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Dang C, Severn-Ellis AA, Bayer P, Anderson N, Gholipour-Kanani H, Batley J, McCauley RD, Day RD, Semmens JM, Speed C, Meekan MG, Parsons MJG. Insights into the transcriptomic responses of silver-lipped pearl oysters Pinctada maxima exposed to a simulated large-scale seismic survey. BMC Genomics 2024; 25:1188. [PMID: 39639203 PMCID: PMC11622493 DOI: 10.1186/s12864-024-11091-7] [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: 08/06/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND The wild stocks of Pinctada maxima pearl oysters found off the coast of northern Australia are of critical importance for the sustainability of Australia's pearling industry. Locations inhabited by pearl oysters often have oil and gas reserves in the seafloor below and are therefore potentially subjected to seismic exploration surveys. The present study assessed the impact of a simulated commercial seismic survey on the transcriptome of pearl oysters. Animals were placed at seven distances (-1000, 0, 300, 500, 1000, 2000, and 6000 m) from the first of six operational seismic source sail lines. Vessel control groups were collected before the seismic survey started and exposed groups were collected after completion of six operational seismic sail lines (operated at varying distances over a four-day period). Samples from these groups were taken immediately and at 1, 3, and 6 months post-exposure. RNA-seq was used to identify candidate genes and pathways impacted by the seismic noise in pearl oyster mantle tissues. The quantified transcripts were compared using DESeq2 and pathway enrichment analysis was conducted using KEGG pathway, identifying differentially expressed genes and pathways associated with the seismic activity. RESULTS The study revealed the highest gene expression and pathway dysregulation after four days of exposure and a month post-exposure. However, this dysregulation diminished after three months, with only oysters at -1000 and 0 m displaying differential gene expression and pathway disruption six months post-exposure. Stress-induced responses were evident and impacted energy production, transcription, translation, and protein synthesis. CONCLUSION Seismic activity impacted the gene expression and pathways of pearl oysters at distances up to 2000 m from the source after four days of exposure, and at distances up to 1000 m from the source one-month post-exposure. At three- and six-months post-exposure, gene and pathway dysregulations were mostly observed in oysters located closest to the seismic source at 0 and - 1000 m. Overall, our results suggest that oysters successfully activated stress responses to mitigate damage and maintain cellular homeostasis and growth in response to seismic noise exposure.
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Affiliation(s)
- Cecile Dang
- Department of Primary Industries and Regional Development, Government of Western Australia, Perth, WA, 6000, Australia.
- School of Biological Sciences, University of Western Australia, Perth, WA, 6009, Australia.
| | - Anita A Severn-Ellis
- Department of Primary Industries and Regional Development, Government of Western Australia, Perth, WA, 6000, Australia
| | - Philipp Bayer
- School of Biological Sciences, University of Western Australia, Perth, WA, 6009, Australia
| | | | - Hosna Gholipour-Kanani
- Department of Primary Industries and Regional Development, Government of Western Australia, Perth, WA, 6000, Australia
| | - Jacqueline Batley
- School of Biological Sciences, University of Western Australia, Perth, WA, 6009, Australia
| | - Robert D McCauley
- Centre for Marine Technology, Curtin University, Bentley, WA, 6102, Australia
| | - Ryan D Day
- Fisheries and Aquaculture Centre, Institute for Marine and Antarctic Studies, University of Tasmania, Hobart, TAS, 7001, Australia
| | - Jayson M Semmens
- Fisheries and Aquaculture Centre, Institute for Marine and Antarctic Studies, University of Tasmania, Hobart, TAS, 7001, Australia
| | - Conrad Speed
- Australian Institute of Marine Science, Perth, WA, 6009, Australia
| | - Mark G Meekan
- Oceans Institute, University of Western Australia, Perth, WA, 6009, Australia
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Yang R, Wang R, Zhao D, Lian K, Shang B, Dong L, Yang X, Dang X, Sun D, Cheng Y. Integrative analysis of transcriptome-wide association study and mRNA expression profile identified risk genes for bipolar disorder. Neurosci Lett 2024; 839:137935. [PMID: 39151574 DOI: 10.1016/j.neulet.2024.137935] [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: 03/08/2024] [Revised: 08/05/2024] [Accepted: 08/09/2024] [Indexed: 08/19/2024]
Abstract
OBJECTIVE Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through "vast but mixed" Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS. METHODS We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0). RESULTS TWAS identified 362 genes with P value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (PTWAS=1.07 × 10-11), ALOX5AP (PTWAS=3.12 × 10-8), and PLEC (PTWAS=1.27 × 10-7). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (PTWAS=0.0020, PmRNA=0.0000), TMPRSS9 (PTWAS=0.0405, PmRNA=0.0032), and SNX10 (PTWAS=0.0104, PmRNA=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species. CONCLUSIONS We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.
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Affiliation(s)
- Runxu Yang
- Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Rui Wang
- Department of Prevention and Health Care, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Dongyan Zhao
- First Affiliated Hospital of Dali University, Dali, Yunnan, China
| | - Kun Lian
- Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Binli Shang
- Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Lei Dong
- Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Xuejuan Yang
- Lincang Psychiatric Hospital, Lincang, Yunnan, China
| | - Xinglun Dang
- 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
| | - Duo Sun
- Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yuqi Cheng
- Psychiatry Department, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Wang Z, Xie Z, Zhang Z, Zhou W, Guo B, Li M. Multi-platform omics sequencing dissects the atlas of plasma-derived exosomes in rats with or without depression-like behavior after traumatic spinal cord injury. Prog Neuropsychopharmacol Biol Psychiatry 2024; 132:110987. [PMID: 38438071 DOI: 10.1016/j.pnpbp.2024.110987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 01/29/2024] [Accepted: 02/28/2024] [Indexed: 03/06/2024]
Abstract
BACKGROUND Exosomes can penetrate the blood-brain barrier for material exchange between the peripheral and central nervous systems. Differences in exosome contents could explain the susceptibility of different individuals to depression-like behavior after traumatic spinal cord injury (TSCI). METHODS Hierarchical clustering was used to integrate multiple depression-related behavioral outcomes in sham and TSCI rats and ultimately identify non-depressed and depressed rats. The difference in plasma exosome contents between non-depressed and depressed rats after TSCI was assessed in 15 random subjects by performing plasma exosome transcriptomics, mass spectroscope-based proteomics, and non-targeted metabolomics analyses. RESULTS The results revealed that about 27.6% of the rats developed depression-like behavior after TSCI. Totally, 10 differential metabolites, 81 differentially expressed proteins (DEPs), 373 differentially expressed genes (DEGs), and 55 differentially expressed miRNAs (DEmiRNAs) were identified between non-depressed TSCI and sham rats. Meanwhile, 37 differential metabolites, 499 DEPs, 1361 DEGs, and 89 DEmiRNAs were identified between depressed and non-depressed TSCI rats. Enrichment analysis showed that the progression of depression-like behavior after TSCI may be related to amino acid metabolism disorder and dysfunction of multiple signaling pathways, including endocytosis, lipid and atherosclerosis, toll-like receptor, TNF, and PI3K-Akt pathway. CONCLUSION Overall, our study systematically revealed for the first time the differences in plasma exosome contents between non-depressed and depressed rats after TSCI, which will help broaden our understanding of the complex molecular mechanisms involved in brain functional recombination after TSCI.
