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1
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Polymorphism in the 3'-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses. J Mol Neurosci 2020; 70:2093-2101. [PMID: 32504404 DOI: 10.1007/s12031-020-01616-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 05/26/2020] [Indexed: 12/17/2022]
Abstract
Schizophrenia (SCZ) is a multifactorial disorder caused by environmental and genetic factors. Studies have shown that various single-nucleotide polymorphisms (SNPs) in the binding sites of microRNAs contribute to the risk of developing SCZ. We aimed to investigate whether the variants located in the 3'-UTR region of LIF (rs929271T>G) and ATF6B (rs8283G>A) were associated with increased susceptibility to SCZ in a population from the south-east of Iran. In this case-control study, a total of 396 subjects were recruited. SNPs were genotyped via polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Genotyping results showed that the G allele of rs929271 significantly increased the risk of SCZ (OR = 1.58 95%CI = 1.19-2.10, p = 0.001). As for rs929271, the GG genotype of co-dominant (OR = 2.54 95%CI = 1.39-4.64, p = 0.002) and recessive (OR = 2.91 95%CI = 1.77-4.80, p < 0.001) models were strongly linked to SCZ. No significant differences were observed between rs8283 polymorphism and predisposition to SCZ. In silico analyses predicted that rs929271 might alter the binding sites of microRNAs, which was believed to have an unclear role in the development of SCZ. Moreover, rs929271 polymorphism changed the LIF-mRNA folding structure. These findings provide fine pieces of evidence regarding the possible effects of LIF polymorphism in the development of SCZ and regulation of the LIF gene targeted by microRNAs.
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2
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Sriretnakumar V, Zai CC, Wasim S, Barsanti-Innes B, Kennedy JL, So J. Copy number variant syndromes are frequent in schizophrenia: Progressing towards a CNV-schizophrenia model. Schizophr Res 2019; 209:171-178. [PMID: 31080157 DOI: 10.1016/j.schres.2019.04.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 02/26/2019] [Accepted: 04/30/2019] [Indexed: 12/23/2022]
Abstract
The genetic underpinnings of schizophrenia (SCZ) remain unclear. SCZ genetic studies thus far have only identified numerous single nucleotide polymorphisms with small effect sizes and a handful of copy number variants (CNVs). This study investigates the prevalence of well-characterized CNV syndromes and candidate CNVs within a cohort of 348 SCZ patients, and explores correlations to their phenotypic findings. There was an enrichment of syndromic CNVs in the cohort, as well as brain-related and immune pathway genes within the detected CNVs. SCZ patients with brain-related CNVs had increased CNV burden, neurodevelopmental features, and types of hallucinations. Based on these results, we propose a CNV-SCZ model wherein specific phenotypic profiles should be prioritized for CNV screening within the SCZ patient population.
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Affiliation(s)
- Venuja Sriretnakumar
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 250 College Street, Toronto M5T 1R8, Canada
| | - Clement C Zai
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 250 College Street, Toronto M5T 1R8, Canada
| | - Syed Wasim
- The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network & Mount Sinai Hospital, 60 Murray Street, Toronto M5T 3L9, Canada
| | - Brianna Barsanti-Innes
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 250 College Street, Toronto M5T 1R8, Canada
| | - James L Kennedy
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 250 College Street, Toronto M5T 1R8, Canada
| | - Joyce So
- Centre for Addiction and Mental Health, Campbell Family Mental Health Research Institute, 250 College Street, Toronto M5T 1R8, Canada; The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network & Mount Sinai Hospital, 60 Murray Street, Toronto M5T 3L9, Canada.
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3
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Nedic Erjavec G, Svob Strac D, Tudor L, Konjevod M, Sagud M, Pivac N. Genetic Markers in Psychiatry. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1192:53-93. [PMID: 31705490 DOI: 10.1007/978-981-32-9721-0_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Psychiatric disorders such as addiction (substance use and addictive disorders), depression, eating disorders, schizophrenia, and post-traumatic stress disorder (PTSD) are severe, complex, multifactorial mental disorders that carry a high social impact, enormous public health costs, and various comorbidities as well as premature morbidity. Their neurobiological foundation is still not clear. Therefore, it is difficult to uncover new set of genes and possible genetic markers of these disorders since the understanding of the molecular imbalance leading to these disorders is not complete. The integrative approach is needed which will combine genomics and epigenomics; evaluate epigenetic influence on genes and their influence on neuropeptides, neurotransmitters, and hormones; examine gene × gene and gene × environment interplay; and identify abnormalities contributing to development of these disorders. Therefore, novel genetic approaches based on systems biology focused on improvement of the identification of the biological underpinnings might offer genetic markers of addiction, depression, eating disorders, schizophrenia, and PTSD. These markers might be used for early prediction, detection of the risk to develop these disorders, novel subtypes of the diseases and tailored, personalized approach to therapy.
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Affiliation(s)
- Gordana Nedic Erjavec
- Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, HR-10000, Zagreb, Croatia
| | - Dubravka Svob Strac
- Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, HR-10000, Zagreb, Croatia
| | - Lucija Tudor
- Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, HR-10000, Zagreb, Croatia
| | - Marcela Konjevod
- Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, HR-10000, Zagreb, Croatia
| | - Marina Sagud
- School of Medicine, University of Zagreb, Salata 2, HR-10000, Zagreb, Croatia
- Department of Psychiatry, University Hospital Centre Zagreb, Kispaticeva 12, HR-10000, Zagreb, Croatia
| | - Nela Pivac
- Division of Molecular Medicine, Rudjer Boskovic Institute, Bijenicka 54, HR-10000, Zagreb, Croatia.
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Gunnarsdóttir ED, Hällgren J, Hultman CM, McNeil TF, Crisby M, Sandin S. Risk of neurological, eye and ear disease in offspring to parents with schizophrenia or depression compared with offspring to healthy parents. Psychol Med 2018; 48:2710-2716. [PMID: 29669615 DOI: 10.1017/s0033291718000338] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Neurological, visual and hearing deviations have been observed in the offspring of parents with schizophrenia. This study test whether children to parents hospitalized with schizophrenia have increased the likelihood of childhood neurological disorder. METHODS Among all parents in Sweden born 1950-1985 and with offspring born 1968-2002: 7107 children with a parent hospitalized for schizophrenia were compared to 172 982 children with no parents hospitalized for schizophrenia or major depression, as well as to 32 494 children with a parent hospitalized for major depression as a control population with another severe psychiatric outcome. We estimated relative risks (RR) and two-sided 95% confidence intervals calculated from Poisson regression. RESULTS Children to parents with schizophrenia were more likely than controls to have been hospitalized before the age of 10 with a diagnosis of cerebral palsy, RR = 1.76 (95% CI: 1.15-2.69); epilepsy, RR = 1.78 (95% CI: 1.33-2.40), combined neurological disease, RR = 1.33 (95% CI: 1.11-1.60) and certain diseases of the eye, RR = 1.92 (95% CI: 1.17-3.15) and ear, RR = 1.18 (95% CI: 1.05-1.32). Similar disease-risk-pattern was found for children to parents hospitalized with a diagnosis of major depression. A specific risk increase for strabismus RR = 1.21 (95%CI: 1.05-1.40) was found for off-spring with parental depression. CONCLUSIONS Compared with children to healthy parents, children to parents with schizophrenia have increased risk of a variety of neurological disorders as well as visual and hearing disorders at an early age. The risk increase was not specific to schizophrenia but was also seen in children to parents with a diagnosis of major depression.
