are sufficient justification to carry out an update on the subject in the search for new therapeutic approaches and targets. The endocannabinoid system has been linked to the development of depression, and its stimulation or antagonism is a promising approach in the treatment of major depressive disorder. Cannabidiol (CBD) and its properties have been widely studied recently; its analgesic, anti-inflammatory, antineoplastic and neuroprotective roles have even been reported in animal models and clinical trials, achieving its approved use for certain neurodegenerative pathologies. The use of CBD in depression biomodels and clinical trials has not been the exception, and here we contrast the current evidence of its administration and pharmacology against the pathological mechanisms of major depressive disorder.
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Affiliation(s)
- Sergio Zarazúa-Guzmán
- Laboratorio de Neurotoxicología, Facultad de Ciencias Químicas, Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico
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Cipriano L, Piscopo R, Aiello C, Novelli A, Iolascon A, Piscopo C. Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation. CHILDREN (BASEL, SWITZERLAND) 2024; 11:541. [PMID: 38790536 PMCID: PMC11119747 DOI: 10.3390/children11050541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 04/23/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024]
Abstract
Background: CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and Results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children's neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.
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Affiliation(s)
- Lorenzo Cipriano
- Department of Molecular Medicine and Medical Biotechnology, University Federico II, 80131 Naples, Italy; (L.C.); (A.I.)
| | - Raffaele Piscopo
- Department of Neuroscience, Reproductive and Odontostomatological Sciences, University Federico II, 80131 Naples, Italy;
| | - Chiara Aiello
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, 00146 Rome, Italy; (C.A.); (A.N.)
| | - Antonio Novelli
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, 00146 Rome, Italy; (C.A.); (A.N.)
| | - Achille Iolascon
- Department of Molecular Medicine and Medical Biotechnology, University Federico II, 80131 Naples, Italy; (L.C.); (A.I.)
| | - Carmelo Piscopo
- Medical and Laboratory Genetics Unit, A.O.R.N. “Antonio Cardarelli”, 80131 Naples, Italy
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Voorhies K, Hecker J, Lee S, Hahn G, Prokopenko D, McDonald ML, Wu AC, Wu A, Hokanson JE, Cho MH, Lange C, Hoth KF, Lutz SM. Examining the Effect of Genes on Depression as Mediated by Smoking and Modified by Sex. Genes (Basel) 2024; 15:565. [PMID: 38790194 PMCID: PMC11120779 DOI: 10.3390/genes15050565] [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: 03/18/2024] [Revised: 04/20/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted for age, sex, current smoking status, genetic ancestry (via principal components), income, education, and living status (urban vs. rural). In addition, we examined sex-stratified mediation models and sex-moderated mediation models. For both analyses, we adjusted for age, current smoking status, and genetic ancestry (via principal components). In the UK Biobank, rs6424532 [LOC105378800] had a statistically significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 4.0 × 10-4) among all participants and a marginally significant indirect effect among females (p = 0.02) and males (p = 4.0 × 10-3). Moreover, rs10501696 [GRM5] had a marginally significant indirect effect on broad depression through the log of pack-years of cigarette smoking (p = 0.01) among all participants and a significant indirect effect among females (p = 2.2 × 10-3). In the secondary analyses, the sex-moderated indirect effect was marginally significant for rs10501696 [GRM5] on broad depression through the log of pack-years of cigarette smoking (p = 0.01). In the COPDGene study, the effect of an SNP (rs10501696) in GRM5 on depressive symptoms and medication was mediated by log of pack-years (p = 0.02); however, no SNPs had a sex-moderated mediated effect on depressive symptoms. In the UK Biobank, we found SNPs in two genes [LOC105378800, GRM5] with an indirect effect on broad depression through the log of pack-years of cigarette smoking. In addition, the indirect effect for GRM5 on broad depression through smoking may be moderated by sex. These results suggest that genetic regions associated with broad depression may be mediated by cigarette smoking and this relationship may be moderated by sex.
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Affiliation(s)
- Kirsten Voorhies
- Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA
| | - Julian Hecker
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Sanghun Lee
- Division of Medicine, Department of Medical Consilience, Graduate School, Dankook University, Yongin 16890, Republic of Korea
| | - Georg Hahn
- Brigham and Women’s Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics, and Department of Medicine, Harvard Medical School, Boston, MA 02120, USA
| | - Dmitry Prokopenko
- Genetics and Aging Research Unit and the McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Merry-Lynn McDonald
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35233, USA
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA
| | | | - Ann Wu
- Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA
| | - John E. Hokanson
- Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Michael H. Cho
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Christoph Lange
- Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
| | - Karin F. Hoth
- Department of Psychiatry and Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA
| | - Sharon M. Lutz
- Department of Population Medicine, Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA
- Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
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Chen X, Liu Y, Cue J, Nimgaonkar MHV, Weinberger D, Han S, Zhao Z, Chen J. Classification of Schizophrenia, Bipolar Disorder and Major Depressive Disorder with Comorbid Traits and Deep Learning Algorithms. RESEARCH SQUARE 2024:rs.3.rs-4001384. [PMID: 38496574 PMCID: PMC10942564 DOI: 10.21203/rs.3.rs-4001384/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2024]
Abstract
Recent GWASs have demonstrated that comorbid disorders share genetic liabilities. But whether and how these shared liabilities can be used for the classification and differentiation of comorbid disorders remains unclear. In this study, we use polygenic risk scores (PRSs) estimated from 42 comorbid traits and the deep neural networks (DNN) architecture to classify and differentiate schizophrenia (SCZ), bipolar disorder (BIP) and major depressive disorder (MDD). Multiple PRSs were obtained for individuals from the schizophrenia (SCZ) (cases = 6,317, controls = 7,240), bipolar disorder (BIP) (cases = 2,634, controls 4,425) and major depressive disorder (MDD) (cases = 1,704, controls = 3,357) datasets, and classification models were constructed with and without the inclusion of PRSs of the target (SCZ, BIP or MDD). Models with the inclusion of target PRSs performed well as expected. Surprisingly, we found that SCZ could be classified with only the PRSs from 35 comorbid traits (not including the target SCZ and directly related traits) (accuracy 0.760 ± 0.007, AUC 0.843 ± 0.005). Similar results were obtained for BIP (33 traits, accuracy 0.768 ± 0.007, AUC 0.848 ± 0.009), and MDD (36 traits, accuracy 0.794 ± 0.010, AUC 0.869 ± 0.004). Furthermore, these PRSs from comorbid traits alone could effectively differentiate unaffected controls, SCZ, BIP, and MDD patients (average categorical accuracy 0.861 ± 0.003, average AUC 0.961 ± 0.041). These results suggest that the shared liabilities from comorbid traits alone may be sufficient to classify SCZ, BIP and MDD. More importantly, these results imply that a data-driven and objective diagnosis and differentiation of SCZ, BIP and MDD may be feasible.
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Affiliation(s)
- Xiangning Chen
- The university of Texas Health Science Center at Houston
| | - Yimei Liu
- Director and CEO, Lieber Institute for Brain Development, Johns Hopkins School of Medicine: Departments of Psychiatry, Neurology, Neuroscience and Genetic Medicine
| | - Joan Cue
- Director and CEO, Lieber Institute for Brain Development, Johns Hopkins School of Medicine: Departments of Psychiatry, Neurology, Neuroscience and Genetic Medicine
| | - Mira Han Vishwajit Nimgaonkar
- Director and CEO, Lieber Institute for Brain Development, Johns Hopkins School of Medicine: Departments of Psychiatry, Neurology, Neuroscience and Genetic Medicine
| | - Daniel Weinberger
- Director and CEO, Lieber Institute for Brain Development, Johns Hopkins School of Medicine: Departments of Psychiatry, Neurology, Neuroscience and Genetic Medicine
| | - Shizhong Han
- Lieber Institute for Brain Development; Johns Hopkins School of Medicine Department of Psychiatry and Behavioral Sciences
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Singh P, Srivastava A, Guin D, Thakran S, Yadav J, Chandna P, Sood M, Chadda RK, Kukreti R. Genetic Landscape of Major Depressive Disorder: Assessment of Potential Diagnostic and Antidepressant Response Markers. Int J Neuropsychopharmacol 2023; 26:692-738. [PMID: 36655406 PMCID: PMC10586057 DOI: 10.1093/ijnp/pyad001] [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: 07/13/2022] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation. METHODS We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values. RESULTS A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response. CONCLUSIONS The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.
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Affiliation(s)
- Priyanka Singh
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Ankit Srivastava
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Debleena Guin
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Delhi, India
| | - Sarita Thakran
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Jyoti Yadav
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
| | - Puneet Chandna
- Indian Society of Colposcopy and Cervical Pathology (ISCCP), Safdarjung Hospital, New Delhi, India
| | - Mamta Sood
- Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Rakesh Kumar Chadda
- Department of Psychiatry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Council of Scientific and Industrial Research (CSIR) - Institute of Genomics and Integrative Biology (IGIB), New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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Yin MY, Guo L, Zhao LJ, Zhang C, Liu WP, Zhang CY, Huo JH, Wang L, Li SW, Zheng CB, Xiao X, Li M, Wang C, Chang H. Reduced Vrk2 expression is associated with higher risk of depression in humans and mediates depressive-like behaviors in mice. BMC Med 2023; 21:256. [PMID: 37452335 PMCID: PMC10349461 DOI: 10.1186/s12916-023-02945-0] [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: 07/18/2022] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have reported single-nucleotide polymorphisms (SNPs) in the VRK serine/threonine kinase 2 gene (VRK2) showing genome-wide significant associations with major depression, but the regulation effect of the risk SNPs on VRK2 as well as their roles in the illness are yet to be elucidated. METHODS Based on the summary statistics of major depression GWAS, we conducted population genetic analyses, epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to identify the functional SNPs regulating VRK2; we also carried out behavioral assessments, dendritic spine morphological analyses, and phosphorylated 4D-label-free quantitative proteomics analyses in mice with Vrk2 repression. RESULTS We identified a SNP rs2678907 located in the 5' upstream of VRK2 gene exhibiting large spatial overlap with enhancer regulatory marks in human neural cells and brain tissues. Using luciferase reporter gene assays and eQTL analyses, the depression risk allele of rs2678907 decreased enhancer activities and predicted lower VRK2 mRNA expression, which is consistent with the observations of reduced VRK2 level in the patients with major depression compared with controls. Notably, Vrk2-/- mice exhibited depressive-like behaviors compared to Vrk2+/+ mice and specifically repressing Vrk2 in the ventral hippocampus using adeno-associated virus (AAV) lead to consistent and even stronger depressive-like behaviors in mice. Compared with Vrk2+/+ mice, the density of mushroom and thin spines in the ventral hippocampus was significantly altered in Vrk2-/- mice, which is in line with the phosphoproteomic analyses showing dysregulated synapse-associated proteins and pathways in Vrk2-/- mice. CONCLUSIONS Vrk2 deficiency mice showed behavioral abnormalities that mimic human depressive phenotypes, which may serve as a useful murine model for studying the pathophysiology of depression.
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Affiliation(s)
- Mei-Yu Yin
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Lei Guo
- Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, Zhejiang, China
- School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang, China
| | - Li-Juan Zhao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Chen Zhang
- Clinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.
| | - Wei-Peng Liu
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Chu-Yi Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Jin-Hua Huo
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Lu Wang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Shi-Wu Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Chang-Bo Zheng
- School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, China
| | - Xiao Xiao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Ming Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
| | - Chuang Wang
- Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, Zhejiang, China.
- School of Basic Medical Science, Health Science Center, Ningbo University, Ningbo, Zhejiang, China.
| | - Hong Chang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.
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9
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Zhang M, Kong X, Chen J, Liu W, Liu C, Dou X, Jiang L, Luo Y, Song M, Miao P, Tang Y, Xiu Y. Dysfunction of GluN3A subunit is involved in depression-like behaviors through synaptic deficits. J Affect Disord 2023; 332:72-82. [PMID: 36997126 DOI: 10.1016/j.jad.2023.03.076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 03/07/2023] [Accepted: 03/24/2023] [Indexed: 04/01/2023]
Abstract
BACKGROUND N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of depression. However, as the unique inhibitory subunit of NMDARs, the role of GluN3A in depression is largely unclear. METHODS Firstly, expression of GluN3A was examined in a mouse model of depression induced by chronic restraint stress (CRS). Then, rescue experiment with rAAV-Grin3a injection into hippocampus of CRS mice was carried out. Lastly, GluN3A knockout (KO) mouse was generated via CRISPR/Cas9 technique, and the molecular mechanism underlying involvement of GluN3A in depression was initially explored using RNA-seq technique, RT-PCR and western blotting. RESULTS GluN3A expression in hippocampus was significantly decreased in CRS mice. Depression-like behaviors induced by CRS were ameliorated when the decrease of GluN3A expression in mice exposed to CRS was restored. GluN3A KO mice exhibited symptoms of anhedonia reported as reduced sucrose preference, and symptoms of despair assayed by a longer immobility time in FST. Transcriptome analysis revealed genetic ablation of GluN3A was associated with downregulation of genes implicated in synapse and axon development. Postsynaptic protein PSD95 was decreased in GluN3A KO mice. More importantly, reduction of PSD95 in CRS mice can be rescued by viral mediated Grin3a re-expression. LIMITATIONS The mechanism underlying GluN3A involvement in depression is not fully determined. CONCLUSIONS Our data suggested that GluN3A dysfunction is involved in depression, which might be mediated by synaptic deficits. These findings will facilitate the understanding of the role of GluN3A in depression, and they might provide a new strategy for the development of subunit-selective NMDAR antagonists as antidepressant drugs.