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Affiliation(s)
- Zhihua Wang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, China.
| | - Zhiping Xie
- Department of Neurosurgery, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China.
| | - Zhixiong Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
| | - Wu Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
| | - Boyu Guo
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
| | - Meihua Li
- Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
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Castellini G, Merola GP, Baccaredda Boy O, Pecoraro V, Bozza B, Cassioli E, Rossi E, Bessi V, Sorbi S, Nacmias B, Ricca V. Emotional dysregulation, alexithymia and neuroticism: a systematic review on the genetic basis of a subset of psychological traits. Psychiatr Genet 2023; 33:79-101. [PMID: 36729042 PMCID: PMC10158611 DOI: 10.1097/ypg.0000000000000335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/24/2022] [Indexed: 02/03/2023]
Abstract
Neuroticism, alexithymia and emotion dysregulation are key traits and known risk factors for several psychiatric conditions. In this systematic review, the aim is to evaluate the genetic contribution to these psychological phenotypes. A systematic review of articles found in PubMed was conducted. Search terms included 'genetic', 'GWAS', 'neuroticism', 'alexithymia' and 'emotion dysregulation'. Risk of bias was assessed utilizing the STREGA checklist. Two hundred two papers were selected from existing literature based on the inclusion and exclusion criteria. Among these, 27 were genome-wide studies and 175 were genetic association studies. Single gene association studies focused on selected groups of genes, mostly involved in neurotransmission, with conflicting results. GWAS studies on neuroticism, on the other hand, found several relevant and replicated intergenic and intronic loci affecting the expression and regulation of crucial and well-known genes (such as DRD2 and CRHR1). Mutations in genes coding for trascriptional factors were also found to be associated with neuroticism (DCC, XKR6, TCF4, RBFOX1), as well as a noncoding regulatory RNA (LINC00461). On the other hand, little GWAS data are available on alexythima and emotional dysregulation.
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Affiliation(s)
| | | | | | | | | | | | | | - Valentina Bessi
- Neurology Unit, Department of Health Sciences, University of Florence, Florence, Italy
| | - Sandro Sorbi
- Neurology Unit, Department of Health Sciences, University of Florence, Florence, Italy
| | - Benedetta Nacmias
- Neurology Unit, Department of Health Sciences, University of Florence, Florence, Italy
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Ping A, Yang M, Xu S, Li Q, Feng Y, Gao K, Wang S, Duan K. Correlations between GRIN2B and GRIN3A gene polymorphisms and postpartum depressive symptoms in Chinese parturients undergoing cesarean section: A prospective cohort study. J Psychosom Res 2023; 168:111210. [PMID: 36898314 DOI: 10.1016/j.jpsychores.2023.111210] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 02/16/2023] [Accepted: 02/26/2023] [Indexed: 03/12/2023]
Abstract
OBJECTIVE To investigate the association of postpartum depressive symptoms (PDS) and self-harm ideation with n-methyl-d-aspartate (NMDA) receptor GRIN2B and GRIN3A gene polymorphisms and other risk factors in women undergoing cesarean section. METHODS A total of 362 parturients undergoing cesarean section under lumbar anesthesia were selected and their postpartum depression level was assessed by the Edinburgh Postpartum Depression Scale (EPDS) at 42 days postpartum, with an EPDS score of 9/10 as the cut-off value. Three GRIN2B SNP loci (rs1805476, rs3026174, rs4522263) and five GRIN3A SNP loci (rs1983812, rs2050639, rs2050641, rs3739722, rs10989563) were selected for genotype detection. The role of each SNP, linkage disequilibrium and haplotypes in the development of postpartum depression was analyzed. Logistic regression analysis was performed for related risk factors. RESULTS PDS incidence was 16.85%, and self-harm ideation incidence was 13.54%. Univariate analysis showed that GRIN2B rs1805476, rs3026174 and rs4522263 gene polymorphisms were associated with PDS (p < 0.05), with GRIN2B rs4522263 gene also associated with maternal self-harm ideation. GRIN3A rs1983812, rs2050639, rest rs2050641, rs3739722 and rs10989563 alleles were not associated with PDS. Logistic regression analysis indicated that high pregnancy stress, as well as rs1805476 and rs4522263 alleles were PDS risk factors following cesarean delivery. GRIN2B (TTG p = 0.002) and GRIN3A (TGTTC p = 0.002) haplotypes were associated with the lower PDS incidence and higher PDS incidence respectively. CONCLUSION GRIN2B rs1805476 GG genotype, rs4522263 CC genotype and high stress during pregnancy were risk factors for PDS, whilst a significantly higher incidence of self-harm ideation was evident in parturients carrying GRIN2B rs4522263 CC genotype.
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Affiliation(s)
- Anqi Ping
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Mi Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Shouyu Xu
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Qiuwen Li
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Yunfei Feng
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Kai Gao
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China
| | - Saiying Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China.
| | - Kaiming Duan
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, PR China.