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Affiliation(s)
| | - Jonas Hällgren
- Department of Neurobiology, Care Sciences and Society, Division of Family Medicine,Karolinska Institutet,Stockholm,Sweden
| | - Christina M Hultman
- Department of Medical Epidemiology and Biostatistics,Karolinska Institutet,Stockholm,Sweden
| | - Thomas F McNeil
- School of Psychiatry and Clinical Neurosciences, University of Western Australia,Perth,Australia
| | - Milita Crisby
- Department of Neurobiology, Care Science and Society,Karolinska Institutet,Stockholm,Sweden
| | - Sven Sandin
- Department of Medical Epidemiology and Biostatistics,Karolinska Institutet,Stockholm,Sweden
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5
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Li G, Bai M, Guo C, Zhu L, Wang L, Yuan D, Jin T, He Y. Association analysis of CHRNA3 polymorphisms with schizophrenia in a Chinese Han population: A case-control study. Medicine (Baltimore) 2018; 97:e10863. [PMID: 29879020 PMCID: PMC5999463 DOI: 10.1097/md.0000000000010863] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/04/2018] [Indexed: 11/25/2022] Open
Abstract
Schizophrenia (SCZ) is a highly heritable, chronic, severe psychiatric disorder associated with significant financial costs to families and societies. In this case-control study, we investigated the associations between seven SNPs in CHRNA3 gene and the risk of SCZ.A total of 1071 (384 cases and 687 controls) unrelated subjects were recruited for our association study. Seven candidate tagging SNPs in CHRNA3 gene (rs3743077, rs1317286, rs938682, rs12914385, rs2869546, rs3743075, rs8040868) selected in HapMap database were genotyped by Sequenom MassARRAY. Finally, association analysis was conducted under various models.According to our results, in genetic model analysis, rs12914385 and rs8040868 are associated with decreased risk of SCZ in female subgroup; rs3743075 is associated with decreased risk of SCZ in subgroup with age <45; while rs3743077 and rs2869546 are associated with increased risk of SCZ. Haplotype analysis suggested that the 3 variants comprised 1 block, and that the haplotype Ars938682Crs12914385Crs2869546 was significantly correlated with an increased risk of SCZ in the subgroup with age ≥45.Our data indicate potential associations between CHRNA3polymorphisms and SCZ susceptibility, and the significant variants identified in our study may be used as genetic biomarkers for SCZ susceptibility in Chinese Han population.
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Affiliation(s)
- Guixin Li
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Mei Bai
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Chenghao Guo
- Key Laboratory of Resource Biology and Biotechnology in Western China, Northwest University, Ministry of Education, Xi’an, Shaanxi, China
| | - Linhao Zhu
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Li Wang
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Dongya Yuan
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
| | - Tianbo Jin
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
- Key Laboratory of Resource Biology and Biotechnology in Western China, Northwest University, Ministry of Education, Xi’an, Shaanxi, China
| | - Yongjun He
- Key Laboratory of Molecular Mechanism and Intervention Research for Plateau Diseases of Tibet Autonomous Region
- Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region
- Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi
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Gao K, Zhang Y, Zhang L, Kong W, Xie H, Wang J, Wu Y, Wu X, Liu X, Zhang Y, Zhang F, Yu ACH, Jiang Y. Large De Novo Microdeletion in Epilepsy with Intellectual and Developmental Disabilities, with a Systems Biology Analysis. ADVANCES IN NEUROBIOLOGY 2018; 21:247-266. [DOI: 10.1007/978-3-319-94593-4_9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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7
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Mighdoll MI, Hyde TM. Brain donation at autopsy: clinical characterization and toxicologic analyses. HANDBOOK OF CLINICAL NEUROLOGY 2018; 150:143-154. [PMID: 29496137 DOI: 10.1016/b978-0-444-63639-3.00011-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The study of postmortem human brain tissue is central to the advancement of neurobiologic studies of psychiatric and neurologic illnesses, particularly the study of brain-specific isoforms and molecules. Due to tissue demands, especially pertaining to brain regions strongly implicated in the pathophysiology of neuropsychiatric disorders, the success and future of this research depend on the availability of high-quality brain specimens from large numbers of subjects, including nonpsychiatric controls, both of which may be obtained from brain banks. In this chapter, we elaborate on the need for and acquisition of well-curated and properly diagnosed postmortem human brains, relying upon our experience with the Human Brain and Tissue Repository located at the Lieber Institute for Brain Development in Baltimore, MD. We explain the advantages of sourcing postmortem human tissue from medical examiner offices, which provide access to cases of all ages, both with and without central nervous system disorders. Neuropathology analyses and toxicologic screenings, along with autopsy reports and extensive interviews with family members and treating physicians, are invaluable to the diagnoses of postmortem cases. Ultimately, the study of psychiatric and neurologic disorders is the study of brain disease, and accordingly, there is no substitution for human brain tissue.
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Affiliation(s)
- Michelle I Mighdoll
- Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
| | - Thomas M Hyde
- Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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8
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Falola O, Osamor VC, Adebiyi M, Adebiyi E. Analyzing a single nucleotide polymorphism in schizophrenia: a meta-analysis approach. Neuropsychiatr Dis Treat 2017; 13:2243-2250. [PMID: 28883732 PMCID: PMC5574680 DOI: 10.2147/ndt.s111900] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Schizophrenia is a severe mental disorder affecting >21 million people worldwide. Some genetic studies reported that single nucleotide polymorphism (SNP) involving variant rs1344706 from the ZNF804A gene in human beings is associated with the risk of schizophrenia in several populations. Similar results tend to conflict with other reports in literature, indicating that no true significant association exists between rs1344706 and schizophrenia. We seek to determine the level of association of this SNP with schizophrenia in the Asian population using more recent genome-wide association study (GWAS) datasets. METHODS Applying a computational approach with inclusion of more recent GWAS datasets, we conducted a meta-analysis to examine the level of association of SNP rs1344706 and the risk of schizophrenia disorder among the Asian population constituting Chinese, Indonesians, Japanese, Kazakhs and Singaporeans. For a total of 21 genetic studies, including a total of 28,842 cases and 35,630 controls, regression analysis, publication bias, Cochran's Q and I2 tests were performed. The DerSimonian and Laird random-effects model was used to assess the association of the genetic variant to schizophrenia. Leave-one-out sensitivity analysis was also conducted to determine the influence of each study on the final outcome of the association study. RESULTS Our summarized analysis for Asian population revealed a pooled odds ratio of 1.06, 95% confidence interval of 1.01-1.11 and two-tailed P-value of 0.0228. Our test for heterogeneity showed the presence of large heterogeneity (I2=53.44%, P =0.00207) and Egger's regression test (P =0.8763) and Begg's test (P =0.8347), indicating no presence of publication bias among our selected studies. In our sensitivity analysis, 10 different studies comprising of ~50% of the entire study had an impact on our final results as each leave-one-out test became insignificant. Our result suggests that genetic variant rs1344706 might be associated with the development of schizophrenia in Asians.