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Affiliation(s)
- Mengmeng Zhang
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Xiangru Kong
- Department of Pediatric Surgical Oncology, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China
| | - Jing Chen
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Wenqin Liu
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Can Liu
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Xiaoyun Dou
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Lin Jiang
- Lab Teaching Management Center, Chongqing Medical University, Chongqing 400016, PR China
| | - Yanmin Luo
- Department of Physiology, Chongqing Medical University, Chongqing 400016, PR China
| | - Mingrui Song
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Peng Miao
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China
| | - Yong Tang
- Department of Histology and Embryology, Chongqing Medical University, Chongqing 400016, PR China.
| | - Yun Xiu
- Molecular Medicine Diagnostic and Testing Center, Institute of Life Science, Chongqing Medical University, Chongqing 400016, PR China.
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10
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Flint J. The genetic basis of major depressive disorder. Mol Psychiatry 2023; 28:2254-2265. [PMID: 36702864 PMCID: PMC10611584 DOI: 10.1038/s41380-023-01957-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 12/30/2022] [Accepted: 01/11/2023] [Indexed: 01/27/2023]
Abstract
The genetic dissection of major depressive disorder (MDD) ranks as one of the success stories of psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 genetic risk loci and proposing more than 200 candidate genes. However, the GWAS results derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating that there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci. I show that inventive uses of biobank data, novel imputation methods, combined with more interviewer diagnosed cases, can identify loci that contribute to the episodic severe shifts of mood, and neurovegetative and cognitive changes that are central to MDD. Furthermore, new theories about the nature and causes of MDD, drawing upon advances in neuroscience and psychology, can provide handles on how best to interpret and exploit genetic mapping results.
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Affiliation(s)
- Jonathan Flint
- Department of Psychiatry and Biobehavioral Sciences, Billy and Audrey Wilder Endowed Chair in Psychiatry and Neuroscience, Center for Neurobehavioral Genetics, 695 Charles E. Young Drive South, 3357B Gonda, Box 951761, Los Angeles, CA, 90095-1761, USA.
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11
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Madrid-Valero JJ, Kirkpatrick RM, González-Javier F, Gregory AM, Ordoñana JR. Sex differences in sleep quality and psychological distress: Insights from a middle-aged twin sample from Spain. J Sleep Res 2023; 32:e13714. [PMID: 36054078 DOI: 10.1111/jsr.13714] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 11/28/2022]
Abstract
There is a moderate association between poor sleep and psychological distress. There are marked sex differences in the prevalence of both variables, with females outnumbering males. However, the origin of these sex differences remains unclear. The objectives of this study were to: (1) study genetic and environmental influences on the relationship between poor sleep quality and psychological distress; and (2) test possible sex differences in this relationship. The sample comprised 3544 participants from the Murcia Twin Registry. Univariate and multivariate twin models were fitted to estimate the magnitude of genetic and environmental influences on both individual variance and covariance between poor sleep quality and psychological distress. Sleep quality and psychological distress were measured using the Pittsburgh Sleep Quality Index and the EuroQol five-dimensions questionnaire, respectively. The results reveal a strong genetic association between poor sleep quality and psychological distress, which accounts for 44% (95%CI: 27%-61%) of the association between these two variables. Substantial genetic (rA = 0.50; 95%CI: 0.32, 0.67) and non-shared environmental (rE = 0.41; 95%CI: 0.30, 0.52) correlations were also found, indicating a moderate overlap between genetic (and non-shared environmental) factors influencing both phenotypes. Equating sexes in sex-limitation models did not result in significant decreases in model fit. Despite the remarkable sex differences in the prevalence of both poor sleep quality and psychological distress, there were no sex differences in the genetic and environmental influences on these variables. This suggests that genetic factors play a similar role for men and women in explaining individual differences in both phenotypes and their relationship.
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Affiliation(s)
- Juan J Madrid-Valero
- Department of Health Psychology, Faculty of Health Sciences, University of Alicante, Spain
| | - Robert M Kirkpatrick
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, USA
| | - Francisca González-Javier
- Department of Human Anatomy and Psychobiology, University of Murcia, Spain.,Murcia Institute of Biomedical Research, IMIB-Arrixaca, Spain
| | - Alice M Gregory
- Department of Psychology, Goldsmiths, University of London, London, UK
| | - Juan R Ordoñana
- Department of Human Anatomy and Psychobiology, University of Murcia, Spain.,Murcia Institute of Biomedical Research, IMIB-Arrixaca, Spain
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12
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Liu D, Meyer D, Fennessy B, Feng C, Cheng E, Johnson JS, Park YJ, Rieder MK, Ascolillo S, de Pins A, Dobbyn A, Lebovitch D, Moya E, Nguyen TH, Wilkins L, Hassan A, Burdick KE, Buxbaum JD, Domenici E, Frangou S, Hartmann AM, Laurent-Levinson C, Malhotra D, Pato CN, Pato MT, Ressler K, Roussos P, Rujescu D, Arango C, Bertolino A, Blasi G, Bocchio-Chiavetto L, Campion D, Carr V, Fullerton JM, Gennarelli M, González-Peñas J, Levinson DF, Mowry B, Nimgaokar VL, Pergola G, Rampino A, Cervilla JA, Rivera M, Schwab SG, Wildenauer DB, Daly M, Neale B, Singh T, O'Donovan MC, Owen MJ, Walters JT, Ayub M, Malhotra AK, Lencz T, Sullivan PF, Sklar P, Stahl EA, Huckins LM, Charney AW. Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations. Nat Genet 2023; 55:369-376. [PMID: 36914870 PMCID: PMC10011128 DOI: 10.1038/s41588-023-01305-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 01/23/2023] [Indexed: 03/14/2023]
Abstract
Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes1. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear. To address this gap, we designed a custom sequencing panel of 161 genes selected based on the current knowledge of SCZ genetics and sequenced a new cohort of 11,580 SCZ cases and 10,555 controls of diverse ancestries. Replicating earlier work, we found that cases carried a significantly higher burden of rare protein-truncating variants (PTVs) among evolutionarily constrained genes (odds ratio = 1.48; P = 5.4 × 10-6). In meta-analyses with existing datasets totaling up to 35,828 cases and 107,877 controls, this excess burden was largely consistent across five ancestral populations. Two genes (SRRM2 and AKAP11) were newly implicated as SCZ risk genes, and one gene (PCLO) was identified as shared by individuals with SCZ and those with autism. Overall, our results lend robust support to the rare allelic spectrum of the genetic architecture of SCZ being conserved across diverse human populations.
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Affiliation(s)
- Dongjing Liu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Dara Meyer
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brian Fennessy
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Claudia Feng
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Wellcome Sanger Institute, Hinxton, UK
| | - Esther Cheng
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jessica S Johnson
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - You Jeong Park
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marysia-Kolbe Rieder
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven Ascolillo
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Agathe de Pins
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Amanda Dobbyn
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Dannielle Lebovitch
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Emily Moya
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Tan-Hoang Nguyen
- Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
| | - Lillian Wilkins
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Katherine E Burdick
- Department of Psychiatry, Brigham and Women's Hospital, Boston, MA, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Joseph D Buxbaum
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Enrico Domenici
- Centre for Computational and Systems Biology, Fondazione The Microsoft Research - University of Trento, Rovereto, Italy
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
| | - Sophia Frangou
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Annette M Hartmann
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | - Claudine Laurent-Levinson
- Faculté de Médecine Sorbonne Université, Groupe de Recherche Clinique n°15-Troubles Psychiatriques et Développement, Department of Child and Adolescent Psychiatry, Hôpital Universitaire de la Pitié-Salpêtrière, Paris, France
- Centre de Référence des Maladies Rares à Expression Psychiatrique, Department of Child and Adolescent Psychiatry, AP-HP Sorbonne Université, Hôpital Universitaire de la Pitié-Salpêtrière, Paris, France
| | - Dheeraj Malhotra
- Department of Neuroscience and Rare Diseases, Roche Pharma Research and Early Development, F. Hoffmann-La Roche, Basel, Switzerland
| | - Carlos N Pato
- Department of Psychiatry and Behavioral Sciences, SUNY Downstate College of Medicine, New York, NY, USA
| | - Michele T Pato
- Department of Psychiatry and Behavioral Sciences, SUNY Downstate College of Medicine, New York, NY, USA
| | - Kerry Ressler
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA
- Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, MA, USA
| | - Panos Roussos
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, New York, NY, USA
| | - Dan Rujescu
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | - Celso Arango
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain
| | - Alessandro Bertolino
- Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Blasi
- Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
| | - Luisella Bocchio-Chiavetto
- Department of Theoretical and Applied Sciences, eCampus University, Novedrate, Italy
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Dominique Campion
- INSERM U1245, Rouen, France
- Centre Hospitalier du Rouvray, Rouen, France
| | - Vaughan Carr
- Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
- Department of Psychiatry, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
| | - Janice M Fullerton
- Neuroscience Research Australia, Sydney, New South Wales, Australia
- School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Massimo Gennarelli
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Javier González-Peñas
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red de Salud Mental, Madrid, Spain
| | | | - Bryan Mowry
- Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia
- Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Queensland, Australia
| | - Vishwajit L Nimgaokar
- Department of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Hospital, Pittsburgh, PA, USA
- Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Giulio Pergola
- Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
| | - Antonio Rampino
- Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, Bari, Italy
| | - Jorge A Cervilla
- Institute of Neurosciences, Biomedical Research Centre, University of Granada, Granada, Spain
- Department of Psychiatry, San Cecilio University Hospital, University of Granada, Granada, Spain
| | - Margarita Rivera
- Institute of Neurosciences, Biomedical Research Centre, University of Granada, Granada, Spain
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Sibylle G Schwab
- Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia
| | | | - Mark Daly
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Benjamin Neale
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Tarjinder Singh
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Michael C O'Donovan
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Michael J Owen
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - James T Walters
- MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Muhammad Ayub
- University College London, London, UK
- Department of Psychiatry, Queen's University, Kingston, Ontario, Canada
| | - Anil K Malhotra
- Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, New York, NY, USA
| | - Todd Lencz
- Department of Psychiatry, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, New York, NY, USA
| | - Patrick F Sullivan
- Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Pamela Sklar
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eli A Stahl
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Regeneron Pharmaceuticals, Tarrytown, NY, USA
| | - Laura M Huckins
- Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Alexander W Charney
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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13
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Rijlaarsdam J, Cosin-Tomas M, Schellhas L, Abrishamcar S, Malmberg A, Neumann A, Felix JF, Sunyer J, Gutzkow KB, Grazuleviciene R, Wright J, Kampouri M, Zar HJ, Stein DJ, Heinonen K, Räikkönen K, Lahti J, Hüls A, Caramaschi D, Alemany S, Cecil CAM. DNA methylation and general psychopathology in childhood: an epigenome-wide meta-analysis from the PACE consortium. Mol Psychiatry 2023; 28:1128-1136. [PMID: 36385171 PMCID: PMC7614743 DOI: 10.1038/s41380-022-01871-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 11/17/2022]
Abstract
The general psychopathology factor (GPF) has been proposed as a way to capture variance shared between psychiatric symptoms. Despite a growing body of evidence showing both genetic and environmental influences on GPF, the biological mechanisms underlying these influences remain unclear. In the current study, we conducted epigenome-wide meta-analyses to identify both probe- and region-level associations of DNA methylation (DNAm) with school-age general psychopathology in six cohorts from the Pregnancy And Childhood Epigenetics (PACE) Consortium. DNAm was examined both at birth (cord blood; prospective analysis) and during school-age (peripheral whole blood; cross-sectional analysis) in total samples of N = 2178 and N = 2190, respectively. At school-age, we identified one probe (cg11945228) located in the Bromodomain-containing protein 2 gene (BRD2) that negatively associated with GPF (p = 8.58 × 10-8). We also identified a significant differentially methylated region (DMR) at school-age (p = 1.63 × 10-8), implicating the SHC Adaptor Protein 4 (SHC4) gene and the EP300-interacting inhibitor of differentiation 1 (EID1) gene that have been previously implicated in multiple types of psychiatric disorders in adulthood, including obsessive compulsive disorder, schizophrenia, and major depressive disorder. In contrast, no prospective associations were identified with DNAm at birth. Taken together, results of this study revealed some evidence of an association between DNAm at school-age and GPF. Future research with larger samples is needed to further assess DNAm variation associated with GPF.
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Affiliation(s)
- Jolien Rijlaarsdam
- Department of Child and Adolescent Psychiatry/ Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Marta Cosin-Tomas
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
- Universitat Pompeu Fabra, Barcelona, Spain.