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van der Walt K, Campbell M, Stein DJ, Dalvie S. Systematic review of genome-wide association studies of anxiety disorders and neuroticism. World J Biol Psychiatry 2022; 24:280-291. [PMID: 35815422 DOI: 10.1080/15622975.2022.2099970] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
OBJECTIVES To summarise SNP associations identified by genome-wide association studies (GWASs) of anxiety disorders and neuroticism; to appraise the quality of individual studies, and to assess the ancestral diversity of study participants. METHODS We searched PubMed, Scopus, PsychInfo and PubPsych for GWASs of anxiety disorders, non-diagnostic traits (such as anxiety sensitivity), and neuroticism, and extracted all SNPs that surpassed genome-wide significance. We graded study quality using Q-genie scores and reviewed the ancestral diversity of included participants. RESULTS 32 studies met our inclusion criteria. A total of 563 independent significant variants were identified, of which 29 were replicated nominally in independent samples, and 3 were replicated significantly. The studies had good global quality, but many smaller studies were underpowered. Phenotypic heterogeneity for anxiety (and less so for neuroticism) seemed to reflect the complexity of capturing this trait. Ancestral diversity was poor, with 70% of studies including only populations of European ancestry. CONCLUSION The functionality of genes identified by GWASs of anxiety and neuroticism deserves further investigation. Future GWASs should have larger sample sizes, more rigorous phenotyping and include more ancestrally diverse population groups.
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Affiliation(s)
- Kristien van der Walt
- Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
| | - Megan Campbell
- MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics. Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa.,Global Initiative for Neuropsychiatric Genetics Education in Research (GINGER) program, Harvard T.H. Chan School of Public Health and the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, Boston, Massachusetts, USA
| | - Dan J Stein
- SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
| | - Shareefa Dalvie
- SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.,Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.,Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Cape Town
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Saez E, Erkoreka L, Moreno-Calle T, Berjano B, Gonzalez-Pinto A, Basterreche N, Arrue A. Genetic variables of the glutamatergic system associated with treatment-resistant depression: A review of the literature. World J Psychiatry 2022; 12:884-896. [PMID: 36051601 PMCID: PMC9331449 DOI: 10.5498/wjp.v12.i7.884] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/29/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
Depression is a common, recurrent mental disorder and one of the leading causes of disability and global burden of disease worldwide. Up to 15%-40% of cases do not respond to diverse pharmacological treatments and, thus, can be defined as treatment-resistant depression (TRD). The development of biomarkers predictive of drug response could guide us towards personalized and earlier treatment. Growing evidence points to the involvement of the glutamatergic system in the pathogenesis of TRD. Specifically, the N-methyl-D-aspartic acid receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), which are targeted by ketamine and esketamine, are proposed as promising pathways. A literature search was performed to identify studies on the genetics of the glutamatergic system in depression, focused on variables related to NMDARs and AMPARs. Our review highlights GRIN2B, which encodes the NR2B subunit of NMDAR, as a candidate gene in the pathogenesis of TRD. In addition, several studies have associated genes encoding AMPAR subunits with symptomatic severity and suicidal ideation. These genes encoding glutamatergic receptors could, therefore, be candidate genes for understanding the etiopathogenesis of TRD, as well as for understanding the pharmacodynamic mechanisms and response to ketamine and esketamine treatment.
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Affiliation(s)
- Estela Saez
- Department of Psychiatry, Barrualde-Galdakao Integrated Health Organization, Osakidetza-Basque Health Service, Galdakao 48960, Spain
| | - Leire Erkoreka
- Department of Psychiatry, Barrualde-Galdakao Integrated Health Organization, Osakidetza-Basque Health Service, Galdakao 48960, Spain
- Mental Health Network Group, Biocruces Bizkaia Health Research Institute, Barakaldo 48903, Spain
- Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa 48940, Spain
| | - Teresa Moreno-Calle
- Department of Psychiatry, Barrualde-Galdakao Integrated Health Organization, Osakidetza-Basque Health Service, Galdakao 48960, Spain
- Mental Health Network Group, Biocruces Bizkaia Health Research Institute, Barakaldo 48903, Spain
| | - Belen Berjano
- Department of Psychiatry, Barrualde-Galdakao Integrated Health Organization, Osakidetza-Basque Health Service, Galdakao 48960, Spain
| | - Ana Gonzalez-Pinto
- Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa 48940, Spain
- Department of Psychiatry, Araba Integrated Health Organization, Osakidetza-Basque Health Service, CIBERSAM, Vitoria-Gasteiz 01004, Spain
- Severe Mental Disorders Group, Bioaraba Health Research Institute, Vitoria-Gasteiz 01009, Spain
| | - Nieves Basterreche
- Zamudio Hospital, Bizkaia Mental Health Network, Osakidetza-Basque Health Service, Zamudio 48170, Spain
- Integrative Research Group in Mental Health, Biocruces Bizkaia Health Research Institute, Barakaldo 48903, Spain
| | - Aurora Arrue
- Mental Health Network Group, Biocruces Bizkaia Health Research Institute, Barakaldo 48903, Spain
- Neurochemical Research Unit, Bizkaia Mental Health Network, Osakidetza-Basque Health Service, Barakaldo 48903, Spain
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Kamran M, Bibi F, ur. Rehman A, Morris DW. Major Depressive Disorder: Existing Hypotheses about Pathophysiological Mechanisms and New Genetic Findings. Genes (Basel) 2022; 13:646. [PMID: 35456452 PMCID: PMC9025468 DOI: 10.3390/genes13040646] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/16/2022] [Accepted: 03/23/2022] [Indexed: 01/08/2023] Open
Abstract
Major depressive disorder (MDD) is a common mental disorder generally characterized by symptoms associated with mood, pleasure and effectiveness in daily life activities. MDD is ranked as a major contributor to worldwide disability. The complex pathogenesis of MDD is not yet understood, and this is a major cause of failure to develop new therapies and MDD recurrence. Here we summarize the literature on existing hypotheses about the pathophysiological mechanisms of MDD. We describe the different approaches undertaken to understand the molecular mechanism of MDD using genetic data. Hundreds of loci have now been identified by large genome-wide association studies (GWAS). We describe these studies and how they have provided information on the biological processes, cell types, tissues and druggable targets that are enriched for MDD risk genes. We detail our understanding of the genetic correlations and causal relationships between MDD and many psychiatric and non-psychiatric disorders and traits. We highlight the challenges associated with genetic studies, including the complexity of MDD genetics in diverse populations and the need for a study of rare variants and new studies of gene-environment interactions.