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Affiliation(s)
| | - Victor Chukwudi Osamor
- Covenant University Bioinformatics Research (CUBRe)
- Department of Computer and Information Sciences, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
| | - Marion Adebiyi
- Covenant University Bioinformatics Research (CUBRe)
- Department of Computer and Information Sciences, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
| | - Ezekiel Adebiyi
- Covenant University Bioinformatics Research (CUBRe)
- Department of Computer and Information Sciences, College of Science and Technology, Covenant University, Ota, Ogun State, Nigeria
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9
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Li J, Chen Z, Wang F, Ouyang Y, Zhang N, Yang M, Yan M, Zhu X, He X, Yuan D, Jin T. Polymorphisms of the TCF4 gene are associated with the risk of schizophrenia in the Han Chinese. Am J Med Genet B Neuropsychiatr Genet 2016; 171:1006-1012. [PMID: 27103199 DOI: 10.1002/ajmg.b.32449] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 03/15/2016] [Indexed: 01/30/2023]
Abstract
Schizophrenia (SCZ) is a complex and severe mental disorder with highly heritability (80%). Several large genome-wide association studies have identified that the transcription factor 4 (TCF4) polymorphisms were strongly associated with SCZ. Therefore, the present study was to replicate the potential relationships between the TCF4 polymorphisms and SCZ. Furthermore, the study also investigated whether other variants were associated with SCZ in the Han Chinese. We conducted a case-control study including 499 patients and 500 healthy controls. Five SNPs were successfully genotyped and evaluated the association with SCZ by using χ2 test and genetic model analysis. We found that the genotype "AG" of rs9320010 and "GA" of rs7235757 decreased SCZ risk (OR = 0.70, 95%CI = 0.50-0.99, P = 0.041; OR = 0.69, 95%CI = 0.49-0.97, P = 0.034, respectively). In the genetic model analysis, we also observed that the allele "A" of rs9320010 and "G" of rs7235757 were inversely related with the risk of SCZ in the dominant model (OR = 0.72, 95%CI = 0.52-0.98, P = 0.039; OR = 0.69, 95%CI = 0.50-0.96, P = 0.025, respectively). Further interaction and stratification analysis suggested that rs1452787 was notably correlated with increased SCZ risk in males (OR = 2.77, 95%CI = 1.43-5.35, P = 0.002). Our study indicated that rs9320010, rs7235757, and rs1452787 were prominently associated with SCZ. Further studies are required to verify our findings and focus on determining the biological functions of the SNPs. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Jingjie Li
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Zhengshuai Chen
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Fengjiao Wang
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Yongri Ouyang
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Ning Zhang
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Min Yang
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Mengdan Yan
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China
| | - Xikai Zhu
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Xue He
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Dongya Yuan
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
| | - Tianbo Jin
- School of Life Sciences, Northwest University, Xi'an, Shaanxi, China.,Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China.,Key Laboratory for Basic Life Science Research of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, China
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10
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Wu S, Zhang R, Nie F, Wang X, Jiang C, Liu M, Valenzuela RK, Liu W, Shi Y, Ma J. MicroRNA-137 Inhibits EFNB2 Expression Affected by a Genetic Variant and Is Expressed Aberrantly in Peripheral Blood of Schizophrenia Patients. EBioMedicine 2016; 12:133-142. [PMID: 27650867 PMCID: PMC5078603 DOI: 10.1016/j.ebiom.2016.09.012] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 09/09/2016] [Accepted: 09/13/2016] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRNAs) are a class of endogenous and non-coding single-stranded RNAs of approximately 22 nucleotides, many of which are evolutionarily conserved. Genome-wide association studies have identified a robust statistical association between the MIR137 gene and schizophrenia in Europeans, which was replicated in the Han Chinese population in a case-control study. In the previous study, we provided evidence for a significant association between the EFNB2 gene and schizophrenia in Han Chinese subjects. In the current study, we utilized computational analysis, vector construction of point mutations, luciferase reporter assays and gene expression assays including RT-qPCR and western blotting methods to investigate miR-137 directly targeting EFNB2 gene and explore the reversal effect of a genetic variant of SNP rs550067317 in the putative seed-pair region of EFNB2 3'-UTR. We also found that miR-137 could be detected in the peripheral blood of a cohort of first-onset schizophrenia patients and healthy controls, and the area under curve was 0.795 (95% confidence interval 0.700-0.890), which is a middle diagnostic value for disease, suggesting that it might be valuable for diagnosing schizophrenia. In summary, this study would improve our understanding of the role of miR-137 in schizophrenia-associated signaling pathways and identify the genetic basis of rs550067317 for schizophrenia. Furthermore, we provided new evidence for the involvement of miR-137 in the etiology and diagnosis of schizophrenia, which might contribute to the discovery of new biomarkers and therapeutic targets for the disease.
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Affiliation(s)
- Shanshan Wu
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China
| | - Rui Zhang
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China; Translational medicine center, Honghui Hospital, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710054, China.
| | - Fayi Nie
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China
| | - Xiaoli Wang
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China
| | - Congshan Jiang
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China
| | - Meng Liu
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China
| | - Robert K Valenzuela
- Department of Human Genetics 4, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Wanqing Liu
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
| | - Yongyong Shi
- Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Jie Ma
- Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi 710061, China.
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11
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Ermakov EA, Smirnova LP, Parkhomenko TA, Dmitrenok PS, Krotenko NM, Fattakhov NS, Bokhan NA, Semke AV, Ivanova SA, Buneva VN, Nevinsky GA. DNA-hydrolysing activity of IgG antibodies from the sera of patients with schizophrenia. Open Biol 2016; 5:150064. [PMID: 26382278 PMCID: PMC4593665 DOI: 10.1098/rsob.150064] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
It is believed that damage to the membranes of brain cells of schizophrenia (SCZ) patients induces the formation of autoantigens and autoantibodies. Nevertheless, the importance of immunological changes leading to the loss of tolerance to self-antigens in the genesis of SCZ has not been established. The MALDI mass spectra of the IgG light chains of 20 healthy donors were relatively homogeneous and characterized by one peak with only one maximum. In contrast to the healthy donors, the MALDI mass spectra of IgG light chains corresponding to 20 SCZ patients demonstrated, similarly to 20 autoimmune systemic lupus erythematosus (SLE) patients, two maxima of a comparable intensity. In addition, the MALDI spectra of the IgG light chains of five SLE and four SCZ patients contained a small additional brightly pronounced peak with remarkably lower molecular mass compared with the main one. DNase autoantibodies (abzymes) can be found in the blood of patients with several autoimmune diseases, while the blood of healthy donors or patients with diseases without a significant disturbance of the immune status does not contain DNase abzymes. Here, we present the first analysis of anti-DNA antibodies and DNase abzymes in the sera of SCZ patients. Several strict criteria have been applied to show that the DNase activity is an intrinsic property of IgGs from the sera of SCZ patients. The sera of approximately 30% of SCZ patients displayed a higher content of antibodies (compared with 37% of SLE) interacting with single- and double-stranded DNA compared with healthy donors. Antibodies with DNase activity were revealed in 80% of the patients. These data indicate that some SCZ patients may show signs of typical autoimmune processes to a certain extent.