- Centro de investigación biomédica en red en epidemiología y salud pública (ciberesp), Madrid, Spain.
| | - Laura Schellhas
- School of Psychological Science, MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Institute for Sex Research, Sexual Medicine and Forensic Psychiatry, University Medical Center Hamburg, Eppendorf, Germany
| | - Sarina Abrishamcar
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Anni Malmberg
- Department of Psychology & Logopedics, University of Helsinki, Helsinki, Finland
| | | | - Janine F Felix
- The Generation R Study Group, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Pediatrics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jordi Sunyer
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra, Barcelona, Spain
- Centro de investigación biomédica en red en epidemiología y salud pública (ciberesp), Madrid, Spain
| | - Kristine B Gutzkow
- Division of Climate and Environmental Health, Norwegian Institute of Public Health (NIPH), Oslo, Norway
| | - Regina Grazuleviciene
- Department of Environmental Science, Vytautas Magnus University, 44248, Kaunas, Lithuania
| | - John Wright
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Mariza Kampouri
- Department of Social Medicine, University of Crete, Crete, Greece
| | - Heather J Zar
- Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa
- South African Medical Research Council (SAMRC) Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa
| | - Dan J Stein
- Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
- South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Kati Heinonen
- Department of Psychology & Logopedics, University of Helsinki, Helsinki, Finland
- Psychology/ Welfare Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Katri Räikkönen
- Department of Psychology & Logopedics, University of Helsinki, Helsinki, Finland
| | - Jari Lahti
- Department of Psychology & Logopedics, University of Helsinki, Helsinki, Finland
| | - Anke Hüls
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
- Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Doretta Caramaschi
- Medical Research Council Integrative Epidemiology Unit, Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK
- Department of Psychology, , University of Exeter, Exeter, UK
| | - Silvia Alemany
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
- Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain
| | - Charlotte A M Cecil
- Department of Child and Adolescent Psychiatry/ Psychology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
- Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
- Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
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14
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Abstract
OBJECTIVE A better understanding of the genetic, molecular and cellular mechanisms of brain-derived neurotrophic factor (BDNF) and its association with neuroplasticity could play a pivotal role in finding future therapeutic targets for novel drugs in major depressive disorder (MDD). Because there are conflicting results regarding the exact role of BDNF polymorphisms in MDD still, we set out to systematically review the current evidence regarding BDNF-related mutations in MDD. METHODS We conducted a keyword-guided search of the PubMed and Embase databases, using 'BDNF' or 'brain-derived neurotrophic factor' and 'major depressive disorder' and 'single-nucleotide polymorphism'. We included all publications in line with our exclusion and inclusion criteria that focused on BDNF-related mutations in the context of MDD. RESULTS Our search yielded 427 records in total. After screening and application of our eligibility criteria, 71 studies were included in final analysis. According to present overall scientific data, there is a possibly major pathophysiological role for BDNF neurotrophic systems to play in MDD. However, on the one hand, the synthesis of evidence makes clear that likely no overall association of BDNF-related mutations with MDD exists. On the other hand, it can be appreciated that solidifying evidence emerged on specific significant sub-conditions and stratifications based on various demographic, clinico-phenotypical and neuromorphological variables. CONCLUSIONS Further research should elucidate specific BDNF-MDD associations based on demographic, clinico-phenotypical and neuromorphological variables. Furthermore, biomarker approaches, specifically combinatory ones, involving BDNF should be further investigated.
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15
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Dattilo V, Ulivi S, Minelli A, La Bianca M, Giacopuzzi E, Bortolomasi M, Bignotti S, Gennarelli M, Gasparini P, Concas MP. Genome-wide association studies on Northern Italy isolated populations provide further support concerning genetic susceptibility for major depressive disorder. World J Biol Psychiatry 2023; 24:135-148. [PMID: 35615967 DOI: 10.1080/15622975.2022.2082523] [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: 10/18/2022]
Abstract
OBJECTIVES Major depressive disorder (MDD) is a psychiatric disorder with pathogenesis influenced by both genetic and environmental factors. To date, the molecular-level understanding of its aetiology remains unclear. Thus, we aimed to identify genetic variants and susceptibility genes for MDD with a genome-wide association study (GWAS) approach. METHODS We performed a meta-analysis of GWASs and a gene-based analysis on two Northern Italy isolated populations (cases/controls n = 166/472 and 33/320), followed by replication and polygenic risk score (PRS) analyses in Italian independent samples (cases n = 464, controls n = 339). RESULTS We identified two novel MDD-associated genes, KCNQ5 (lead SNP rs867262, p = 3.82 × 10-9) and CTNNA2 (rs6729523, p = 1.25 × 10-8). The gene-based analysis revealed another six genes (p < 2.703 × 10-6): GRM7, CTNT4, SNRK, SRGAP3, TRAPPC9, and FHIT. No replication of the genome-wide significant SNPs was found in the independent cohort, even if 14 SNPs around CTNNA2 showed association with MDD and related phenotypes at the nominal level of p (<0.05). Furthermore, the PRS model developed in the discovery cohort discriminated cases and controls in the replication cohort. CONCLUSIONS Our work suggests new possible genes associated with MDD, and the PRS analysis confirms the polygenic nature of this disorder. Future studies are required to better understand the role of these findings in MDD.
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Affiliation(s)
- Vincenzo Dattilo
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Sheila Ulivi
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
| | - Alessandra Minelli
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.,Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Martina La Bianca
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
| | - Edoardo Giacopuzzi
- Wellcome Centre for Human Genetics, Oxford University, Oxford, UK.,NIHR Oxford Biomedical Research Centre, Oxford, UK
| | | | - Stefano Bignotti
- Unit of Psychiatry, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
| | - Massimo Gennarelli
- Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.,Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Paolo Gasparini
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy.,Department of Medicine, Surgery and Health Science, University of Trieste, Trieste, Italy
| | - Maria Pina Concas
- Institute for Maternal and Child Health-IRCCS Burlo Garofolo, Trieste, Italy
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16
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Correlation between variants of the CREB1 and GRM7 genes and risk of depression. BMC Psychiatry 2023; 23:3. [PMID: 36597080 PMCID: PMC9811780 DOI: 10.1186/s12888-022-04458-1] [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: 03/13/2022] [Accepted: 12/08/2022] [Indexed: 01/04/2023] Open
Abstract
The pathogenesis of depression involves cAMP-response element binding protein1 (CREB1) and metabotropic glutamate receptor 7 (GRM7), and their genetic polymorphisms may affect susceptibility to depression. The purpose of this study was to investigate whether the CREB1 polymorphisms rs2253206 and rs10932201 and the GRM7 polymorphism rs162209 are associated with the risk of depression. Using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing, we analyzed the rs2253206, rs10932201, and rs162209 frequencies in 479 patients with depression and 329 normal controls. The results showed that the rs2253206 and rs10932201 polymorphisms were significantly associated with an increased risk of depression. However, no association was found between rs162209 and depression risk. When the data were stratified for several disease-related variables, none of the three polymorphisms were found to be correlated to onset, disease severity, family history, or suicidal tendency. Thus, the present findings indicate that the CREB1 polymorphisms rs2253206 and rs10932201 may be related to the occurrence of depression.
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17
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Abstract
The CACNA1C gene encodes the pore-forming subunit of the CaV1.2 L-type Ca2+ channel, a critical component of membrane physiology in multiple tissues, including the heart, brain, and immune system. As such, mutations altering the function of these channels have the potential to impact a wide array of cellular functions. The first mutations identified within CACNA1C were shown to cause a severe, multisystem disorder known as Timothy syndrome (TS), which is characterized by neurodevelopmental deficits, long-QT syndrome, life-threatening cardiac arrhythmias, craniofacial abnormalities, and immune deficits. Since this initial description, the number and variety of disease-associated mutations identified in CACNA1C have grown tremendously, expanding the range of phenotypes observed in affected patients. CACNA1C channelopathies are now known to encompass multisystem phenotypes as described in TS, as well as more selective phenotypes where patients may exhibit predominantly cardiac or neurological symptoms. Here, we review the impact of genetic mutations on CaV1.2 function and the resultant physiological consequences.
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Affiliation(s)
- Kevin G Herold
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - John W Hussey
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Ivy E Dick
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
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18
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Qi C, Luo LD, Feng I, Ma S. Molecular mechanisms of synaptogenesis. Front Synaptic Neurosci 2022; 14:939793. [PMID: 36176941 PMCID: PMC9513053 DOI: 10.3389/fnsyn.2022.939793] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/27/2022] [Indexed: 11/29/2022] Open
Abstract
Synapses are the basic units for information processing and storage in the nervous system. It is only when the synaptic connection is established, that it becomes meaningful to discuss the structure and function of a circuit. In humans, our unparalleled cognitive abilities are correlated with an increase in the number of synapses. Additionally, genes involved in synaptogenesis are also frequently associated with neurological or psychiatric disorders, suggesting a relationship between synaptogenesis and brain physiology and pathology. Thus, understanding the molecular mechanisms of synaptogenesis is the key to the mystery of circuit assembly and neural computation. Furthermore, it would provide therapeutic insights for the treatment of neurological and psychiatric disorders. Multiple molecular events must be precisely coordinated to generate a synapse. To understand the molecular mechanisms underlying synaptogenesis, we need to know the molecular components of synapses, how these molecular components are held together, and how the molecular networks are refined in response to neural activity to generate new synapses. Thanks to the intensive investigations in this field, our understanding of the process of synaptogenesis has progressed significantly. Here, we will review the molecular mechanisms of synaptogenesis by going over the studies on the identification of molecular components in synapses and their functions in synaptogenesis, how cell adhesion molecules connect these synaptic molecules together, and how neural activity mobilizes these molecules to generate new synapses. Finally, we will summarize the human-specific regulatory mechanisms in synaptogenesis and results from human genetics studies on synaptogenesis and brain disorders.
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Affiliation(s)
- Cai Qi
- Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
- *Correspondence: Cai Qi,
| | - Li-Da Luo
- Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
- Department of Cellular and Molecular Physiology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, United States
| | - Irena Feng
- Boston University School of Medicine, Boston, MA, United States
| | - Shaojie Ma
- Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
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19
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Mohammad GS, Joca S, Starnawska A. The Cannabis-Induced Epigenetic Regulation of Genes Associated with Major Depressive Disorder. Genes (Basel) 2022; 13:1435. [PMID: 36011346 PMCID: PMC9407536 DOI: 10.3390/genes13081435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/28/2022] [Accepted: 07/29/2022] [Indexed: 11/17/2022] Open
Abstract
The prevalence of depression is increasing worldwide, as is the number of people suffering from treatment-resistant depression; these patients constitute 30% of those treated. Unfortunately, there have not been significant advances in the treatment of this disorder in the past few decades. Exposure to cannabis and cannabis-derived compounds impacts depression symptomatology in different ways, with evidence indicating that cannabidiol has antidepressant effects; there have been mixed results with medical cannabis. Even though the exact molecular mechanisms of the action underlying changes in depression symptomatology upon exposure to cannabis and cannabis-derived compounds are still unknown, there is strong evidence that these agents have a widespread impact on epigenetic regulation. We hypothesized that exposure to cannabis or cannabis-derived compounds changes the DNA methylation levels of genes associated with depression. To test this hypothesis, we first performed a literature search to identify genes that are differentially methylated upon exposure to cannabis and cannabis-derived compounds, as reported in methylome-wide association studies. We next checked whether genes residing in loci associated with depression, as identified in the largest currently available genome-wide association study of depression, were reported to be epigenetically regulated by cannabis or cannabis-related compounds. Multiple genes residing in loci associated with depression were found to be epigenetically regulated by exposure to cannabis or cannabis-derived compounds. This epigenomic regulation of depression-associated genes by cannabis or cannabis-derived compounds was reported across diverse organisms, tissues, and developmental stages and occurred in genes crucial for neuronal development, functioning, survival, and synapse functioning, as well as in genes previously implicated in other mental disorders.
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Affiliation(s)
| | - Sâmia Joca
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
- Department of BioMolecular Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo (USP), Ribeirão Preto 14040-903, Brazil
| | - Anna Starnawska
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
- The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8000 Aarhus, Denmark
- Center for Genomics and Personalized Medicine, CGPM, Center for Integrative Sequencing, iSEQ, 8000 Aarhus, Denmark
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20
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Xue K, Liang S, Yang B, Zhu D, Xie Y, Qin W, Liu F, Zhang Y, Yu C. Local dynamic spontaneous brain activity changes in first-episode, treatment-naïve patients with major depressive disorder and their associated gene expression profiles. Psychol Med 2022; 52:2052-2061. [PMID: 33121546 DOI: 10.1017/s0033291720003876] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Major depressive disorder (MDD) is a common debilitating disorder characterized by impaired spontaneous brain activity, yet little is known about its alterations in dynamic properties and the molecular mechanisms associated with these changes. METHODS Based on the resting-state functional MRI data of 65 first-episode, treatment-naïve patients with MDD and 66 healthy controls, we compared dynamic regional homogeneity (dReHo) of spontaneous brain activity between the two groups, and we investigated gene expression profiles associated with dReHo alterations in MDD by leveraging transcriptional data from the Allen Human Brain Atlas and weighted gene co-expression network analysis. RESULTS Compared with healthy controls, patients with MDD consistently showed reduced dReHo in both fusiform gyri and in the right temporal pole and hippocampus. The expression profiles of 16 gene modules were correlated with dReHo alterations in MDD. These gene modules were enriched for various biological process terms, including immune, synaptic signalling, ion channels, mitochondrial function and protein metabolism, and were preferentially expressed in different cell types. CONCLUSIONS Patients with MDD have reduced dReHo in brain areas associated with emotional and cognitive regulation, and these changes may be related to complex polygenetic and polypathway mechanisms.