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Affiliation(s)
- Muhammad Kamran
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (M.K.); (A.u.R.)
- Centre for Neuroimaging, Cognition and Genomics (NICOG), Discipline of Biochemistry, National University of Ireland Galway, H91 CF50 Galway, Ireland
| | - Farhana Bibi
- Department of Microbiology, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan;
| | - Asim. ur. Rehman
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan; (M.K.); (A.u.R.)
| | - Derek W. Morris
- Centre for Neuroimaging, Cognition and Genomics (NICOG), Discipline of Biochemistry, National University of Ireland Galway, H91 CF50 Galway, Ireland
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Ghieh F, Barbotin AL, Prasivoravong J, Ferlicot S, Mandon-Pepin B, Fortemps J, Garchon HJ, Serazin V, Leroy C, Marcelli F, Vialard F. Azoospermia and reciprocal translocations: should whole-exome sequencing be recommended? Basic Clin Androl 2021; 31:27. [PMID: 34758722 PMCID: PMC8582189 DOI: 10.1186/s12610-021-00145-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 09/07/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements. RESULTS We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections. CONCLUSIONS Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients.
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Affiliation(s)
- Farah Ghieh
- Université Paris-Saclay, UVSQ, INRAE, BREED, F-78350, Jouy-en-Josas, France
- École Nationale Vétérinaire d'Alfort, BREED, F-94700, Maisons-Alfort, France
| | - Anne-Laure Barbotin
- Institut de Biologie de la Reproduction-Spermiologie-CECOS, Hôpital Jeanne de Flandre, Centre Hospitalier et Universitaire, F-59000, Lille, France
| | - Julie Prasivoravong
- Institut de Biologie de la Reproduction-Spermiologie-CECOS, Hôpital Jeanne de Flandre, Centre Hospitalier et Universitaire, F-59000, Lille, France
| | - Sophie Ferlicot
- Service d'Anatomie Pathologique, AP-HP, Université Paris-Saclay, Hôpital de Bicêtre, F-94270, Le Kremlin-Bicêtre, France
| | - Béatrice Mandon-Pepin
- Université Paris-Saclay, UVSQ, INRAE, BREED, F-78350, Jouy-en-Josas, France
- École Nationale Vétérinaire d'Alfort, BREED, F-94700, Maisons-Alfort, France
| | - Joanne Fortemps
- Service d'Anatomie Pathologique, CHI de Poissy/Saint-Germain-en-Laye, F-78100, Saint- Germain-en-Laye, France
| | | | - Valérie Serazin
- Université Paris-Saclay, UVSQ, INRAE, BREED, F-78350, Jouy-en-Josas, France
- École Nationale Vétérinaire d'Alfort, BREED, F-94700, Maisons-Alfort, France
- Département de Génétique, Laboratoire de Biologie Médicale, CHI de Poissy/Saint-Germain- en-Laye, F-78300, Poissy, France
| | - Clara Leroy
- Institut de Biologie de la Reproduction-Spermiologie-CECOS, Hôpital Jeanne de Flandre, Centre Hospitalier et Universitaire, F-59000, Lille, France
| | - François Marcelli
- Institut de Biologie de la Reproduction-Spermiologie-CECOS, Hôpital Jeanne de Flandre, Centre Hospitalier et Universitaire, F-59000, Lille, France
| | - François Vialard
- Université Paris-Saclay, UVSQ, INRAE, BREED, F-78350, Jouy-en-Josas, France.
- École Nationale Vétérinaire d'Alfort, BREED, F-94700, Maisons-Alfort, France.
- Département de Génétique, Laboratoire de Biologie Médicale, CHI de Poissy/Saint-Germain- en-Laye, F-78300, Poissy, France.
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10
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Inoue M, Arichi S, Hachiya T, Ohtera A, Kim SW, Yu E, Nishimura M, Shiosakai K, Ohira T. An exploratory assessment of the applicability of direct-to-consumer genetic testing to translational research in Japan. BMC Res Notes 2021; 14:282. [PMID: 34301328 PMCID: PMC8305957 DOI: 10.1186/s13104-021-05696-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 07/14/2021] [Indexed: 11/24/2022] Open
Abstract
Objective In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. Results A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire. Supplementary Information The online version contains supplementary material available at 10.1186/s13104-021-05696-4.