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Affiliation(s)
- Evgeny A Ermakov
- Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, 8 Lavrentiev Avenue, Novosibirsk 630090, Russia Novosibirsk State University, 2 Pirogova Street, Novosibirsk 630090, Russia
| | - Ludmila P Smirnova
- Mental Health Research Institute, Russian Academy of Medical Sciences, 4 Aleutskaya Avenue, Tomsk 634014, Russia
| | - Taisiya A Parkhomenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, 8 Lavrentiev Avenue, Novosibirsk 630090, Russia
| | - Pavel S Dmitrenok
- Pacific Institute of Bioorganic Chemistry, Far East Division, Russian Academy of Sciences, Vladivostok 690022, Russia
| | - Nina M Krotenko
- Mental Health Research Institute, Russian Academy of Medical Sciences, 4 Aleutskaya Avenue, Tomsk 634014, Russia
| | - Nikolai S Fattakhov
- Mental Health Research Institute, Russian Academy of Medical Sciences, 4 Aleutskaya Avenue, Tomsk 634014, Russia
| | - Nikolay A Bokhan
- Mental Health Research Institute, Russian Academy of Medical Sciences, 4 Aleutskaya Avenue, Tomsk 634014, Russia
| | - Arkadiy V Semke
- Mental Health Research Institute, Russian Academy of Medical Sciences, 4 Aleutskaya Avenue, Tomsk 634014, Russia
| | - Svetlana A Ivanova
- Mental Health Research Institute, Russian Academy of Medical Sciences, 4 Aleutskaya Avenue, Tomsk 634014, Russia
| | - Valentina N Buneva
- Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, 8 Lavrentiev Avenue, Novosibirsk 630090, Russia Novosibirsk State University, 2 Pirogova Street, Novosibirsk 630090, Russia
| | - Georgy A Nevinsky
- Institute of Chemical Biology and Fundamental Medicine, Siberian Division of Russian Academy of Sciences, 8 Lavrentiev Avenue, Novosibirsk 630090, Russia Novosibirsk State University, 2 Pirogova Street, Novosibirsk 630090, Russia
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O'Tuathaigh CMP, Desbonnet L, Moran PM, Kirby BP, Waddington JL. Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges. Curr Top Behav Neurosci 2016; 7:87-119. [PMID: 21298380 DOI: 10.1007/7854_2010_111] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions.
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Affiliation(s)
- Colm M P O'Tuathaigh
- Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland,
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Genomic DISC1 Disruption in hiPSCs Alters Wnt Signaling and Neural Cell Fate. Cell Rep 2015; 12:1414-29. [PMID: 26299970 DOI: 10.1016/j.celrep.2015.07.061] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/08/2015] [Accepted: 07/29/2015] [Indexed: 02/08/2023] Open
Abstract
Genetic and clinical association studies have identified disrupted in schizophrenia 1 (DISC1) as a candidate risk gene for major mental illness. DISC1 is interrupted by a balanced chr(1;11) translocation in a Scottish family in which the translocation predisposes to psychiatric disorders. We investigate the consequences of DISC1 interruption in human neural cells using TALENs or CRISPR-Cas9 to target the DISC1 locus. We show that disruption of DISC1 near the site of the translocation results in decreased DISC1 protein levels because of nonsense-mediated decay of long splice variants. This results in an increased level of canonical Wnt signaling in neural progenitor cells and altered expression of fate markers such as Foxg1 and Tbr2. These gene expression changes are rescued by antagonizing Wnt signaling in a critical developmental window, supporting the hypothesis that DISC1-dependent suppression of basal Wnt signaling influences the distribution of cell types generated during cortical development.
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Abstract
OBJECTIVE Copy number variations encompassing the chromosome 15q11-q13 region have been implicated in the pathogenesis of several neurodevelopmental disorders including schizophrenia. The study aimed to investigate whether the GABRB3 gene mapped to 15q12 was associated with schizophrenia. MATERIALS AND METHODS We resequenced the promoter and all the exonic regions of the GABRB3 gene in 349 patients with schizophrenia and 386 control participants from Taiwan using the Sanger sequencing method. We also used a reporter gene assay to assess the functional impact of variants identified from the promoter region. RESULTS We identified a total of six common single nucleotide polymorphisms and eight rare variants in this sample. No genetic association of these common single nucleotide polymorphisms with schizophrenia was detected. A missense mutation Y402H at exon 9 was detected in two patients and two controls. Polyphen-2 predicted that the impact of this variant was benign. In addition, we identified two patient-specific variants at the promoter of GABRB3 that showed significantly increased promoter activity in a reporter gene assay. CONCLUSION The identification of two private patient-only variants at the promoter region with enhanced promoter activity supports the rare allele hypothesis of schizophrenia and suggests that increased GABRB3 expression may confer an increased risk of schizophrenia.
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Randall AD, Kurihara M, Brandon NJ, Brown JT. Disrupted in schizophrenia 1 and synaptic function in the mammalian central nervous system. Eur J Neurosci 2014; 39:1068-73. [PMID: 24712987 PMCID: PMC4232872 DOI: 10.1111/ejn.12500] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/02/2014] [Accepted: 01/07/2014] [Indexed: 11/28/2022]
Abstract
The disrupted in schizophrenia 1 (DISC1) gene is found at the breakpoint of an inherited chromosomal translocation, and segregates with major mental illnesses. Its potential role in central nervous system (CNS) malfunction has triggered intensive investigation of the biological roles played by DISC1, with the hope that this may shed new light on the pathobiology of psychiatric disease. Such work has ranged from investigations of animal behavior to detailed molecular-level analysis of the assemblies that DISC1 forms with other proteins. Here, we discuss the evidence for a role of DISC1 in synaptic function in the mammalian CNS.