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Affiliation(s)
- Kaizhong Xue
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Sixiang Liang
- Tianjin Anding Hospital, Tianjin 300222, China
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100088, China
| | - Bingbing Yang
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Dan Zhu
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yingying Xie
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Wen Qin
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Feng Liu
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yong Zhang
- Tianjin Anding Hospital, Tianjin 300222, China
| | - Chunshui Yu
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
- CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
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21
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Kusui Y, Izuo N, Uno K, Ge B, Muramatsu SI, Nitta A. Knockdown of Piccolo in the Nucleus Accumbens Suppresses Methamphetamine-Induced Hyperlocomotion and Conditioned Place Preference in Mice. Neurochem Res 2022; 47:2856-2864. [PMID: 35906352 DOI: 10.1007/s11064-022-03680-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 11/30/2022]
Abstract
Methamphetamine (METH), the most widely distributed psychostimulant, aberrantly activates the reward system in the brain to induce addictive behaviors. The presynaptic protein "Piccolo", encoded by Pclo, was identified as a METH-responsive protein with enhanced expression in the nucleus accumbens (NAc) in mice. Although the physiological and pathological significance of Piccolo has been identified in dopaminergic signaling, its role in METH-induced behavioral abnormalities and the underlying mechanisms remain unclear. To clarify such functions, mice with Piccolo knockdown in the NAc (NAc-miPiccolo mice) by local injection of an adeno-associated virus vector carrying miRNA targeting Pclo were generated and investigated. NAc-miPiccolo mice exhibited suppressed hyperlocomotion, sensitization, and conditioned place preference behavior induced by systemic administration of METH. The excessive release of dopamine in the NAc was reduced in NAc-miPiccolo mice at baseline and in response to METH. These results suggest that Piccolo in the NAc is involved in METH-induced behavioral alterations and is a candidate therapeutic target for the treatment of drug addiction.
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Affiliation(s)
- Yuka Kusui
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Naotaka Izuo
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Kyosuke Uno
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
- Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Japan
| | - Bin Ge
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Shin-Ichi Muramatsu
- Division of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University, Shimotsuke, Japan
- Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Atsumi Nitta
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
- Department of Pharmaceutical Therapy and Neuropharmacology, School of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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22
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Han H, Xu M, Wen L, Chen J, Liu Q, Wang J, Li MD, Yang Z. Identification of a Novel Functional Non-synonymous Single Nucleotide Polymorphism in Frizzled Class Receptor 6 Gene for Involvement in Depressive Symptoms. Front Mol Neurosci 2022; 15:882396. [PMID: 35875672 PMCID: PMC9302575 DOI: 10.3389/fnmol.2022.882396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 06/16/2022] [Indexed: 12/05/2022] Open
Abstract
Although numerous susceptibility loci for depression have been identified in recent years, their biological function and molecular mechanism remain largely unknown. By using an exome-wide association study for depressive symptoms assessed by the Center for Epidemiological Studies Depression (CES-D) score, we discovered a novel missense single nucleotide polymorphism (SNP), rs61753730 (Q152E), located in the fourth exon of the frizzled class receptor 6 gene (FZD6), which is a potential causal variant and is significantly associated with the CES-D score. Computer-based in silico analysis revealed that the protein configuration and stability, as well as the secondary structure of FZD6 differed greatly between the wild-type (WT) and Q152E mutant. We further found that rs61753730 significantly affected the luciferase activity and expression of FZD6 in an allele-specific way. Finally, we generated Fzd6-knockin (Fzd6-KI) mice with rs61753730 mutation using the CRISPR/Cas9 genome editing system and found that these mice presented greater immobility in the forced swimming test, less preference for sucrose in the sucrose preference test, as well as decreased center entries, center time, and distance traveled in the open filed test compared with WT mice after exposed to chronic social defeat stress. These results indicate the involvement of rs61753730 in depression. Taken together, our findings demonstrate that SNP rs61753730 is a novel functional variant and plays an important role in depressive symptoms.
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Affiliation(s)
- Haijun Han
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mengxiang Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Li Wen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiali Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiang Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ju Wang
- Department of Medical Engineering, Tianjin Medical University, Tianjin, China
| | - Ming D. Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
- *Correspondence: Ming D. Li,
| | - Zhongli Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhongli Yang,
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23
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Cohen-Paes ADN, de Carvalho DC, Pastana LF, Dobbin EAF, Moreira FC, de Souza TP, Fernandes MR, Leal DFDVB, de Sá RBA, de Alcântara AL, Guerreiro JF, Ribeiro-dos-Santos Â, dos Santos SEB, de Assumpção PP, dos Santos NPC. Characterization of PCLO Gene in Amazonian Native American Populations. Genes (Basel) 2022; 13:genes13030499. [PMID: 35328053 PMCID: PMC8950494 DOI: 10.3390/genes13030499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/19/2022] [Accepted: 01/24/2022] [Indexed: 11/16/2022] Open
Abstract
Genetic variations in PCLO have been associated with different pathologies in global literature, but there are no data regarding this gene in Native American populations. The Amazonian Native American populations have lower genetic diversity and are more different from other continental groups. We investigated 18 genetic variants in the PCLO gene in Amazonian indigenous and compared our results with the ones found in global populations, which were publicly available in the 1000 Genomes Project, gnmAD and ABraOM databases. The results demonstrated that the variants of the PCLO, especially rs17156844, rs550369696, rs61741659 and rs2877, have a significantly higher frequency in Amerindian populations in comparison with other continental populations. These data outline the singular genetic profile of the Native American population from the Brazilian Amazon region.
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Affiliation(s)
- Amanda de Nazaré Cohen-Paes
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Darlen Cardoso de Carvalho
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
| | - Lucas Favacho Pastana
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Elizabeth Ayres Fragoso Dobbin
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Fabiano Cordeiro Moreira
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Tatiane Piedade de Souza
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Marianne Rodrigues Fernandes
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
- Correspondence: ; Tel.: +55-91-99123-4727
| | - Diana Feio da Veiga Borges Leal
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Roberta Borges Andrade de Sá
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Angélica Leite de Alcântara
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - João Farias Guerreiro
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Ândrea Ribeiro-dos-Santos
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Sidney Emanuel Batista dos Santos
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
| | - Paulo Pimentel de Assumpção
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
| | - Ney Pereira Carneiro dos Santos
- Núcleo de Pesquisa em Oncologia, Federal University of Pará, Belém 66073-000, Brazil; (A.d.N.C.-P.); (D.C.d.C.); (L.F.P.); (E.A.F.D.); (F.C.M.); (D.F.d.V.B.L.); (R.B.A.d.S.); (A.L.d.A.); (Â.R.-d.-S.); (S.E.B.d.S.); (P.P.d.A.); (N.P.C.d.S.)
- Laboratório de Genética Humana e Médica, Federal University of Pará, Belém 66073-000, Brazil; (T.P.d.S.); (J.F.G.)
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Grant CW, Barreto EF, Kumar R, Kaddurah-Daouk R, Skime M, Mayes T, Carmody T, Biernacka J, Wang L, Weinshilboum R, Trivedi MH, Bobo WV, Croarkin PE, Athreya AP. Multi-Omics Characterization of Early- and Adult-Onset Major Depressive Disorder. J Pers Med 2022; 12:jpm12030412. [PMID: 35330412 PMCID: PMC8949112 DOI: 10.3390/jpm12030412] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 02/24/2022] [Accepted: 03/02/2022] [Indexed: 01/14/2023] Open
Abstract
Age at depressive onset (AAO) corresponds to unique symptomatology and clinical outcomes. Integration of genome-wide association study (GWAS) results with additional “omic” measures to evaluate AAO has not been reported and may reveal novel markers of susceptibility and/or resistance to major depressive disorder (MDD). To address this gap, we integrated genomics with metabolomics using data-driven network analysis to characterize and differentiate MDD based on AAO. This study first performed two GWAS for AAO as a continuous trait in (a) 486 adults from the Pharmacogenomic Research Network-Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS), and (b) 295 adults from the Combining Medications to Enhance Depression Outcomes (CO-MED) study. Variants from top signals were integrated with 153 p180-assayed metabolites to establish multi-omics network characterizations of early (<age 18) and adult-onset depression. The most significant variant (p = 8.77 × 10−8) localized to an intron of SAMD3. In silico functional annotation of top signals (p < 1 × 10−5) demonstrated gene expression enrichment in the brain and during embryonic development. Network analysis identified differential associations between four variants (in/near INTU, FAT1, CNTN6, and TM9SF2) and plasma metabolites (phosphatidylcholines, carnitines, biogenic amines, and amino acids) in early- compared with adult-onset MDD. Multi-omics integration identified differential biosignatures of early- and adult-onset MDD. These biosignatures call for future studies to follow participants from childhood through adulthood and collect repeated -omics and neuroimaging measures to validate and deeply characterize the biomarkers of susceptibility and/or resistance to MDD development.
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Grants
- R01 MH124655 NIMH NIH HHS
- R01 MH113700 NIMH NIH HHS
- K23 AI143882 NIAID NIH HHS
- U19GM61388, R01GM028157, R01AA027486, R01MH108348, R24GM078233, RC2GM092729, U19AG063744, N01MH90003, R01AG04617, U01AG061359, RF1AG051550, R01MH113700, R01MH124655, K23AI143882 NIH HHS
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Affiliation(s)
- Caroline W. Grant
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55901, USA; (C.W.G.); (L.W.); (R.W.)
| | - Erin F. Barreto
- Department of Pharmacy, Mayo Clinic, Rochester, MN 55901, USA;
| | - Rakesh Kumar
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55901, USA; (R.K.); (M.S.)
| | - Rima Kaddurah-Daouk
- Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27701, USA;
- Department of Medicine, Duke University, Durham, NC 27708, USA
- Duke Institute for Brain Sciences, Duke University, Durham, NC 27710, USA
| | - Michelle Skime
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55901, USA; (R.K.); (M.S.)
| | - Taryn Mayes
- Department of Psychiatry, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (T.M.); (M.H.T.)
| | - Thomas Carmody
- Department Population and Data Sciences, University of Texas Southwestern Medical Center in Dallas, Dallas, TX 75390, USA;
| | - Joanna Biernacka
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55901, USA;
| | - Liewei Wang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55901, USA; (C.W.G.); (L.W.); (R.W.)
| | - Richard Weinshilboum
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55901, USA; (C.W.G.); (L.W.); (R.W.)
| | - Madhukar H. Trivedi
- Department of Psychiatry, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA; (T.M.); (M.H.T.)
| | - William V. Bobo
- Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Paul E. Croarkin
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55901, USA; (R.K.); (M.S.)
- Correspondence: (P.E.C.); (A.P.A.); Tel.: +1-507-422-6073 (A.P.A.)
| | - Arjun P. Athreya
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55901, USA; (C.W.G.); (L.W.); (R.W.)
- Correspondence: (P.E.C.); (A.P.A.); Tel.: +1-507-422-6073 (A.P.A.)
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25
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Anguita-Ruiz A, Zarza-Rebollo JA, Pérez-Gutiérrez AM, Molina E, Gutiérrez B, Bellón JÁ, Moreno-Peral P, Conejo-Cerón S, Aiarzagüena JM, Ballesta-Rodríguez MI, Fernández A, Fernández-Alonso C, Martín-Pérez C, Montón-Franco C, Rodríguez-Bayón A, Torres-Martos Á, López-Isac E, Cervilla J, Rivera M. Body mass index interacts with a genetic-risk score for depression increasing the risk of the disease in high-susceptibility individuals. Transl Psychiatry 2022; 12:30. [PMID: 35075110 PMCID: PMC8786870 DOI: 10.1038/s41398-022-01783-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 11/24/2021] [Accepted: 01/04/2022] [Indexed: 11/22/2022] Open
Abstract
Depression is strongly associated with obesity among other chronic physical diseases. The latest mega- and meta-analysis of genome-wide association studies have identified multiple risk loci robustly associated with depression. In this study, we aimed to investigate whether a genetic-risk score (GRS) combining multiple depression risk single nucleotide polymorphisms (SNPs) might have utility in the prediction of this disorder in individuals with obesity. A total of 30 depression-associated SNPs were included in a GRS to predict the risk of depression in a large case-control sample from the Spanish PredictD-CCRT study, a national multicentre, randomized controlled trial, which included 104 cases of depression and 1546 controls. An unweighted GRS was calculated as a summation of the number of risk alleles for depression and incorporated into several logistic regression models with depression status as the main outcome. Constructed models were trained and evaluated in the whole recruited sample. Non-genetic-risk factors were combined with the GRS in several ways across the five predictive models in order to improve predictive ability. An enrichment functional analysis was finally conducted with the aim of providing a general understanding of the biological pathways mapped by analyzed SNPs. We found that an unweighted GRS based on 30 risk loci was significantly associated with a higher risk of depression. Although the GRS itself explained a small amount of variance of depression, we found a significant improvement in the prediction of depression after including some non-genetic-risk factors into the models. The highest predictive ability for depression was achieved when the model included an interaction term between the GRS and the body mass index (BMI), apart from the inclusion of classical demographic information as marginal terms (AUC = 0.71, 95% CI = [0.65, 0.76]). Functional analyses on the 30 SNPs composing the GRS revealed an over-representation of the mapped genes in signaling pathways involved in processes such as extracellular remodeling, proinflammatory regulatory mechanisms, and circadian rhythm alterations. Although the GRS on its own explained a small amount of variance of depression, a significant novel feature of this study is that including non-genetic-risk factors such as BMI together with a GRS came close to the conventional threshold for clinical utility used in ROC analysis and improves the prediction of depression. In this study, the highest predictive ability was achieved by the model combining the GRS and the BMI under an interaction term. Particularly, BMI was identified as a trigger-like risk factor for depression acting in a concerted way with the GRS component. This is an interesting finding since it suggests the existence of a risk overlap between both diseases, and the need for individual depression genetics-risk evaluation in subjects with obesity. This research has therefore potential clinical implications and set the basis for future research directions in exploring the link between depression and obesity-associated disorders. While it is likely that future genome-wide studies with large samples will detect novel genetic variants associated with depression, it seems clear that a combination of genetics and non-genetic information (such is the case of obesity status and other depression comorbidities) will still be needed for the optimization prediction of depression in high-susceptibility individuals.