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Affiliation(s)
- Masahiro Inoue
- HealthData Lab, Yahoo! Japan Corporation, Kioi Tower, Tokyo Garden Terrace Kioicho, 1-3, Kioi-cho, Chiyoda-ku, Tokyo, 102-8282, Japan
| | - Shota Arichi
- HealthData Lab, Yahoo! Japan Corporation, Kioi Tower, Tokyo Garden Terrace Kioicho, 1-3, Kioi-cho, Chiyoda-ku, Tokyo, 102-8282, Japan
| | - Tsuyoshi Hachiya
- HealthData Lab, Yahoo! Japan Corporation, Kioi Tower, Tokyo Garden Terrace Kioicho, 1-3, Kioi-cho, Chiyoda-ku, Tokyo, 102-8282, Japan
| | - Anna Ohtera
- Real World Evidence Solutions, IQVIA Solutions Japan K.K, Takanawa 4-10-18, Minato-ku, Tokyo, 108-0074, Japan
| | - Seok-Won Kim
- Real World Evidence Solutions, IQVIA Solutions Japan K.K, Takanawa 4-10-18, Minato-ku, Tokyo, 108-0074, Japan
| | - Eric Yu
- Real World Evidence Solutions, IQVIA Solutions Japan K.K, Takanawa 4-10-18, Minato-ku, Tokyo, 108-0074, Japan
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11
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Wang HQ, Wang ZZ, Chen NH. The receptor hypothesis and the pathogenesis of depression: Genetic bases and biological correlates. Pharmacol Res 2021; 167:105542. [PMID: 33711432 DOI: 10.1016/j.phrs.2021.105542] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/24/2021] [Accepted: 03/07/2021] [Indexed: 02/08/2023]
Abstract
Depression has become one of the most prevalent neuropsychiatric disorders characterized by anhedonia, anxiety, pessimism, or even suicidal thoughts. Receptor theory has been pointed out to explain the pathogenesis of depression, while it is still subject to debate. Additionally, gene abnormality accounts for nearly 40-50% of depression risk, which is a significant factor contributing to the onset of depression. Accordingly, studying on receptors and their gene abnormality are critical parts of the research on internal causes of depression. This review summarizes the pathogenesis of depression from six of the most related receptors and their associated genes, including N-methyl-D-aspartate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glucocorticoid receptor, 5-hydroxytryptamine receptor, GABAA receptor α2, and dopamine receptor; and several "non-classic" receptors, such as metabotropic glutamate receptor, opioid receptor, and insulin receptor. These receptors have received considerable critical attention and are highly implicated in the onset of depression. We begin by providing the biological mechanisms of action of these receptors on the pathogenesis of depression. Then we review the historical and social context about these receptors. Finally, we discuss the limitations of the current state of knowledge and outline insights on future research directions, aiming to provide more novel targets and theoretical basis for the early prevention, accurate diagnosis and prompt treatment of depression.
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Affiliation(s)
- Hui-Qin Wang
- Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, Hunan, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Zhen-Zhen Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
| | - Nai-Hong Chen
- Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, Hunan, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
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12
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Morgenroth E, Orlov N, Lythgoe DJ, Stone JM, Barker H, Munro J, Eysenck M, Allen P. Altered relationship between prefrontal glutamate and activation during cognitive control in people with high trait anxiety. Cortex 2019; 117:53-63. [PMID: 30928721 DOI: 10.1016/j.cortex.2019.02.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/06/2018] [Accepted: 02/22/2019] [Indexed: 01/08/2023]
Abstract
Trait anxiety can affect cognitive control resulting in ineffective and/or inefficient task performance. Moreover, previous functional Magnetic Resonance Imaging (fMRI) studies have reported altered dorsolateral prefrontal cortex (DLPFC) activity in anxious cohorts, particularly when executive control is required. Recently, it has been demonstrated that cortical glutamate levels can predict both functional activation during cognitive control, and anxiety levels. In the present study we sought to investigate the relationship between trait anxiety, prefrontal glutamate levels and functional activation in DLPFC during a cognitive control task. Thirty-nine participants assigned to either low trait anxiety (LTA) or high trait anxiety (HTA) groups underwent 1H-Magnetic Resonance Spectroscopy (1H-MRS) to measure levels of resting glutamate in the prefrontal cortex (PFC). Participants also completed fMRI during a Stroop task comprising congruent and incongruent colour word trials. The HTA group showed reduced task performance relative to the LTA group. In the LTA group, there was a positive association between PFC Glu levels and DLPFC activation during incongruent trials. This association was absent in the HTA group. Individual differences in trait anxiety affect the relationship between PFC glutamate levels and DLPFC activation, possibly contributing to ineffective task performance when cognitive control is required.
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Affiliation(s)
| | - Natasza Orlov
- Department of Psychology, University of Roehampton, London, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - David J Lythgoe
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - James M Stone
- Centre for Neuroimaging Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Holly Barker
- Department of Psychology, University of Roehampton, London, UK
| | - James Munro
- Department of Psychology, University of Roehampton, London, UK; Department of Psychology, Edinburgh Napier University, Edinburgh, UK
| | - Michael Eysenck
- Department of Psychology, University of Roehampton, London, UK; Department of Psychology, Royal Holloway University of London, London, UK
| | - Paul Allen
- Department of Psychology, University of Roehampton, London, UK; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Combined Universities Brain Imaging Centre, London, UK
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13
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Fudalej S, Klimkiewicz A, Mach A, Jakubczyk A, Fudalej M, Wasilewska K, Podgórska A, Krajewski P, Płoski R, Wojnar M. An association between genetic variation in the glutamatergic system and suicide attempts in alcohol-dependent individuals. Am J Addict 2017; 26:595-601. [DOI: 10.1111/ajad.12571] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 03/19/2017] [Accepted: 05/11/2017] [Indexed: 12/21/2022] Open
Affiliation(s)
- Sylwia Fudalej
- Department of Psychiatry; Medical University of Warsaw; Warsaw Poland
| | - Anna Klimkiewicz
- Department of Psychiatry; Medical University of Warsaw; Warsaw Poland
| | - Anna Mach
- Department of Psychiatry; Medical University of Warsaw; Warsaw Poland
| | - Andrzej Jakubczyk
- Department of Psychiatry; Medical University of Warsaw; Warsaw Poland
| | - Marcin Fudalej
- Department of Forensic Medicine; Medical University of Warsaw; Warsaw Poland
| | | | - Anna Podgórska
- The Institute of Physiology and Pathology of Hearing; Kajetany Poland
| | - Paweł Krajewski
- Department of Forensic Medicine; Medical University of Warsaw; Warsaw Poland
| | - Rafał Płoski
- Department of Medical Genetics; Medical University of Warsaw; Warsaw Poland
| | - Marcin Wojnar
- Department of Psychiatry; Medical University of Warsaw; Warsaw Poland
- Department of Psychiatry; University of Michigan; Ann Arbor Michigan
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14