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Affiliation(s)
- Andrew D Randall
- School of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol, UK; Institute of Biomedical and Clinical Sciences, University of Exeter, The Hatherley Building, Prince of Wales Road, Exeter, EX4 4PS, UK
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Quednow BB, Brzózka MM, Rossner MJ. Transcription factor 4 (TCF4) and schizophrenia: integrating the animal and the human perspective. Cell Mol Life Sci 2014; 71:2815-35. [PMID: 24413739 PMCID: PMC11113759 DOI: 10.1007/s00018-013-1553-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 12/04/2013] [Accepted: 12/30/2013] [Indexed: 02/06/2023]
Abstract
Schizophrenia is a genetically complex disease considered to have a neurodevelopmental pathogenesis and defined by a broad spectrum of positive and negative symptoms as well as cognitive deficits. Recently, large genome-wide association studies have identified common alleles slightly increasing the risk for schizophrenia. Among the few schizophrenia-risk genes that have been consistently replicated is the basic Helix-Loop-Helix (bHLH) transcription factor 4 (TCF4). Haploinsufficiency of the TCF4 (formatting follows IUPAC nomenclature: TCF4 protein/protein function, Tcf4 rodent gene cDNA mRNA, TCF4 human gene cDNA mRNA) gene causes the Pitt-Hopkins syndrome-a neurodevelopmental disease characterized by severe mental retardation. Accordingly, Tcf4 null-mutant mice display developmental brain defects. TCF4-associated risk alleles are located in putative coding and non-coding regions of the gene. Hence, subtle changes at the level of gene expression might be relevant for the etiopathology of schizophrenia. Behavioural phenotypes obtained with a mouse model of slightly increased gene dosage and electrophysiological investigations with human risk-allele carriers revealed an overlapping spectrum of schizophrenia-relevant endophenotypes. Most prominently, early information processing and higher cognitive functions appear to be associated with TCF4 risk genotypes. Moreover, a recent human study unravelled gene × environment interactions between TCF4 risk alleles and smoking behaviour that were specifically associated with disrupted early information processing. Taken together, TCF4 is considered as an integrator ('hub') of several bHLH networks controlling critical steps of various developmental, and, possibly, plasticity-related transcriptional programs in the CNS and changes of TCF4 expression also appear to affect brain networks important for information processing. Consequently, these findings support the neurodevelopmental hypothesis of schizophrenia and provide a basis for identifying the underlying molecular mechanisms.
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Affiliation(s)
- Boris B. Quednow
- Department of Psychiatry, Psychotherapy and Psychosomatics, Experimental and Clinical Pharmacopsychology, Psychiatric Hospital, University of Zurich, Lenggstrasse 31, 8032 Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Magdalena M. Brzózka
- Department of Psychiatry, Molecular and Behavioral Neurobiology, Ludwig-Maximillians-University, Nussbaumstr. 7, 80336 Munich, Germany
| | - Moritz J. Rossner
- Department of Psychiatry, Molecular and Behavioral Neurobiology, Ludwig-Maximillians-University, Nussbaumstr. 7, 80336 Munich, Germany
- Research Group Gene Expression, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, Goettingen, 37075 Germany
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Chen SF, Chao YL, Shen YC, Chen CH, Weng CF. Resequencing and association study of the NFKB activating protein-like gene (NKAPL) in schizophrenia. Schizophr Res 2014; 157:169-74. [PMID: 24972756 DOI: 10.1016/j.schres.2014.05.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 05/28/2014] [Accepted: 05/31/2014] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Schizophrenia is a highly inheritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Recently, in the Han Chinese population, a SNP rs1635 located within the exon of the NKAPL gene (encoding NFKB activating protein-like) achieved genome-wide significance in schizophrenia. METHODS In order to find the causal variants of the NKAPL gene in schizophrenia, we searched for genetic variants in the promoter region, and exons (including both UTR ends) using direct sequencing in a sample of patients with schizophrenia (n=515) and non-psychotic controls (n=456), all Han Chinese from Taiwan, and conducted an association and rudimentary functional study. RESULTS We identified 5 common SNPs (defined as minor allele frequency (MAF)>0.01) in the NKAPL gene. In a case-control association analysis, the minor allele (A) of rs1635 was significantly more common among patients than controls (P=0.0003, OR=1.41, 95% CI=1.17-1.71). A haplotype analysis of the 5 common SNPs indicated a risk haplotype (rs12000C-rs1635A-rs9461446C-rs3734564G-rs1679709G) associated with schizophrenia (P=2.77e-005, OR=1.53, 95% CI=1.25-1.87). In addition, we identified 4 patient-specific rare SNPs (MAF<0.01) (c.137G>A, c.213G>A, c.752C>T (rs370337122), and c.844G>A (rs147161729)) within the NKAPL gene. In silico analysis demonstrated their functional impact on the protein; however, there was also 1 control-specific rare SNP (c.119G>A) detected within the NKAPL gene, indicating that the clinical relevance of these putatively pathological rare SNPs is not straightforward. CONCLUSIONS This study suggested that rs1635 in the NKAPL gene appeared to play a role in conferring susceptibility to schizophrenia. In addition, some rare SNPs in the NKAPL gene with possibly damaging effects may be important in our patients. Our study provides genetic clues to indicate the involvement of NKAPL in schizophrenia.
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Affiliation(s)
- Shih-Fen Chen
- Department of Life Science and Institute of Biotechnology, National Dong-Hwa University, Hualien, Taiwan
| | - Yu-Lin Chao
- Department of Psychiatry, Tzu-Chi General Hospital at Hualien, and School of Medicine, Tzu-Chi University, Hualien, Taiwan
| | - Yu-Chih Shen
- Department of Psychiatry, Tzu-Chi General Hospital at Hualien, and School of Medicine, Tzu-Chi University, Hualien, Taiwan.
| | - Chia-Hsiang Chen
- Department of Psychiatry, Chang Gung Memorial Hospital at Linkou, and Chang Gung University, School of Medicine, Taoyuan, Taiwan
| | - Ching-Feng Weng
- Department of Life Science and Institute of Biotechnology, National Dong-Hwa University, Hualien, Taiwan.
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The "DGPPN-Cohort": A national collaboration initiative by the German Association for Psychiatry and Psychotherapy (DGPPN) for establishing a large-scale cohort of psychiatric patients. Eur Arch Psychiatry Clin Neurosci 2013; 263:695-701. [PMID: 23545941 DOI: 10.1007/s00406-013-0401-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Accepted: 03/01/2013] [Indexed: 10/27/2022]
Abstract
The German Association for Psychiatry and Psychotherapy (DGPPN) has committed itself to establish a prospective national cohort of patients with major psychiatric disorders, the so-called DGPPN-Cohort. This project will enable the scientific exploitation of high-quality data and biomaterial from psychiatric patients for research. It will be set up using harmonised data sets and procedures for sample generation and guided by transparent rules for data access and data sharing regarding the central research database. While the main focus lies on biological research, it will be open to all kinds of scientific investigations, including epidemiological, clinical or health-service research.