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Affiliation(s)
- Augusto Anguita-Ruiz
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.4489.10000000121678994Institute of Nutrition and Food Technology “José Mataix”, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.413448.e0000 0000 9314 1427CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Juan Antonio Zarza-Rebollo
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain. .,Institute of Neurosciences 'Federico Olóriz', Biomedical Research Center (CIBM), University of Granada, Granada, Spain.
| | - Ana M Pérez-Gutiérrez
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain
| | - Esther Molina
- grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.4489.10000000121678994Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain
| | - Blanca Gutiérrez
- grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.4489.10000000121678994Department of Psychiatry, Faculty of Medicine, University of Granada, Granada, Spain
| | - Juan Ángel Bellón
- grid.452525.1Primary Care District of Málaga-Guadalhorce, Biomedical Research Institute of Málaga (IBIMA), Primary Care Prevention and Health Promotion Network (redIAPP), Málaga, Spain ,grid.10215.370000 0001 2298 7828Department of Public Health and Psychiatry, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Patricia Moreno-Peral
- grid.452525.1Primary Care District of Málaga-Guadalhorce, Biomedical Research Institute of Málaga (IBIMA), Primary Care Prevention and Health Promotion Network (redIAPP), Málaga, Spain
| | - Sonia Conejo-Cerón
- grid.452525.1Primary Care District of Málaga-Guadalhorce, Biomedical Research Institute of Málaga (IBIMA), Primary Care Prevention and Health Promotion Network (redIAPP), Málaga, Spain
| | | | | | - Anna Fernández
- grid.428876.7Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona, Spain ,grid.466571.70000 0004 1756 6246CIBERESP, Centro de Investigacion Biomedica en Red de Epidemiologia y Salud Publica, Madrid, Spain
| | | | - Carlos Martín-Pérez
- grid.418355.eMarquesado Health Centre, Servicio Andaluz de Salud, Granada, Spain
| | - Carmen Montón-Franco
- grid.488737.70000000463436020Casablanca Health Centre, Aragonese Institute of Health Sciences, IIS Aragón, Zaragoza, Spain ,grid.11205.370000 0001 2152 8769Department of Medicine and Psychiatry, University of Zaragoza, Zaragoza, Spain
| | | | - Álvaro Torres-Martos
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Elena López-Isac
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain
| | - Jorge Cervilla
- grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.4489.10000000121678994Department of Psychiatry, Faculty of Medicine, University of Granada, Granada, Spain
| | - Margarita Rivera
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain
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Schizophrenia Outside the Brain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1400:53-63. [DOI: 10.1007/978-3-030-97182-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Bondy E, Bogdan R. Understanding Anhedonia from a Genomic Perspective. Curr Top Behav Neurosci 2022; 58:61-79. [PMID: 35152374 PMCID: PMC9375777 DOI: 10.1007/7854_2021_293] [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] [Indexed: 06/14/2023]
Abstract
Anhedonia, or the decreased ability to experience pleasure, is a cardinal symptom of major depression that commonly occurs within other forms of psychopathology. Supportive of long-held theory that anhedonia represents a genetically influenced vulnerability marker for depression, evidence from twin studies suggests that it is moderately-largely heritable. However, the genomic sources of this heritability are just beginning to be understood. In this review, we survey what is known about the genomic architecture underlying anhedonia and related constructs. We briefly review twin and initial candidate gene studies before focusing on genome-wide association study (GWAS) and polygenic efforts. As large samples are needed to reliably detect the small effects that typically characterize common genetic variants, the study of anhedonia and related phenotypes conflicts with current genomic research requirements and frameworks that prioritize sample size over precise phenotyping. This has resulted in few and underpowered studies of anhedonia-related constructs that have largely failed to reliably identify individual variants. Nonetheless, the polygenic architecture of anhedonia-related constructs identified in these studies has genetic overlap with depression and schizophrenia as well as related brain structure (e.g., striatal volume), providing important clues to etiology that may usefully guide refinement in nosology. As we await the accumulation of larger samples for more well-powered GWAS of reward-related constructs, novel analytic techniques that leverage GWAS summary statistics (e.g., genomic structural equation modeling) may currently be used to help characterize how the genomic architecture of anhedonia is shared and distinct from that underlying other constructs (e.g., depression, neuroticism, anxiety).
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Affiliation(s)
- Erin Bondy
- Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA
| | - Ryan Bogdan
- Department of Psychological and Brain Sciences, Washington University in Saint Louis, St. Louis, MO, USA.
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28
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Wang H, Kan WJ, Feng Y, Feng L, Yang Y, Chen P, Xu JJ, Si TM, Zhang L, Wang G, Du J. Nuclear receptors modulate inflammasomes in the pathophysiology and treatment of major depressive disorder. World J Psychiatry 2021; 11:1191-1205. [PMID: 35070770 PMCID: PMC8717028 DOI: 10.5498/wjp.v11.i12.1191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/29/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Major depressive disorder (MDD) is highly prevalent and is a significant cause of mortality and morbidity worldwide. Currently, conventional pharmacological treatments for MDD produce temporary remission in < 50% of patients; therefore, there is an urgent need for a wider spectrum of novel antidepressants to target newly discovered underlying disease mechanisms. Accumulated evidence has shown that immune inflammation, particularly inflammasome activity, plays an important role in the pathophysiology of MDD. In this review, we summarize the evidence on nuclear receptors (NRs), such as glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor, aryl hydrocarbon receptor, and peroxisome proliferator-activated receptor, in modulating the inflammasome activity and depression-associated behaviors. This review provides evidence from an endocrine perspective to understand the role of activated NRs in the pathophysiology of MDD, and to provide insight for the discovery of antidepressants with novel mechanisms for this devastating disorder.
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Affiliation(s)
- Han Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Wei-Jing Kan
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Yuan Feng
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Lei Feng
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Yang Yang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Pei Chen
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Jing-Jie Xu
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Tian-Mei Si
- Department of Clinical Psychopharmacology, Peking University Institute of Mental Health, Beijing 100191, Beijing Province, China
| | - Ling Zhang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Gang Wang
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
| | - Jing Du
- The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Beijing 100088, Beijing Province, China
- State Key Laboratory for Conservation and Utilization of Bio-resources in Yunnan, Yunnan University, Kunming 650091, Yunnan Province, China
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Lang X, Liu Q, Fang H, Zhou Y, Forster MT, Li Z, Zhang X. The prevalence and clinical correlates of metabolic syndrome and cardiometabolic alterations in 430 drug-naive patients in their first episode of schizophrenia. Psychopharmacology (Berl) 2021; 238:3643-3652. [PMID: 34586464 DOI: 10.1007/s00213-021-05983-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 09/15/2021] [Indexed: 11/26/2022]
Abstract
RATIONALE Although metabolic abnormalities and metabolic syndrome (MetS) have been extensively investigated in schizophrenia, few studies have examined them in first-episode drug-naive (FEDN) patients. OBJECTIVES This study aimed to investigate the prevalence and clinical correlates of metabolic abnormalities in FEDN schizophrenia patients. METHODS A total of 430 FEDN schizophrenia patients and 453 controls were recruited. Various parameters were measured including BMI, waist circumference, blood pressure, lipid profiles, blood glucose, glycosylated hemoglobin (HbA1c), insulin, and homeostatic model assessment for insulin resistance (HOMA-IR). RESULTS Patients had a higher prevalence of MetS, hypertension, hypertriglyceridemia, hypo-HDL-C, elevated HAb1c, and elevated insulin than controls (19.1% vs. 6.6%, OR = 2.52; 33.3% vs. 12.1%, OR = 3.05; 30.5% vs. 16.1%, OR = 2.25; 43.1% vs. 24.0%, OR = 2.21; 25.6% vs. 10.8%, OR = 2.62; 9.1% vs. 0.9%, OR = 10.29; all pBonferroni < 0.001). Waist circumference was associated with PANSS general psychopathology and total score (correlation coefficient r = 0.17, pBonferroni < 0.001; correlation coefficient r = 0.16, pBonferroni = 0.004). Fasting glucose was associated with PANSS negative, general psychopathology, and total score (correlation coefficient r = 0.13, pBonferroni = 0.03; correlation coefficient r = 0.19, pBonferroni < 0.001; correlation coefficient r = 0.20, pBonferroni < 0.001). BMI (OR = 1.37), smoking (OR = 3.39), and HOMA-IR (OR = 5.60) were associated with MetS in FEDN schizophrenia (all p < 0.001). CONCLUSIONS Our results demonstrate that MetS and metabolic abnormalities co-existed in the early stages of schizophrenia without antipsychotics. Waist circumference and glucose were associated with psychopathological symptoms, while BMI, smoking, and HOMA-IR were associated with MetS in FEDN schizophrenia.
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Affiliation(s)
- Xiaoe Lang
- Department of Psychiatry, The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Qinqin Liu
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Hanliu Fang
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Yongjie Zhou
- Shenzhen Kangning Hospital, Shenzhen, Guangdong, China
| | - Mattew T Forster
- Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Zezhi Li
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, 36 Mingxin Road, Guangzhou, 510370, China.
| | - Xiangyang Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, 36 Mingxin Road, Guangzhou, 510370, China.
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui Road, Chaoyang District, 100101, Beijing, China.
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Vornholt E, Drake J, Mamdani M, McMichael G, Taylor ZN, Bacanu S, Miles MF, Vladimirov VI. Identifying a novel biological mechanism for alcohol addiction associated with circRNA networks acting as potential miRNA sponges. Addict Biol 2021; 26:e13071. [PMID: 34164896 PMCID: PMC8590811 DOI: 10.1111/adb.13071] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/21/2021] [Accepted: 05/31/2021] [Indexed: 12/11/2022]
Abstract
Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD-matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co-expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA-miRNA-mRNA interactions (FDR ≤ 0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome-wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.