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Otto JM, Gizer IR, Ellingson JM, Wilhelmsen KC. Genetic variation in the exome: Associations with alcohol and tobacco co-use. PSYCHOLOGY OF ADDICTIVE BEHAVIORS 2017; 31:354-366. [PMID: 28368157 DOI: 10.1037/adb0000270] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Shared genetic factors represent one underlying mechanism thought to contribute to high rates of alcohol and tobacco co-use and dependence. Common variants identified by molecular genetic studies tend to confer only small disease risk, and rare protein-coding variants are posited to contribute to disease risk, as well. However, given that genotyping technologies allowing for their inclusion in association studies have only recently become available, the magnitude of their contribution is poorly understood. The current study examined genetic variation in protein-coding regions (i.e., the exome) for associations with measures of lifetime alcohol and tobacco co-use. Participants from the UCSF Family Alcoholism Study (N = 1,862) were genotyped using an exome-focused genotyping array, and assessed for DSM-IV diagnoses of alcohol and tobacco dependence and quantitative consumption measures using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism. Analyses included single variant, gene-based, and pathway-based tests of association. One EMR3 variant and a pathway related to genes upregulated in mesenchymal stem cells during the late phase of adipogenesis met criteria for statistical significance. Suggestive associations were consistent with previous findings from studies of substance use and dependence, including variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster with cigarettes smoked per day. Further, several variants and genes demonstrated suggestive association across phenotypes, suggesting that shared genetic factors may underlie risk for increased levels of alcohol and tobacco use, as well as psychopathology more broadly, providing insight into our understanding of the genetic architecture underlying these traits. (PsycINFO Database Record
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Affiliation(s)
- Jacqueline M Otto
- Department of Psychological Sciences, University of Missouri-Columbia
| | - Ian R Gizer
- Department of Psychological Sciences, University of Missouri-Columbia
| | | | - Kirk C Wilhelmsen
- Department of Genetics and Neurology, University of North Carolina at Chapel Hill
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15
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Bagshaw ATM, Horwood LJ, Fergusson DM, Gemmell NJ, Kennedy MA. Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction. BMC MEDICAL GENETICS 2017; 18:12. [PMID: 28158988 PMCID: PMC5291968 DOI: 10.1186/s12881-017-0374-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 01/25/2017] [Indexed: 02/05/2023]
Abstract
Background The genetic and environmental influences on human personality and behaviour are a complex matter of ongoing debate. Accumulating evidence indicates that short tandem repeats (STRs) in regulatory regions are good candidates to explain heritability not accessed by genome-wide association studies. Methods We tested for associations between the genotypes of four selected repeats and 18 traits relating to personality, behaviour, cognitive ability and mental health in a well-studied longitudinal birth cohort (n = 458-589) using one way analysis of variance. The repeats were a highly conserved poly-AC microsatellite in the upstream promoter region of the T-box brain 1 (TBR1) gene and three previously studied STRs in the activating enhancer-binding protein 2-beta (AP2-β) and androgen receptor (AR) genes. Where significance was found we used multiple regression to assess the influence of confounding factors. Results Carriers of the shorter, most common, allele of the AR gene’s GGN microsatellite polymorphism had fewer anxiety-related symptoms, which was consistent with previous studies, but in our study this was not significant following Bonferroni correction. No associations with two repeats in the AP2-β gene withstood this correction. A novel finding was that carriers of the minor allele of the TBR1 AC microsatellite were at higher risk of conduct problems in childhood at age 7-9 (p = 0.0007, which did pass Bonferroni correction). Including maternal smoking during pregnancy (MSDP) in models controlling for potentially confounding influences showed that an interaction between TBR1 genotype and MSDP was a significant predictor of conduct problems in childhood and adolescence (p < 0.001), and of self-reported criminal behaviour up to age 25 years (p ≤ 0.02). This interaction remained significant after controlling for possible confounders including maternal age at birth, socio-economic status and education, and offspring birth weight. Conclusions The potential functional importance of the TBR1 gene’s promoter microsatellite deserves further investigation. Our results suggest that it participates in a gene-environment interaction with MDSP and antisocial behaviour. However, previous evidence that mothers who smoke during pregnancy carry genes for antisocial behaviour suggests that epistasis may influence the interaction. Electronic supplementary material The online version of this article (doi:10.1186/s12881-017-0374-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Andrew T M Bagshaw
- Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand.
| | - L John Horwood
- Department of Psychological Medicine, University of Otago, Christchurch, New Zealand
| | - David M Fergusson
- Department of Psychological Medicine, University of Otago, Christchurch, New Zealand
| | - Neil J Gemmell
- Department of Anatomy, University of Otago, Dunedin, New Zealand.,Gravida - National Centre for Growth and Development, University of Otago, Dunedin, New Zealand
| | - Martin A Kennedy
- Department of Pathology, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand
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16
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Limon A, Mamdani F, Hjelm BE, Vawter MP, Sequeira A. Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission. Neurosci Biobehav Rev 2016; 66:80-91. [PMID: 27108532 DOI: 10.1016/j.neubiorev.2016.04.010] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/09/2016] [Accepted: 04/13/2016] [Indexed: 01/19/2023]
Abstract
Major depressive disorder (MDD) is a leading cause of disability worldwide characterized by altered neuronal activity in brain regions involved in the control of stress and emotion. Although multiple lines of evidence suggest that altered stress-coping mechanisms underlie the etiology of MDD, the homeostatic control of neuronal excitability in MDD at the molecular level is not well established. In this review, we examine past and current evidence implicating dysregulation of the polyamine system as a central factor in the homeostatic response to stress and the etiology of MDD. We discuss the cellular effects of abnormal metabolism of polyamines in the context of their role in sensing and modulation of neuronal, electrical, and synaptic activity. Finally, we discuss evidence supporting an allostatic model of depression based on a chronic elevation in polyamine levels resulting in self-sustained stress response mechanisms maintained by maladaptive homeostatic mechanisms.
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Affiliation(s)
- Agenor Limon
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627, USA
| | - Firoza Mamdani
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627, USA
| | - Brooke E Hjelm
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627, USA
| | - Marquis P Vawter
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627, USA
| | - Adolfo Sequeira
- Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92627, USA.