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Hosak L. New findings in the genetics of schizophrenia. World J Psychiatry 2013; 3:57-61. [PMID: 24255876 PMCID: PMC3832862 DOI: 10.5498/wjp.v3.i3.57] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 06/05/2013] [Accepted: 07/18/2013] [Indexed: 02/05/2023] Open
Abstract
New findings in schizophrenia genetics are based on genome-wide association studies (GWAS), research into DNA copy number variations (CNVs), and endophenotypes. More than 70 genes have recently been suspected to be involved in the genetic background of schizophrenia based on the GWAS´s results. They are typically related to neurodevelopment/neuroplasticity, immunology and neuroendocrinology. Nevertheless, for many detected genes their possible relationship to schizophrenia etiopathogenesis is still unknown. The CNVs at genome loci 1q21.1 (candidate gene e.g., PRKAB2), 2p16.3 (candidate gene e.g., NRXN1), 3q29 (candidate genes e.g., BDH1, DLG1, PAK2 or TFRC), 15q11.2 (candidate gene e.g., CYFIP1), 15q13.3 (candidate gene e.g., CHRNA7), 16p13.1 (candidate genes e.g.,NTAN1 or NDE1) and 22q11.2 (candidate genes e.g., COMT, GSTT2 or PRODH) were associated with schizophrenia most frequently. Genetic research of schizophrenia endophenotypes, usually neurophysiological, neuromotoric, neurocognitive, neuroanatomical, neurological or personality-related, will help us to discover the role of relevant genes in the pathogenesis of schizophrenia. It is also necessary to integrate knowledge from other research platforms in schizophrenia, like epigenetics, studies of gene-environment interactions, transcriptomics, proteomics, metabolomics, neuroimaging and psychopathology. A better knowledge of the genetic background of schizophrenia can lead to changes in the treatment, prevention and genetic counselling. It may also reduce stigma in this severe mental disorder.
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Abstract
Despite rigorous research into the genetics of neuropsychiatric disorders, the mechanism by which polygenic risk leads to complex clinical phenotypes remains unclear. The Encyclopedia of DNA Elements (ENCODE) project gives us new insight into gene regulation, and gene-gene and gene-environment interaction. Better understanding of these key genomic mechanisms may provide the answers we have been searching for.
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Li M, Zhang H, Luo XJ, Gao L, Qi XB, Gourraud PA, Su B. Meta-analysis indicates that the European GWAS-identified risk SNP rs1344706 within ZNF804A is not associated with schizophrenia in Han Chinese population. PLoS One 2013; 8:e65780. [PMID: 23776546 PMCID: PMC3680487 DOI: 10.1371/journal.pone.0065780] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 04/28/2013] [Indexed: 01/13/2023] Open
Abstract
Recent genetic association studies have implicated several candidate susceptibility variants for schizophrenia among general populations. Rs1344706, an intronic SNP within ZNF804A, was identified as one of the most compelling candidate risk SNPs for schizophrenia in Europeans through genome-wide association studies (GWASs) and replications as well as large-scale meta-analyses. However, in Han Chinese, the results for rs1344706 are inconsistent, and whether rs1344706 is an authentic risk SNP for schizophrenia in Han Chinese is inconclusive. Here, we conducted a systematic meta-analysis of rs1344706 with schizophrenia in Chinese population by combining all available case-control samples (N = 12), including a total of 8,982 cases and 12,342 controls. The results of our meta-analysis were not able to confirm an association of rs1344706 A-allele with schizophrenia (p = 0.10, odds ratio = 1.06, 95% confidence interval = 0.99-1.13). Such absence of association was further confirmed by the non-superiority test (p = 0.0003), suggesting that rs1344706 is not a risk SNP for schizophrenia in Han Chinese. Detailed examinations of individual samples revealed potential sampling bias in previous replication studies in Han Chinese. The absence of rs1344706 association in Han Chinese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating genome-wide association findings of schizophrenia across different ethnic populations.
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Affiliation(s)
- Ming Li
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Hui Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Xiong-jian Luo
- University of Rochester Flaum Eye Institute, University of Rochester, Rochester, New York, United States of America
| | - Lei Gao
- Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, People's Republic of China
| | - Xue-bin Qi
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Pierre-Antoine Gourraud
- Department of Neurology, School of Medicine, University of California San Francisco, San Francisco, California, United States of America
| | - Bing Su
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
- * E-mail:
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Guan F, Wei S, Zhang C, Zhang H, Zhang B, Xing B, Feng Z, Gao C, Liu X, Li S. A population-based association study of 2q32.3 and 8q21.3 loci with schizophrenia in Han Chinese. J Psychiatr Res 2013; 47:712-717. [PMID: 23490065 DOI: 10.1016/j.jpsychires.2013.01.025] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Revised: 01/29/2013] [Accepted: 01/29/2013] [Indexed: 12/21/2022]
Abstract
It has been reported that two new schizophrenia susceptibility loci (2q32.3 and 8q21.3) containing two single-nucleotide polymorphisms (SNPs; rs17662626 and rs7004633) have been identified in Europeans by a genome-wide association study. To determine if the two regions are associated with schizophrenia in Han Chinese, which are distinct from Europeans, we analyzed 9 SNPs, including rs17662626 and rs7004633, within 2 regions involving 1430 cases and 1570 controls from the Han population. Single SNP association, haplotype association, and gender-specific association analyses were performed. Single SNP analyses revealed that there was no association with schizophrenia in the region of 2q32.3, but rs7004633 mapping to the region of 8q21.3 was significantly associated with schizophrenia (p = 5.1 × 10(-5); OR = 1.274; 95% CI, 1.134-1.429). Further genotype and haplotype association analyses for the region of 8q21.3 suggested a similar pattern. Additionally, analyses by haplotypes indicated that a haplotype block in the region of 8q21.3 highly associated with schizophrenia and one haplotype in this haploblock had a 1.5-fold increase in the cases. Our results provide further evidence regarding the association of the region of 8q21.3 with schizophrenia in Han Chinese, as well as Europeans, which confirmed the previous report that 8q21.3 may play important roles in the etiology of schizophrenia.
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Affiliation(s)
- Fanglin Guan
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, China.
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DeRosse P, Malhotra AK, Lencz T. Molecular genetics of the psychosis phenotype. CANADIAN JOURNAL OF PSYCHIATRY. REVUE CANADIENNE DE PSYCHIATRIE 2012; 57:446-53. [PMID: 22762300 PMCID: PMC4211610 DOI: 10.1177/070674371205700708] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Relative to recent successes in elucidating the genetic mechanisms associated with complex diseases, including macular degeneration, diabetes mellitus, type 2, heart disease, and cancer, molecular genetic approaches to psychiatric illness have met with more limited success. While factors such as small allelic effects, allelic heterogeneity, and variation in population substructure have received considerable attention in attempt to explain the paucity of significant results in psychiatric genetics, significantly less focus has been directed toward phenotypic factors. METHOD Data derived from molecular genetic studies of the psychosis phenotype in patients with a range of psychiatric illnesses are reviewed. RESULTS Available data suggest that genes do not respect the boundaries of the current diagnostic system but may confer risk for symptom-based phenotypic variation that traverses those boundaries. CONCLUSIONS Molecular genetic studies offer convincing evidence for a relation between genetic variation and symptom-based phenotypic variation within psychiatric illness. These data may provide novel insights into the pathophysiology of schizophrenia and other related disorders. The exploration of relations between genetic variation and symptom variation that traverses traditional diagnostic boundaries may ultimately lead to more refined classification systems that more closely reflect the genetic etiology of psychiatric illness.