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Affiliation(s)
- Eric Vornholt
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
- Integrative Life Sciences Doctoral ProgramVirginia Commonwealth UniversityRichmondVirginiaUSA
- Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - John Drake
- Department of Psychiatry and Behavioral SciencesTexas A&M UniversityCollege StationTexasUSA
| | - Mohammed Mamdani
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Gowon McMichael
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Zachary N. Taylor
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Silviu‐Alin Bacanu
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
- Department of PsychiatryVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Michael F. Miles
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
- VCU‐Alcohol Research CenterVirginia Commonwealth UniversityRichmondVirginiaUSA
- Department of Pharmacology and ToxicologyVirginia Commonwealth UniversityRichmondVirginiaUSA
- Department of NeurologyVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Vladimir I. Vladimirov
- Virginia Institute for Psychiatric and Behavioral GeneticsVirginia Commonwealth UniversityRichmondVirginiaUSA
- Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Center for Biomarker Research and Precision MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
- Department of Physiology & BiophysicsVirginia Commonwealth UniversityRichmondVirginiaUSA
- School of PharmacyVirginia Commonwealth UniversityRichmondVirginiaUSA
- Lieber Institute for Brain DevelopmentJohns Hopkins UniversityBaltimoreMarylandUSA
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31
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Amidfar M, Quevedo J, Z Réus G, Kim YK. Grey matter volume abnormalities in the first depressive episode of medication-naïve adult individuals: a systematic review of voxel based morphometric studies. Int J Psychiatry Clin Pract 2021; 25:407-420. [PMID: 33351672 DOI: 10.1080/13651501.2020.1861632] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND To identify the reliable and consistent grey matter volume (GMV) abnormalities associated with major depressive disorder (MDD), we excluded the influence of confounding clinical characteristics, comorbidities and brain degeneration on brain morphological abnormalities by inclusion of non-comorbid and non-geriatric drug-naïve MDD individuals experiencing first episode depressive. METHODS The PubMed, Scopus, Web of Science, Science Direct and Google scholar databases were searched for papers published in English up to April 2020. RESULTS A total of 21 voxel based morphometric (VBM) studies comparing 845 individuals in the first depressive episode and medication-naïve with 940 healthy control subjects were included. The results showed a grey matter volumes reductions in the orbitofrontal cortex (OFC), prefrontal cortex (PFC), frontal and temporal gyri, temporal pole, insular lobe, thalamus, basal ganglia, cerebellum, hippocampus, cingulate cortex, and amygdala. In addition, increased grey matter volumes in the postcentral gyrus, superior frontal gyrus, insula, basal ganglia, thalamus, amygdala, cuneus, and precuneus differentiated the first depressive episode in medication-naïve individuals from healthy subjects. CONCLUSION The present systematic review provided additional support for the involvement of grey matter structural abnormalities in limbic-cortical circuits as possibly specific structural abnormalities in the early stage of MDD.Key pointsDistinct brain regions in MDD patients might be associated with the early stages of illness, and thus it is critical to study the causal relationship between brain structures and the onset of the disease to improve the evaluation in clinic.Grey matter alterations in the fronto-limbic networks in the first episode, medication-naïve MDD might suggest that these abnormalities may play an important role in the neuropathophysiology of MDD at its onset.First episode, medically naïve depressive patients show grey matter volume alterations in brain regions mainly associated with emotion regulation including parietal-temporal regions, PFC, insular lobe, thalamus, basal ganglia, cerebellum and limbic structures that may be specific changes in early stage of MDD.Genotype-diagnosis interaction effects on brain morphology in the cortico-limbic-striatal circuits, including the PFC, amygdala, hippocampus and striatum that might be implicated in the dysfunctional regulation of emotion in first-episode MDD patients.Future longitudinal and prospective studies should be conducted to identify the core structural brain changes in people at-risk for MDD and explore the association of their brain volumes with symptom onset.
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Affiliation(s)
| | - João Quevedo
- Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Center of Excellence on Mood Disorders, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.,Neuroscience Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.,Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Gislaine Z Réus
- Translational Psychiatry Laboratory, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma, SC, Brazil
| | - Yong-Ku Kim
- Departments of Psychiatry, College of Medicine, Korea University, Seoul, South Korea
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32
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DNA methylation of the KLK8 gene in depression symptomatology. Clin Epigenetics 2021; 13:200. [PMID: 34715912 PMCID: PMC8556955 DOI: 10.1186/s13148-021-01184-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 10/12/2021] [Indexed: 12/02/2022] Open
Abstract
Background Depression is a common, complex, and debilitating mental disorder estimated to be under-diagnosed and insufficiently treated in society. Liability to depression is influenced by both genetic and environmental risk factors, which are both capable of impacting DNA methylation (DNAm). Accordingly, numerous studies have researched for DNAm signatures of this disorder. Recently, an epigenome-wide association study of monozygotic twins identified an association between DNAm status in the KLK8 (neuropsin) promoter region and severity of depression symptomatology. Methods In this study, we aimed to investigate: (i) if blood DNAm levels, quantified by pyrosequencing, at two CpG sites in the KLK8 promoter are associated with depression symptomatology and depression diagnosis in an independent clinical cohort and (ii) if KLK8 DNAm levels are associated with depression, postpartum depression, and depression symptomatology in four independent methylomic cohorts, with blood and brain DNAm quantified by either MBD-seq or 450 k methylation array. Results DNAm levels in KLK8 were not significantly different between depression cases and controls, and were not significantly associated with any of the depression symptomatology scores after correction for multiple testing (minimum p value for KLK8 CpG1 = 0.12 for ‘Depressed mood,’ and for CpG2 = 0.03 for ‘Loss of self-confidence with other people’). However, investigation of the link between KLK8 promoter DNAm levels and depression-related phenotypes collected from four methylomic cohorts identified significant association (p value < 0.05) between severity of depression symptomatology and blood DNAm levels at seven CpG sites. Conclusions Our findings suggest that variance in blood DNAm levels in KLK8 promoter region is associated with severity of depression symptoms, but not depression diagnosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01184-5.
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Chen CH, Huang YS, Liao DL, Huang CY, Lin CH, Fang TH. Identification of Rare Mutations of Two Presynaptic Cytomatrix Genes BSN and PCLO in Schizophrenia and Bipolar Disorder. J Pers Med 2021; 11:jpm11111057. [PMID: 34834409 PMCID: PMC8625612 DOI: 10.3390/jpm11111057] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/11/2021] [Accepted: 10/19/2021] [Indexed: 12/14/2022] Open
Abstract
Schizophrenia and bipolar disorder are severe mental disorders with a major component of genetic factors in their etiology. Rare mutations play a significant role in these two disorders, and they are highly heterogeneous and personalized. Identification of personalized mutations is essential for the establishment of molecular diagnosis, providing insight into pathogenesis and guiding the personalized treatment for each affected patient. We conducted whole-genome sequencing analysis of families with schizophrenia and bipolar disorder to search for their genetic underpinnings. This report identified a rare missense mutation Arg1087Gln of BSN (bassoon presynaptic cytomatrix protein) co-segregating with schizophrenia in a family with multiple affected members. Furthermore, we identified the rare missense mutation Ser1535Leu of PCLO (piccolo presynaptic cytomatrix protein) in two sisters with bipolar disorder and another rare missense mutation, His5142Arg in PCLO, in a patient with schizophrenia. These three missense mutations were very rare and were predicted to be pathogenic. The BSN and PCLO genes encode two structurally related proteins of the presynaptic cytomatrix at the active zone that regulates neurotransmission at the presynaptic neuronal terminal. Our findings suggest the involvement of the presynaptic matrix in the pathogenesis of schizophrenia and bipolar disorder, and BSN and PCLO are the risk genes for schizophrenia and bipolar disorder.
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Affiliation(s)
- Chia-Hsiang Chen
- Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan;
- Department and Institute of Biomedical Sciences, Chang Gung University, Taoyuan 333, Taiwan;
- Correspondence:
| | - Yu-Shu Huang
- Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan 333, Taiwan;
| | - Ding-Lieh Liao
- Taoyuan Psychiatric Center, Department of General Psychiatry, Taoyuan 330, Taiwan; (D.-L.L.); (C.-H.L.)
| | - Cheng-Yi Huang
- Bali Psychiatric Center, Department of Community Psychiatry, New Taipei City 249, Taiwan;
| | - Chia-Heng Lin
- Taoyuan Psychiatric Center, Department of General Psychiatry, Taoyuan 330, Taiwan; (D.-L.L.); (C.-H.L.)
| | - Ting-Hsuan Fang
- Department and Institute of Biomedical Sciences, Chang Gung University, Taoyuan 333, Taiwan;
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34
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Ginerete RP, Mascio G, Liberatore F, Bucci D, Antenucci N, Di Pietro P, Cannella M, Imbriglio T, Notartomaso S, Nicoletti F, Bruno V, Battaglia G. Repeated episodes of transient reduction of oxygen exposure simulating aircraft cabin conditions enhance resilience to stress in mice. Eur J Neurosci 2021; 54:7109-7124. [PMID: 34655118 DOI: 10.1111/ejn.15495] [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: 05/28/2021] [Revised: 09/01/2021] [Accepted: 10/01/2021] [Indexed: 11/30/2022]
Abstract
Pilots and crew of domestic flights are exposed to transient periods of mild reductions of partial pressure of inspired oxygen each day, and this might have functional consequence on their performance in the long range. Here, we exposed mice to mild reductions of oxygen exposure (ROE) four times per day for 21 days by lowering oxygen partial pressure to levels corresponding to an altitude of about 2300 m, which is the quote of pressurization of the air cabin. Four groups of mice were studied: unstressed or stressed mice exposed to ROE or normoxic conditions. Mice were exposed to chronic unpredictable stress (CUS) for 28 days, and ROE was delivered in the last 21 days of CUS. In normoxic mice, CUS caused anhedonia in the sucrose preference test, anxiety-like behaviour in the open field test, learning impairment in the Morris water maze, reduced hippocampal neurogenesis, increased serum corticosterone levels and increased expression of depression-related genes (Pclo, Mthfr and Grm5) in the hippocampus. All these changes were reversed by ROE, which had little or no effect in unstressed mice. These findings suggest that ROE simulating air cabin conditions of domestic flights may enhance resilience to stress improving mood, anxiety and learning ability.
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Affiliation(s)
- Roxana Paula Ginerete
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Giada Mascio
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Francesca Liberatore
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Domenico Bucci
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Nico Antenucci
- Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Paola Di Pietro
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Milena Cannella
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Tiziana Imbriglio
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Serena Notartomaso
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy
| | - Ferdinando Nicoletti
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy.,Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Valeria Bruno
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy.,Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
| | - Giuseppe Battaglia
- Department of Molecular Pathology, Neuropharmacology Unit, I.R.C.C.S. Neuromed, Pozzilli, Italy.,Department of Physiology and Pharmacology, Sapienza University, Rome, Italy
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35
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Abstract
Epigenetic mechanisms such as DNA methylation (DNAm) have been associated with stress responses and increased vulnerability to depression. Abnormal DNAm is observed in stressed animals and depressed individuals. Antidepressant treatment modulates DNAm levels and regulates gene expression in diverse tissues, including the brain and the blood. Therefore, DNAm could be a potential therapeutic target in depression. Here, we reviewed the current knowledge about the involvement of DNAm in the behavioural and molecular changes associated with stress exposure and depression. We also evaluated the possible use of DNAm changes as biomarkers of depression. Finally, we discussed current knowledge limitations and future perspectives.
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36
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Kendall KM, Van Assche E, Andlauer TFM, Choi KW, Luykx JJ, Schulte EC, Lu Y. The genetic basis of major depression. Psychol Med 2021; 51:2217-2230. [PMID: 33682643 DOI: 10.1017/s0033291721000441] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Major depressive disorder (MDD) is a common, debilitating, phenotypically heterogeneous disorder with heritability ranges from 30% to 50%. Compared to other psychiatric disorders, its high prevalence, moderate heritability, and strong polygenicity have posed major challenges for gene-mapping in MDD. Studies of common genetic variation in MDD, driven by large international collaborations such as the Psychiatric Genomics Consortium, have confirmed the highly polygenic nature of the disorder and implicated over 100 genetic risk loci to date. Rare copy number variants associated with MDD risk were also recently identified. The goal of this review is to present a broad picture of our current understanding of the epidemiology, genetic epidemiology, molecular genetics, and gene-environment interplay in MDD. Insights into the impact of genetic factors on the aetiology of this complex disorder hold great promise for improving clinical care.
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Affiliation(s)
- K M Kendall
- MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK
| | - E Van Assche
- Department of Psychiatry, University of Muenster, Muenster, Germany
| | - T F M Andlauer
- Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - K W Choi
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA02114, USA
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA02114, USA
- Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA02115, USA
| | - J J Luykx
- Department of Psychiatry, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Outpatient Second Opinion Clinic, GGNet Mental Health, Warnsveld, The Netherlands
| | - E C Schulte
- Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany
- Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
| | - Y Lu
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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37
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Lang X, Zhou Y, Zhao L, Gu Y, Wu X, Zhao Y, Li Z, Zhang X. Differences in patterns of metabolic abnormality and metabolic syndrome between early-onset and adult-onset first-episode drug-naive schizophrenia patients. Psychoneuroendocrinology 2021; 132:105344. [PMID: 34274733 DOI: 10.1016/j.psyneuen.2021.105344] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 06/19/2021] [Accepted: 06/24/2021] [Indexed: 12/18/2022]
Abstract
Although metabolic abnormalities and metabolic syndrome (MetS) often occur in schizophrenia, few studies have investigated them in early-onset schizophrenia (EOS) patients. To our knowledge, this was the first to compare clinical correlates of metabolic abnormalities between first-episode drug-naïve (FEDN) EOS and adult-onset schizophrenia (AOS) patients. A total of 489 Chinese FEDN schizophrenia patients (116 EOS and 373 AOS) and 451 healthy controls were recruited in this cross-sectional study. Blood pressure, waist circumference (WC), Body mass index (BMI), total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), glucose, hemoglobin A1c (HbA1c), insulin and insulin resistance were measured. The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate the clinical symptoms of schizophrenia patients, and higher scores on PANSS indicate increased severity. EOS patients had lower rates of: MetS, elevated WC, hypertriglyceridemia, hypercholesterolemia, and hyper-LDLC than EOS patients (all p < 0.05). In EOS patients, WC was positively associated with PANSS general psychopathology score (p = 0.04). In AOS patients, WC (p = 0.01; p = 0.02) and glucose (p < 0.001; p < 0.001) were positively associated with PANSS general psychopathology and total score. HOMA-IR was positively associated with PANSS total score (p = 0.04). Systolic BP, triglycerides and HDLC were main contributors to MetS in AOS (all p < 0.05), but not in EOS. BMI was a risk factor of MetS in EOS, while BMI and HOMA-IR were risk factors of MetS in AOS (all p < 0.05). Our results indicate differences in metabolic abnormalities patterns, risk factors and their association with clinical characteristics between Chinese EOS and AOS patients. DATA AVAILABILITY STATEMENT: The datasets that support the findings of this study are not publically available due to ongoing analyses for further publications, but are available from the corresponding author X.Z. upon reasonable request.