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17
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Viggiano A, Cacciola G, Widmer DAJ, Viggiano D. Anxiety as a neurodevelopmental disorder in a neuronal subpopulation: Evidence from gene expression data. Psychiatry Res 2015; 228:729-40. [PMID: 26089015 DOI: 10.1016/j.psychres.2015.05.032] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2015] [Revised: 05/14/2015] [Accepted: 05/26/2015] [Indexed: 12/20/2022]
Abstract
The relationship between genes and anxious behavior, is nor linear nor monotonic. To address this problem, we analyzed with a meta-analytic method the literature data of the behavior of knockout mice, retrieving 33 genes whose deletion was accompanied by increased anxious behavior, 34 genes related to decreased anxious behavior and 48 genes not involved in anxiety. We correlated the anxious behavior resulting from the deletion of these genes to their brain expression, using the Allen Brain Atlas and Gene Expression Omnibus (GEO) database. The main finding is that the genes accompanied, after deletion, by a modification of the anxious behavior, have lower expression in the cerebral cortex, the amygdala and the ventral striatum. The lower expression level was putatively due to their selective presence in a neuronal subpopulation. This difference was replicated also using a database of human gene expression, further showing that the differential expression pertained, in humans, a temporal window of young postnatal age (4 months up to 4 years) but was not evident at fetal or adult human stages. Finally, using gene enrichment analysis we also show that presynaptic genes are involved in the emergence of anxiety and postsynaptic genes in the reduction of anxiety after gene deletion.
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Affiliation(s)
- Adela Viggiano
- Department of Health Sciences, University of Molise, Campobasso 86100, Italy
| | - Giovanna Cacciola
- Department of Health Sciences, University of Molise, Campobasso 86100, Italy
| | | | - Davide Viggiano
- Department of Health Sciences, University of Molise, Campobasso 86100, Italy; Department of Cardio-Thoracic and Respiratory Science, Second University of Naples, Naples, Italy.
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18
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Januar V, Saffery R, Ryan J. Epigenetics and depressive disorders: a review of current progress and future directions. Int J Epidemiol 2015; 44:1364-87. [DOI: 10.1093/ije/dyu273] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2014] [Indexed: 12/26/2022] Open
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19
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Transcriptional evidence for the role of chronic venlafaxine treatment in neurotrophic signaling and neuroplasticity including also Glutamatergic [corrected] - and insulin-mediated neuronal processes. PLoS One 2014; 9:e113662. [PMID: 25423262 PMCID: PMC4244101 DOI: 10.1371/journal.pone.0113662] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 10/27/2014] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVES Venlafaxine (VLX), a serotonine-noradrenaline reuptake inhibitor, is one of the most commonly used antidepressant drugs in clinical practice for the treatment of major depressive disorder (MDD). Despite being more potent than its predecessors, similarly to them, the therapeutical effect of VLX is visible only 3-4 weeks after the beginning of treatment. Furthermore, recent papers show that antidepressants, including also VLX, enhance the motor recovery after stroke even in non depressed persons. In the present, transcriptomic-based study we looked for changes in gene expressions after a long-term VLX administration. METHODS Osmotic minipumps were implanted subcutaneously into Dark Agouti rats providing a continuous (40 mg/kg/day) VLX delivery for three weeks. Frontal regions of the cerebral cortex were isolated and analyzed using Illumina bead arrays to detect genes showing significant chances in expression. Gene set enrichment analysis was performed to identify specific regulatory networks significantly affected by long term VLX treatment. RESULTS Chronic VLX administration may have an effect on neurotransmitter release via the regulation of genes involved in vesicular exocytosis and receptor endocytosis (such as Kif proteins, Myo5a, Sv2b, Syn2 or Synj2). Simultaneously, VLX activated the expression of genes involved in neurotrophic signaling (Ntrk2, Ntrk3), glutamatergic transmission (Gria3, Grin2b and Grin2a), neuroplasticity (Camk2g/b, Cd47), synaptogenesis (Epha5a, Gad2) and cognitive processes (Clstn2). Interestingly, VLX increased the expression of genes involved in mitochondrial antioxidant activity (Bcl2 and Prdx1). Additionally, VLX administration also modulated genes related to insulin signaling pathway (Negr1, Ppp3r1, Slc2a4 and Enpp1), a mechanism that has recently been linked to neuroprotection, learning and memory. CONCLUSIONS Our results strongly suggest that chronic VLX treatment improves functional reorganization and brain plasticity by influencing gene expression in regulatory networks of motor cortical areas. These results are consonant with the synaptic (network) hypothesis of depression and antidepressant-induced motor recovery after stroke.
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The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 2014; 39:2673-80. [PMID: 24871546 PMCID: PMC4207347 DOI: 10.1038/npp.2014.123] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 05/22/2014] [Accepted: 05/24/2014] [Indexed: 11/08/2022]
Abstract
Paradoxically, N-methyl-D-aspartate (NMDA) receptor antagonists are used to model certain aspects of schizophrenia as well as to treat refractory depression. However, the role of different subunits of the NMDA receptor in both conditions is poorly understood. Here we used biochemical and behavioral readouts to examine the in vivo prefrontal efflux of serotonin and glutamate as well as the stereotypical behavior and the antidepressant-like activity in the forced swim test elicited by antagonists selective for the GluN2A (NVP-AAM077) and GluN2B (Ro 25-6981) subunits. The effects of the non-subunit selective antagonist, MK-801; were also studied for comparison. The administration of MK-801 dose dependently increased the prefrontal efflux of serotonin and glutamate and markedly increased the stereotypy scores. NVP-AAM077 also increased the efflux of serotonin and glutamate, but without the induction of stereotypies. In contrast, Ro 25-6981 did not change any of the biochemical and behavioral parameters tested. Interestingly, the administration of NVP-AAM077 and Ro 25-6981 alone elicited antidepressant-like activity in the forced swim test, in contrast to the combination of both compounds that evoked marked stereotypies. Our interpretation of the results is that both GluN2A and GluN2B subunits are needed to induce stereotypies, which might be suggestive of potential psychotomimetic effects in humans, but the antagonism of only one of these subunits is sufficient to evoke an antidepressant response. We also propose that GluN2A receptor antagonists could have potential antidepressant activity in the absence of potential psychotomimetic effects.