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Affiliation(s)
- Pamela DeRosse
- Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
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Shen YC, Tsai HM, Ruan JW, Liao YC, Chen SF, Chen CH. Genetic and functional analyses of the gene encoding synaptophysin in schizophrenia. Schizophr Res 2012; 137:14-9. [PMID: 22348818 DOI: 10.1016/j.schres.2012.01.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Revised: 01/06/2012] [Accepted: 01/22/2012] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Synaptophysin (SYP) has been shown to be critical for regulating neurotransmitter release and synaptic plasticity, a process thought to be disrupted in schizophrenia. In addition, abnormal SYP expression in different brain regions has been linked to this disorder in postmortem brain studies. We investigated the involvement of the SYP gene in the susceptibility to schizophrenia. METHODS We searched for genetic variants in the promoter region, all exons, and both UTR ends of the SYP gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study. RESULTS We identified 2 common SNPs (c.*4+271A>G and c.*4+565T>C) in the SYP gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. In addition, we identified 6 rare variants in 7 out of 586 patients, including 1 variant (g.-511T>C) located at the promoter region, 1 synonymous (A104A) and 2 missense variants (G293A and A324T) located at the exonic regions, and 2 variants (c.*31G>A and c.*1001G>T) located at the 3'UTR. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated the influence of g.-511T>C and c.*1001G>T on the regulatory function of the SYP gene, while that the influence of c.*31G>A may be tolerated. In silico analysis demonstrated the functional relevance of other rare variants. CONCLUSION Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and provides genetic clues that indicate the involvement of SYP in this disorder.
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Affiliation(s)
- Yu-Chih Shen
- Department of Psychiatry, Tzu Chi General Hospital, Hualien, Taiwan
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Genetic and functional analysis of the gene encoding neurogranin in schizophrenia. Schizophr Res 2012; 137:7-13. [PMID: 22306195 DOI: 10.1016/j.schres.2012.01.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Revised: 12/21/2011] [Accepted: 01/13/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Schizophrenia is a highly heritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Recently, a SNP rs12807809 located upstream of the neurogranin (NRGN) gene achieved genome-wide significance in this disorder. METHODS In order to find the causal variants of NRGN gene in schizophrenia, we searched for genetic variants in the promoter region and all the exons (including both UTR ends and rs12807809) using direct sequencing in a sample of patients with schizophrenia (n=346) and non-psychotic controls (n=345), both being Han Chinese from Taiwan, and conducted an association and functional study. RESULTS We identified 7 common polymorphisms in the NRGN gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 5 rare variants in 6 out of 346 patients, including 3 rare variants located at the promoter region (g.-620A>G, g.-578C>G, and g.-344G>A) and 2 rare variants located at 5' UTR (c.-74C>G, and c.-41G>A). No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing g.-620G, g.-578G, g.-344A, c.-74G, and c.-41A was significantly lower as compared to the wild type construct (P<0.01 for g.-578G; P<0.001 for the other constructs). In silico analysis also demonstrated their influences on the regulatory function of NRGN gene. CONCLUSIONS Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and provides genetic clues that indicate the involvement of NRGN in this disorder.
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Abstract
Fourteen years ago, the first article on molecular genetics was published in this journal: Child Development, Molecular Genetics, andWhat to Do With Genes Once They Are Found (R. Plomin & M. Rutter, 1998). The goal of the article was to outline what developmentalists can do with genes once they are found. These new directions for developmental research are still relevant today. The problem lies with the phrase “once they are found”: It has been much more difficult than expected to identify genes responsible for the heritability of complex traits and common disorders, the so-called missing heritability problem. The present article considers reasons for the missing heritability problem and possible solutions.
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Abstract
Schizophrenia is a prevalent complex trait disorder manifested by severe neurocognitive dysfunctions and lifelong disability. During the past few years several studies have provided direct evidence for the involvement of different signaling pathways in schizophrenia. In this review, we mainly focus on AKT/GSK3 signaling pathway in schizophrenia. The original study on the involvement of this pathway in schizophrenia was published by Emamian et al. in 2004. This study reported convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK-3β in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. It also showed that haloperidol can induce a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for the impaired function of this signaling pathway in schizophrenia. Following this study, several independent studies were published that not only confirmed the association of this signaling pathway with schizophrenia across different populations, but also shed light on the mechanisms by which AKT/GSK3 pathway may contribute to the development of this complex disorder. In this review, following an introduction on the role of AKT in human diseases and its functions in neuronal and non-neuronal cells, a review on the results of studies published on AKT/GSK3 signaling pathway in schizophrenia after the original 2004 paper will be provided. A brief review on other signaling pathways involved in schizophrenia and the possible connections with AKT/GSK3 signaling pathway will be discussed. Moreover, some possible molecular mechanisms acting through this pathway will be discussed besides the mechanisms by which they may contribute to the pathogenesis of schizophrenia. Finally, different transcription factors related to schizophrenia will be reviewed to see how hypo-activity of AKT signaling pathway may impact such transcriptional mechanisms.
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Affiliation(s)
- Effat S Emamian
- Advanced Technologies for Novel Therapeutics (ATNT), Newark NJ, USA.
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Do psychiatric registries include all persons with schizophrenia in the general population? A population-based longitudinal study. Schizophr Res 2012; 135:187-91. [PMID: 22260965 DOI: 10.1016/j.schres.2011.12.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Revised: 12/12/2011] [Accepted: 12/28/2011] [Indexed: 11/20/2022]
Abstract
BACKGROUND Psychiatric hospitalization registries are utilized to investigate the incidence and prevalence of schizophrenia for both research and administrative purposes. The assumption behind this is that most individuals with schizophrenia will be hospitalized at least once in their life-time. METHOD In an epidemiological survey conducted in the 1980s, a population-based sample (n = 4914) of Israel-born individuals then aged 25-34 were screened in the community, and 29 (0.6%) were subsequently diagnosed by psychiatrists using SADS/RDC criteria. Twenty four years later we linked data from the epidemiological survey with the Israeli National Psychiatric Hospitalization Registry. RESULTS Twenty seven of the 29 individuals (93%) diagnosed with schizophrenia in the survey were identified in the hospitalization registry with the same diagnosis. Fifty-two (1.0%) participants not diagnosed during the survey with schizophrenia were identified in the psychiatric hospitalization registry 24 years later with schizophrenia. The majority of them were diagnosed with other psychiatric disorders in the survey. If all diagnoses of schizophrenia are accepted at face value, the lifetime prevalence rate would be 1.8% for this cohort. CONCLUSION The overwhelming majority of individuals diagnosed with schizophrenia at ages 25-34 in an epidemiological survey were present in the Psychiatric Hospitalization Registry. However, the assessment of life-time rates of schizophrenia at these ages is problematic because some future cases are asymptomatic, others have premorbid non-psychotic disorders, while in others it is difficult to differentiate between affective disorders and schizophrenia. Availability of psychiatric services and hospitalization policy must be considered when generalizing these findings to other countries.