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Affiliation(s)
- Xiaoe Lang
- Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Yang Zhou
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Lei Zhao
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Yinjun Gu
- Shanghai Jinshan Mental Health Center, Shanghai, China
| | - Xi Wu
- Department of Neurosurgery, Shanghai Changhai Hospital, Shanghai, China
| | - Yuefeng Zhao
- University of Shanghai For Science and Technology, Shanghai, China
| | - Zezhi Li
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Xiangyang Zhang
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
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Sall S, Thompson W, Santos A, Dwyer DS. Analysis of Major Depression Risk Genes Reveals Evolutionary Conservation, Shared Phenotypes, and Extensive Genetic Interactions. Front Psychiatry 2021; 12:698029. [PMID: 34335334 PMCID: PMC8319724 DOI: 10.3389/fpsyt.2021.698029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/21/2021] [Indexed: 12/29/2022] Open
Abstract
Major depressive disorder (MDD) affects around 15% of the population at some stage in their lifetime. It can be gravely disabling and it is associated with increased risk of suicide. Genetics play an important role; however, there are additional environmental contributions to the pathogenesis. A number of possible risk genes that increase liability for developing symptoms of MDD have been identified in genome-wide association studies (GWAS). The goal of this study was to characterize the MDD risk genes with respect to the degree of evolutionary conservation in simpler model organisms such as Caenorhabditis elegans and zebrafish, the phenotypes associated with variation in these genes and the extent of network connectivity. The MDD risk genes showed higher conservation in C. elegans and zebrafish than genome-to-genome comparisons. In addition, there were recurring themes among the phenotypes associated with variation of these risk genes in C. elegans. The phenotype analysis revealed enrichment for essential genes with pleiotropic effects. Moreover, the MDD risk genes participated in more interactions with each other than did randomly-selected genes from similar-sized gene sets. Syntenic blocks of risk genes with common functional activities were also identified. By characterizing evolutionarily-conserved counterparts to the MDD risk genes, we have gained new insights into pathogenetic processes relevant to the emergence of depressive symptoms in man.
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Affiliation(s)
- Saveen Sall
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Willie Thompson
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Aurianna Santos
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
| | - Donard S. Dwyer
- Department of Psychiatry and Behavioral Medicine, Louisiana State University Health Shreveport, Shreveport, LA, United States
- Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Shreveport, Shreveport, LA, United States
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39
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Nitta A, Izuo N, Hamatani K, Inagaki R, Kusui Y, Fu K, Asano T, Torii Y, Habuchi C, Sekiguchi H, Iritani S, Muramatsu SI, Ozaki N, Miyamoto Y. Schizophrenia-Like Behavioral Impairments in Mice with Suppressed Expression of Piccolo in the Medial Prefrontal Cortex. J Pers Med 2021; 11:jpm11070607. [PMID: 34206873 PMCID: PMC8304324 DOI: 10.3390/jpm11070607] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/12/2021] [Accepted: 06/18/2021] [Indexed: 11/22/2022] Open
Abstract
Piccolo, a presynaptic cytomatrix protein, plays a role in synaptic vesicle trafficking in the presynaptic active zone. Certain single-nucleotide polymorphisms of the Piccolo-encoding gene PCLO are reported to be associated with mental disorders. However, a few studies have evaluated the relationship between Piccolo dysfunction and psychotic symptoms. Therefore, we investigated the neurophysiological and behavioral phenotypes in mice with Piccolo suppression in the medial prefrontal cortex (mPFC). Downregulation of Piccolo in the mPFC reduced regional synaptic proteins, accompanied with electrophysiological impairments. The Piccolo-suppressed mice showed an enhanced locomotor activity, impaired auditory prepulse inhibition, and cognitive dysfunction. These abnormal behaviors were partially ameliorated by the antipsychotic drug risperidone. Piccolo-suppressed mice received mild social defeat stress showed additional behavioral despair. Furthermore, the responses of these mice to extracellular glutamate and dopamine levels induced by the optical activation of mPFC projection in the dorsal striatum (dSTR) were inhibited. Similarly, the Piccolo-suppressed mice showed decreased depolarization-evoked glutamate and -aminobutyric acid elevations and increased depolarization-evoked dopamine elevation in the dSTR. These suggest that Piccolo regulates neurotransmission at the synaptic terminal of the projection site. Reduced neuronal connectivity in the mPFC-dSTR pathway via suppression of Piccolo in the mPFC may induce behavioral impairments observed in schizophrenia.
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Affiliation(s)
- Atsumi Nitta
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
- Correspondence: ; Tel.: +81-76-415-8822 (ext. 8823); Fax: +81-76-415-8826
| | - Naotaka Izuo
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
| | - Kohei Hamatani
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
| | - Ryo Inagaki
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
| | - Yuka Kusui
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
| | - Kequan Fu
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China
| | - Takashi Asano
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
| | - Youta Torii
- Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (Y.T.); (C.H.); (H.S.); (S.I.); (N.O.)
| | - Chikako Habuchi
- Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (Y.T.); (C.H.); (H.S.); (S.I.); (N.O.)
| | - Hirotaka Sekiguchi
- Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (Y.T.); (C.H.); (H.S.); (S.I.); (N.O.)
| | - Shuji Iritani
- Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (Y.T.); (C.H.); (H.S.); (S.I.); (N.O.)
| | - Shin-ichi Muramatsu
- Open Innovation Center, Division of Neurological Gene Therapy, Jichi Medical University, Shimotsuke 329-0498, Japan;
- Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Norio Ozaki
- Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan; (Y.T.); (C.H.); (H.S.); (S.I.); (N.O.)
| | - Yoshiaki Miyamoto
- Department of Pharmaceutical Therapy and Neuropharmacology, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; (N.I.); (K.H.); (R.I.); (Y.K.); (K.F.); (T.A.); (Y.M.)
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Li Z, Wang S, Chen Y, Wu X, Gu Y, Lang X, Wu F, Zhang XY. Smoking Affects the Patterns of Metabolic Disorders and Metabolic Syndrome in Patients With First-Episode Drug-Naive Schizophrenia: A Large Sample Study Based on the Chinese Han Population. Int J Neuropsychopharmacol 2021; 24:798-807. [PMID: 34153098 PMCID: PMC8538889 DOI: 10.1093/ijnp/pyab038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/22/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Although metabolic disorders and smoking are common in schizophrenia, few studies have investigated the effects of smoking on metabolic disorders or metabolic syndrome (MetS) in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. We sought to investigate the differences in metabolic disorders and MetS between smoking and nonsmoking FEDN schizophrenia patients. METHODS A total of 428 FEDN schizophrenia patients and 435 controls were recruited. Blood pressure, waist circumference, body mass index (BMI), lipid profiles, and glucose metabolism were measured. The psychopathology was evaluated by Positive and Negative Syndrome Scale. RESULTS FEDN schizophrenia patients had a higher smoking rate than controls (23.8% vs 14.0%, P < .001). After adjusting for confounding variables, the prevalence of MetS, overweight, hypertension, hypertriglyceridemia, elevated insulin, and insulin resistance in smoking patients was higher than those in nonsmoking patients, while overweight and hypertension were higher in the smoking controls than in nonsmoking controls (all P < .05). In smoking patients, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS, while in nonsmoking patients, waist circumference, systolic blood pressure, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS. In smoking patients, BMI and homeostatic model assessment for insulin resistance were associated factors of MetS (both P < .05). In nonsmoking patients, sex, BMI, insulin, and homeostatic model assessment for insulin resistance were associated factors of MetS (all P < .05). CONCLUSIONS Our study indicates that smoking schizophrenia patients have a higher prevalence of MetS and metabolic disorders than nonsmoking patients. Moreover, smoking and nonsmoking patients have different contributing components and associated factors for MetS.
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Affiliation(s)
- Zezhi Li
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuning Wang
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Yuping Chen
- Department of Neurosurgery, Shanghai Changhai Hospital, Shanghai, China
| | - Xi Wu
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yinjun Gu
- Jinshan Mental Health Center, Shanghai, China
| | - Xiaoe Lang
- Department of Psychiatry, The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Fengchun Wu
- Department of Neurosurgery, Shanghai Changhai Hospital, Shanghai, China
- Correspondence: Fengchun Wu, Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China ()
| | - Xiang Yang Zhang
- Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
- Xiang Yang Zhang, Institute of Psychology, Chinese Academy of Sciences, Beijing, China ()
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van Tol MJ, van der Wee NJA, Veltman DJ. Fifteen years of NESDA Neuroimaging: An overview of results related to clinical profile and bio-social risk factors of major depressive disorder and common anxiety disorders. J Affect Disord 2021; 289:31-45. [PMID: 33933910 DOI: 10.1016/j.jad.2021.04.009] [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: 12/24/2020] [Revised: 04/05/2021] [Accepted: 04/07/2021] [Indexed: 10/21/2022]
Abstract
The longitudinal Netherlands Study of Depression and Anxiety (NESDA) Neuroimaging study was set up in 2003 to investigate whether neuroanatomical and functional abnormalities during tasks of primary emotional processing, executive planning and memory formation, and intrinsic brain connectivity are i) shared by individuals with major depressive disorder (MDD) and common anxiety disorders; and ii) characterized by symptomatology-specific abnormalities. Furthermore, questions related to individual variations in vulnerability for onset, comorbidity, and longitudinal course could be investigated. Between 2005 and 2007, 233 individuals fulfilling a diagnosis of MDD, panic disorder, social anxiety disorder and/or generalized anxiety disorder and 68 healthy controls aging between 18 and 57 were invited from the NESDA main sample (n = 2981). An emotional faces processing task, an emotional word-encoding task, and an executive planning task were administered during 3T BOLD-fMRI acquisitions. In addition, resting state BOLD-fMRI was acquired and T1-weighted structural imaging was performed. All participants were invited to participate in the two-year and nine-year follow-up MRI measurement. Fifteen years of NESDA Neuroimaging demonstrated common morphological and neurocognitive abnormalities across individuals with depression and anxiety disorders. It however provided limited support for the idea of more extensive abnormalities in patients suffering from both depression and anxiety, despite their worse prognosis. Risk factors including childhood maltreatment and specific risk genes had an emotion processing modulating effect, apparently stronger than effects of diagnostic labels. Furthermore, brain imaging data, especially during emotion processing seemed valuable for predicting the long-term course of affective disorders, outperforming prediction based on clinical information alone.
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Affiliation(s)
- M J van Tol
- University of Groningen, University Medical Center Groningen, Department of Biomedical Sciences of Cells and Systems, Cognitive Neuroscience Center, Groningen, the Netherlands.
| | - N J A van der Wee
- Department of Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Department of Psychiatry, Leiden, the Netherlands
| | - D J Veltman
- Department of Psychiatry, Amsterdam University Medical Center, Location VUMC and Amsterdam Neuroscience, Amsterdam, the Netherlands
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Penninx BWJH, Eikelenboom M, Giltay EJ, van Hemert AM, Riese H, Schoevers RA, Beekman ATF. Cohort profile of the longitudinal Netherlands Study of Depression and Anxiety (NESDA) on etiology, course and consequences of depressive and anxiety disorders. J Affect Disord 2021; 287:69-77. [PMID: 33773360 DOI: 10.1016/j.jad.2021.03.026] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The Netherlands Study of Depression and Anxiety (NESDA, www.nesda.nl) is a longitudinal, multi-site, naturalistic, case-control cohort study set up to examine the etiology, course and consequences of depressive and anxiety disorders. This paper presents a cohort profile of NESDA. METHODS AND RESULTS The NESDA sample recruited initially 2329 persons with a remitted or current DSM-IV based depressive (major depressive disorder, dysthymia) and/or anxiety disorder (panic disorder, social phobia, agoraphobia, generalized anxiety disorder), 367 of their siblings and 652 healthy controls, yielding a total of 3348 participants. Half-day face-to-face assessments of participants started in 2004 and since then have been repeated six times over a period of 9 years. A 13-year follow-up assessment is ongoing, at what time we also recruit offspring of participants. Retention rates are generally high, ranging from 87.1% (after 2 years) to 69.4% (after 9 years). Psychiatric diagnostic interviews have been administered at all face-to-face assessments, as was monitoring of clinical characteristics, psychosocial functioning and somatic health. Assessed etiological factors include e.g. early and current environmental risk factors, psychological vulnerability and resilience factors as well as (neuro)biology through hypothesis-driven biomarker assessments, genome-wide and large-scale '-omics' assessments, and neuroimaging assessments. LIMITATIONS The naturalistic design allows research into course and consequences of affective disorders but is limited in treatment response interpretation. CONCLUSIONS NESDA provides a strong research infrastructure for research into depressive and/or anxiety disorders. Its data have been used for many scientific papers describing either NESDA-based analyses or joint collaborative consortia-projects, and are in principle available to researchers outside the NESDA consortium.