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Disentangling the molecular genetic basis of personality: From monoamines to neuropeptides. Neurosci Biobehav Rev 2014; 43:228-39. [DOI: 10.1016/j.neubiorev.2014.04.006] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Revised: 03/26/2014] [Accepted: 04/15/2014] [Indexed: 12/27/2022]
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Zhang C, Li Z, Wu Z, Chen J, Wang Z, Peng D, Hong W, Yuan C, Wang Z, Yu S, Xu Y, Xu L, Xiao Z, Fang Y. A study of N-methyl-D-aspartate receptor gene (GRIN2B) variants as predictors of treatment-resistant major depression. Psychopharmacology (Berl) 2014; 231:685-693. [PMID: 24114429 DOI: 10.1007/s00213-013-3297-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2013] [Accepted: 09/05/2013] [Indexed: 12/19/2022]
Abstract
RATIONALE In clinical practice, ketamine, an antagonist of the N-methyl-D-aspartate receptor (NMDAR), is used to alleviate depressive symptoms in patients with major depressive disorder (MDD), especially in those with treatment-resistant depression (TRD). Accordingly, the human gene coding for the 2B subunit of the NMDAR (GRIN2B) is considered a promising candidate gene for MDD susceptibility. OBJECTIVES The primary aim of this study is to examine whether potentially functional polymorphisms of GRIN2B confer risk for MDD, and second to investigate whether GRIN2B acts as a genetic predictor for TRD in MDD patients. METHODS We enrolled 178 TRD and 612 non-TRD patients as well as 779 healthy controls. RESULTS Four potentially functional polymorphisms (rs1805502, rs890, rs1806201, and rs7301328) within GRIN2B were genotyped in all participants. The haplotype analysis found significant differences in the distribution of the G-T haplotype between the TRD and control groups (corrected P = 0.007), and the frequency of the G-T haplotype in TRD group was significantly higher than that in the controls (TRD/control ratio 0.31:0.21). Statistically significant differences in allele and genotype frequencies were detected between TRD and non-TRD groups for the rs1805502 polymorphism within GRIN2B. There was a significant allelic association between rs1805502 and TRD with an excess of the G allele in the TRD group, compared to non-TRD group (OR = 1.55, 95 % CI = 1.18-2.05, corrected P = 0.008). CONCLUSIONS These initial findings strengthen the hypothesis that GRIN2B not only confers susceptibility to TRD, but also plays a genetic predictor for TRD in MDD patients.
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Affiliation(s)
- Chen Zhang
- Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China
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Haga S, Nakaoka H, Yamaguchi T, Yamamoto K, Kim YI, Samoto H, Ohno T, Katayama K, Ishida H, Park SB, Kimura R, Maki K, Inoue I. A genome-wide association study of third molar agenesis in Japanese and Korean populations. J Hum Genet 2013; 58:799-803. [DOI: 10.1038/jhg.2013.106] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 09/09/2013] [Accepted: 09/11/2013] [Indexed: 11/09/2022]
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Dimassi S, Andrieux J, Labalme A, Lesca G, Cordier MP, Boute O, Neut D, Edery P, Sanlaville D, Schluth-Bolard C. Interstitial 12p13.1 deletion involving GRIN2B in three patients with intellectual disability. Am J Med Genet A 2013; 161A:2564-9. [PMID: 23918416 DOI: 10.1002/ajmg.a.36079] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 05/13/2013] [Indexed: 11/07/2022]
Abstract
We report on three patients presenting moderate intellectual disability, delayed language acquisition, and mild facial dysmorphia. Array-CGH studies revealed overlapping interstitial 12p13.1 microdeletions encompassing all or part of GRIN2B. GRIN2B encodes the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. This receptor is a heteromeric glutamate-activated ion channel, present throughout the central nervous system. It plays a critical role in corticogenesis, neuronal migration, and synaptogenesis during brain development. GRIN2B alterations, including mutation and gene disruption by apparently balanced chromosomal rearrangements, have been described in patients with intellectual disability and autism spectrum disorder. We report here on the first cases of GRIN2B deletion, enlarging the spectrum of GRIN2B abnormalities. Our findings confirm the involvement of this gene in neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.
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Affiliation(s)
- Sarra Dimassi
- Service de Génétique, Laboratoire de Cytogénétique Constitutionnelle, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France
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López-Rodríguez R, Cabaleiro T, Ochoa D, Román M, Borobia AM, Carcas AJ, Ayuso C, Novalbos J, Abad-Santos F. Pharmacodynamic genetic variants related to antipsychotic adverse reactions in healthy volunteers. Pharmacogenomics 2013; 14:1203-14. [DOI: 10.2217/pgs.13.106] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Aim: Clinical trials with healthy volunteers are a useful model for evaluating safety and tolerability, without the interference of concomitant diseases and drugs. The present study aims to improve our understanding of antipsychotic-related adverse reactions (ARs) and their possible association with common genetic variants of pharmacodynamic proteins such as neurotransmitter receptors/transporters. Materials & methods: A total of eight polymorphisms located in seven pharmacodynamic-related genes (SCL6A4, MDR1, 5HT2A, DRD2, DRD3, COMT and GRIN2B) were genotyped in a cohort of 211 healthy volunteers who received a single dose of risperidone (1 mg), olanzapine (5 mg) or quetiapine (25 mg). Results: Interestingly, a significant association was found between the incidence of neurological ARs and specific polymorphisms in key genes (DRD2 and SCL6A4). Conclusion: Genetic variants in pharmacodynamic genes could represent valuable markers of AR risk and antipsychotic safety. Original submitted 7 February 2013; Revision submitted 3 June 2013
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Affiliation(s)
- Rosario López-Rodríguez
- Liver Unit, Gastroenterology Service, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Diego de Leon 62, 3ª, 28006 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Teresa Cabaleiro
- Service of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - Dolores Ochoa
- Service of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - Manuel Román
- Service of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - Alberto M Borobia
- Service of Clinical Pharmacology, Hospital Universitario La Paz, Pharmacology Department, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Antonio J Carcas
- Service of Clinical Pharmacology, Hospital Universitario La Paz, Pharmacology Department, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
| | - Carmen Ayuso
- Department of Genetics & Genomics, Instituto de Investigación Sanitaria Fundacion Jimenez Diaz, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Jesús Novalbos
- Service of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
| | - Francisco Abad-Santos
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Service of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain
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