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Affiliation(s)
- Brenda W J H Penninx
- Department of Psychiatry, Amsterdam Public Health, Amsterdam University Medical Center, Vrije Universiteit, and GGZ InGeest Specialized Mental Health Care, Amsterdam, The Netherlands (Oldenaller 1, 1081 HJ Amsterdam, The Netherlands).
| | - Merijn Eikelenboom
- Department of Psychiatry, Amsterdam Public Health, Amsterdam University Medical Center, Vrije Universiteit, and GGZ InGeest Specialized Mental Health Care, Amsterdam, The Netherlands (Oldenaller 1, 1081 HJ Amsterdam, The Netherlands)
| | - Erik J Giltay
- Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands (Albinusdreef 2, 2333 ZA Leiden, The Netherlands)
| | - Albert M van Hemert
- Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands (Albinusdreef 2, 2333 ZA Leiden, The Netherlands)
| | - Harriëtte Riese
- University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Interdisciplinary Centre for Psychopathology and Emotion regulation, Groningen (Hanzeplein 1, 9713 GZ Groningen, The Netherlands)
| | - Robert A Schoevers
- University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Interdisciplinary Centre for Psychopathology and Emotion regulation, Groningen (Hanzeplein 1, 9713 GZ Groningen, The Netherlands)
| | - Aartjan T F Beekman
- Department of Psychiatry, Amsterdam Public Health, Amsterdam University Medical Center, Vrije Universiteit, and GGZ InGeest Specialized Mental Health Care, Amsterdam, The Netherlands (Oldenaller 1, 1081 HJ Amsterdam, The Netherlands)
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Hu G, Yu S, Yuan C, Hong W, Wang Z, Zhang R, Wang D, Li Z, Yi Z, Fang Y. Gene expression signatures differentiating major depressive disorder from subsyndromal symptomatic depression. Aging (Albany NY) 2021; 13:13124-13137. [PMID: 33971621 PMCID: PMC8148500 DOI: 10.18632/aging.202995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/27/2021] [Indexed: 12/11/2022]
Abstract
Subsyndromal symptomatic depression (SSD) and major depressive disorder (MDD) have been classified as distinct diseases, due to their dissimilar gene expression profiles and responses to venlafaxine. To identify specific biomarkers of these two diseases, we conducted a secondary analysis of the gene expression signatures of SSD patients, MDD patients and healthy controls (n=8/group) from the study of Yi et al. Global, individual, specific, enrichment and co-expression analyses were used to compare the transcriptomic profiles of peripheral blood lymphocytes from the three groups. The global and individual analyses revealed that different genes were up- and downregulated in the SSD and MDD groups. Through our specific analysis, we identified 1719 and 3278 differentially expressed genes specifically associated with MDD and SSD, respectively. Enrichment and co-expression analyses demonstrated that the genes specific to MDD were enriched in pathways associated with hormone levels and immune responses, while those specific to SSD were associated with immune function. The specific hub gene for the MDD co-expression network was transmembrane protein 132B (TMEM132B), while the hub genes for SSD were actin-related protein 2/3 complex (ARPC2) and solute carrier family 5 member 5 (SLC5A5). This bioinformatic analysis has provided potential biomarkers that can distinguish SSD from MDD.
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Affiliation(s)
- Guoqin Hu
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.,Department of Psychiatry, Huangpu District Mental Health Center, Shanghai 200023, China
| | - Shunying Yu
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Chengmei Yuan
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Wu Hong
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Zuowei Wang
- Department of Psychiatry, Hongkou District Mental Health Center, Shanghai 200083, China
| | - Ran Zhang
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Dongxiang Wang
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Zezhi Li
- Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
| | - Zhenghui Yi
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Yiru Fang
- Clinical Research Center, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 20000, China.,Shanghai Key Laboratory of Psychotic Disorders, Shanghai 201108, 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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MORC1 methylation and BDI are associated with microstructural features of the hippocampus and medial prefrontal cortex. J Affect Disord 2021; 282:91-97. [PMID: 33401128 DOI: 10.1016/j.jad.2020.12.056] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 12/14/2020] [Accepted: 12/17/2020] [Indexed: 01/16/2023]
Abstract
BACKGROUND Alterations in the hippocampus and prefrontal cortex (PFC) have frequently been reported in depressed patients. These parameters might prove to be a consistent finding in depression. In addition, peripheral DNA methylation of the MORC1 gene promoter showed stable associations with depression across independent samples. However, the question arises whether MORC1, supposedly acting as transcription factor, might also be involved in neurobiological alterations accompanying depression. This study further analyses the role of MORC1 in depression by investigating a potential correlation between peripheral MORC1 DNA methylation and neuronal structural properties previously associated with depression in humans. METHODS Beck Depression Inventory (BDI) was assessed in 52 healthy participants. DNA was extracted from buccal cells and MORC1 methylation correlated with micro- and macrostructural properties derived from magnetic resonance imaging (MRI) and neurite orientation dispersion and density imaging (NODDI) in the hippocampus and medial prefrontal cortex (mPFC). RESULTS MORC1 methylation was associated with volume reduction and neurite orientation dispersion and density markers in the hippocampus and mPFC. BDI was positively associated with neurite orientation dispersion and density markers in the hippocampus. LIMITATIONS The study was conducted in a small sample of healthy participants with subclinical depressive symptoms. Peripheral tissue was analyzed. CONCLUSION We found significant negative associations between peripheral MORC1 methylation and macro- and microstructural markers in the hippocampus and mPFC. Thus, MORC1 might be involved in neurobiological properties. Studies investigating neuronal methylation patterns of MORC1 are needed to support this hypothesis.
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Li Z, Ruan M, Chen J, Fang Y. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Neurosci Bull 2021; 37:863-880. [PMID: 33582959 PMCID: PMC8192601 DOI: 10.1007/s12264-021-00638-3] [Citation(s) in RCA: 137] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023] Open
Abstract
Major depressive disorder (MDD), also referred to as depression, is one of the most common psychiatric disorders with a high economic burden. The etiology of depression is still not clear, but it is generally believed that MDD is a multifactorial disease caused by the interaction of social, psychological, and biological aspects. Therefore, there is no exact pathological theory that can independently explain its pathogenesis, involving genetics, neurobiology, and neuroimaging. At present, there are many treatment measures for patients with depression, including drug therapy, psychotherapy, and neuromodulation technology. In recent years, great progress has been made in the development of new antidepressants, some of which have been applied in the clinic. This article mainly reviews the research progress, pathogenesis, and treatment of MDD.
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Affiliation(s)
- Zezhi Li
- Clinical Research Center and Division of Mood Disorders of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.,Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Meihua Ruan
- Shanghai Institute of Nutrition and Health, Shanghai Information Center for Life Sciences, Chinese Academy of Science, Shanghai, 200031, China
| | - Jun Chen
- Clinical Research Center and Division of Mood Disorders of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.,Shanghai Key Laboratory of Psychotic Disorders, Shanghai, 201108, China
| | - Yiru Fang
- Clinical Research Center and Division of Mood Disorders of Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. .,Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Science, Shanghai, 200031, China. .,Shanghai Key Laboratory of Psychotic Disorders, Shanghai, 201108, China.
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Zhou Y, Song X, Guo Y, Lang X, Li Z, Zhang XY. Sex differences in metabolic disorder patterns of first-episode drug-naive patients with schizophrenia. Psychoneuroendocrinology 2021; 124:105061. [PMID: 33291004 DOI: 10.1016/j.psyneuen.2020.105061] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 12/16/2022]
Abstract
Although metabolic disorders are common in schizophrenia, few studies investigated sex differences in metabolic disorder. This study aimed to examine the sex differences in the clinical correlates of metabolic disorders and MetS in patients with first-episode drug-naïve (FEDN) schizophrenia. A total of 257 FEDN schizophrenia patients and 118 controls were recruited. Body mass index (BMI), waist circumference (WC) and blood pressure were measured. Fasting blood samples were drawn to detect triglycerides, cholesterol, high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), blood glucose, glycosylated hemoglobin (HbA1c) and insulin. The Positive and Negative Syndrome Scale (PANSS) was applied to assess the clinical symptoms. There was sex difference in the prevalence of high BMI and dyslipidemia of schizophrenia patients. Female patients had lower prevalence of high BMI (p = 0.03) and hypertriglyceridemia (p = 0.006), but had higher prevalence of hypo-HDLC (p = 0.005), compared with male patients. Further, there were sex differences in the relationship between metabolic parameters and psychopathological dimensions. In male patients, WC was associated with positive symptoms and negative symptoms (r = 0.26, p Bonferroni = 0.02; r = 0.26, p Bonferroni = 0.02). In female patients, BMI (r = 0.26, p Bonferroni = 0.01), WC (r = 0.30, p Bonferroni = 0.004) and HAb1c were associated with positive symptoms (r = 0.27, p Bonferroni = 0.008). Insulin (r = 0.24, p Bonferroni = 0.02; r = 0.23, p Bonferroni = 0.04) and HOMA-IR (r = 0.29, p Bonferroni = 0.004; r = 0.25, p Bonferroni = 0.02) were associated with positive symptoms and general psychopathology symptoms. The contribution of clinical and metabolic components to MetS was almost same between male and female patients. Our study demonstrates sex difference in metabolic disorder patterns in schizophrenia patients.
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Affiliation(s)
- Yongjie Zhou
- Shenzhen Kangning Hospital, Shenzhen, Guangdong, China
| | - Xinxin Song
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Yanhong Guo
- Qingdao Mental Health Center, Qingdao University, Qingdao, China
| | - Xiaoe Lang
- Department of Psychiatry, The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Zezhi Li
- Department of Neurology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xiang Yang Zhang
- Shenzhen Kangning Hospital, Shenzhen, Guangdong, China; CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China; Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
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Tubbs JD, Ding J, Baum L, Sham PC. Systemic neuro-dysregulation in depression: Evidence from genome-wide association. Eur Neuropsychopharmacol 2020; 39:1-18. [PMID: 32896454 DOI: 10.1016/j.euroneuro.2020.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 06/10/2020] [Accepted: 08/17/2020] [Indexed: 12/16/2022]
Abstract
Depression is the world's leading cause of disability. Greater understanding of the neurobiological basis of depression is necessary for developing novel treatments with improved efficacy and acceptance. Recently, major advances have been made in the search for genetic variants associated with depression which may help to elucidate etiological mechanisms. The present review has two major objectives. First, we offer a brief review of two major biological systems with strong evidence for involvement in depression pathology: neurotransmitter systems and the stress response. Secondly, we provide a synthesis of the functions of the 269 genes implicated by the most recent genome-wide meta-analysis, supporting the importance of these systems in depression and providing insights into other possible mechanisms involving neurodevelopment, neurogenesis, and neurodegeneration. Our goal is to undertake a broad, preliminary stock-taking of the most recent hypothesis-free findings and examine the weight of the evidence supporting these existing theories and highlighting novel directions. This qualitative review and accompanying gene function table provides a valuable resource and guide for basic and translational researchers, with suggestions for future mechanistic research, leveraging genetics to prioritize studies on the neurobiological processes involved in depression etiology and treatment.
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Affiliation(s)
- Justin D Tubbs
- Department of Psychiatry, The University of Hong Kong, Hong Kong
| | - Jiahong Ding
- Department of Psychiatry, The University of Hong Kong, Hong Kong
| | - Larry Baum
- Department of Psychiatry, The University of Hong Kong, Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong
| | - Pak C Sham
- Department of Psychiatry, The University of Hong Kong, Hong Kong; State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong; Centre of PanorOmic Sciences, The University of Hong Kong, Hong Kong.
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Rafikova EI, Ryskov AP, Vasilyev VA. Genetics of Depressive Disorders: Candidate Genes and Genome-Wide Association Studies. RUSS J GENET+ 2020. [DOI: 10.1134/s1022795420080116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Abstract
The prevalence and clinical characteristics of depressive disorders differ between women and men; however, the genetic contribution to sex differences in depressive disorders has not been elucidated. To evaluate sex-specific differences in the genetic architecture of depression, whole exome sequencing of samples from 1000 patients (70.7% female) with depressive disorder was conducted. Control data from healthy individuals with no psychiatric disorder (n = 72, 26.4% female) and East-Asian subpopulation 1000 Genome Project data (n = 207, 50.7% female) were included. The genetic variation between men and women was directly compared using both qualitative and quantitative research designs. Qualitative analysis identified five genetic markers potentially associated with increased risk of depressive disorder in females, including three variants (rs201432982 within PDE4A, and rs62640397 and rs79442975 within FDX1L) mapping to chromosome 19p13.2 and two novel variants (rs820182 and rs820148) within MYO15B at the chromosome 17p25.1 locus. Depressed patients homozygous for these variants showed more severe depressive symptoms and higher suicidality than those who were not homozygotes (i.e., heterozygotes and homozygotes for the non-associated allele). Quantitative analysis demonstrated that the genetic burden of protein-truncating and deleterious variants was higher in males than females, even after permutation testing. Our study provides novel genetic evidence that the higher prevalence of depressive disorders in women may be attributable to inherited variants.
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