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Abstract
PURPOSE OF REVIEW Numerous genome-wide association studies (GWAS) of schizophrenia have been published in the past 6 years, with a number of key reports published in the last year. The studies have evolved in scale from small individual samples to large collaborative endeavors. This review aims to critically assess whether the results have improved as the sample size and scale of genetic association studies have grown. RECENT FINDINGS Genomic genotyping and increasing sample sizes for schizophrenia association studies have led to parallel increases in the number of risk genes discovered with high statistical confidence. Nearly 20 genes or loci have surpassed the genome-wide significance threshold (P = 5 × 10) in a single study, and several have been replicated in more than one GWAS. SUMMARY Identifying the genetic underpinnings of complex diseases offers insight into the etiological mechanisms leading to manifestation of the disease. New and more effective treatments for schizophrenia are desperately needed, and the ability to target the relevant biological processes grows with our understanding of the genes involved. As the size of GWAS samples has increased, more genes have been identified with high confidence that have begun to provide insight into the etiological and pathophysiological foundations of this disorder.
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Affiliation(s)
- Sarah E Bergen
- Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Sui J, Yu Q, He H, Pearlson GD, Calhoun VD. A selective review of multimodal fusion methods in schizophrenia. Front Hum Neurosci 2012; 6:27. [PMID: 22375114 PMCID: PMC3285795 DOI: 10.3389/fnhum.2012.00027] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2011] [Accepted: 02/08/2012] [Indexed: 12/29/2022] Open
Abstract
Schizophrenia (SZ) is one of the most cryptic and costly mental disorders in terms of human suffering and societal expenditure (van Os and Kapur, 2009). Though strong evidence for functional, structural, and genetic abnormalities associated with this disease exists, there is yet no replicable finding which has proven accurate enough to be useful in clinical decision making (Fornito et al., 2009), and its diagnosis relies primarily upon symptom assessment (Williams et al., 2010a). It is likely in part that the lack of consistent neuroimaging findings is because most models favor only one data type or do not combine data from different imaging modalities effectively, thus missing potentially important differences which are only partially detected by each modality (Calhoun et al., 2006a). It is becoming increasingly clear that multimodal fusion, a technique which takes advantage of the fact that each modality provides a limited view of the brain/gene and may uncover hidden relationships, is an important tool to help unravel the black box of schizophrenia. In this review paper, we survey a number of multimodal fusion applications which enable us to study the schizophrenia macro-connectome, including brain functional, structural, and genetic aspects and may help us understand the disorder in a more comprehensive and integrated manner. We also provide a table that characterizes these applications by the methods used and compare these methods in detail, especially for multivariate models, which may serve as a valuable reference that helps readers select an appropriate method based on a given research question.
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Affiliation(s)
- Jing Sui
- The Mind Research NetworkAlbuquerque, NM, USA
| | - Qingbao Yu
- The Mind Research NetworkAlbuquerque, NM, USA
| | - Hao He
- The Mind Research NetworkAlbuquerque, NM, USA
- Department of Electrical and Computer Engineering, University of New MexicoAlbuquerque, NM, USA
| | - Godfrey D. Pearlson
- Olin Neuropsychiatry Research CenterHartford, CT, USA
- Department of Psychiatry, Yale UniversityNew Haven, CT, USA
- Department of Neurobiology, Yale UniversityNew Haven, CT, USA
| | - Vince D. Calhoun
- The Mind Research NetworkAlbuquerque, NM, USA
- Department of Electrical and Computer Engineering, University of New MexicoAlbuquerque, NM, USA
- Olin Neuropsychiatry Research CenterHartford, CT, USA
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Shen YC, Tsai HM, Cheng MC, Hsu SH, Chen SF, Chen CH. Genetic and functional analysis of the gene encoding GAP-43 in schizophrenia. Schizophr Res 2012; 134:239-45. [PMID: 22138049 DOI: 10.1016/j.schres.2011.11.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Revised: 10/29/2011] [Accepted: 11/13/2011] [Indexed: 10/14/2022]
Abstract
OBJECTIVES In earlier reports, growth-associated protein 43 (GAP-43) has been shown to be critical for initial establishment or reorganization of synaptic connections, a process thought to be disrupted in schizophrenia. Additionally, abnormal GAP-43 expression in different brain regions has been linked to this disorder in postmortem brain studies. In this study, we investigated the involvement of the gene encoding GAP-43 in the susceptibility to schizophrenia. METHODS We searched for genetic variants in the promoter region and 3 exons (including both UTR ends) of the GAP-43 gene using direct sequencing in a sample of patients with schizophrenia (n=586) and non-psychotic controls (n=576), both being Han Chinese from Taiwan, and conducted an association and functional study. RESULTS We identified 11 common polymorphisms in the GAP-43 gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 4 rare variants in 5 out of 586 patients, including 1 variant located at the promoter region (c.-258-4722G>T) and 1 synonymous (V110V) and 2 missense (G150R and P188L) variants located at exon 2. No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing c.-258-4722T was significantly lower as compared to the wild type construct (c.-258-4722G; p<0.001). In silico analysis also demonstrated the functional relevance of other rare variants. CONCLUSIONS Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and it provides genetic clues that indicate the involvement of GAP-43 in this disorder.
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Affiliation(s)
- Yu-Chih Shen
- Department of Psychiatry, Tzu Chi General Hospital, Hualien, Taiwan.
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Spruyt K, Gozal D. Sleep disturbances in children with attention-deficit/hyperactivity disorder. Expert Rev Neurother 2011; 11:565-77. [PMID: 21469929 DOI: 10.1586/ern.11.7] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this article, we advocate the need for better understanding and treatment of children exhibiting inattentive, hyperactive, impulsive behaviors, by in-depth questioning on sleepiness, sleep-disordered breathing or problematic behaviors at bedtime, during the night and upon awakening, as well as night-to-night sleep duration variability. The relationships between sleep and attention-deficit/hyperactivity disorder (ADHD) are complex and are routinely overlooked by practitioners. Motricity and somnolence, the most consistent complaints and objectively measured sleep problems in children with ADHD, may develop as a consequence of multidirectional and multifactorial pathways. Therefore, subjectively perceived or reported restless sleep should be evaluated with specific attention to restless legs syndrome or periodic limb movement disorder, and awakenings should be queried with regard to parasomnias, dyssomnias and sleep-disordered breathing. Sleep hygiene logs detailing sleep onset and offset quantitatively, as well as qualitatively, are required. More studies in children with ADHD are needed to reveal the 24-h phenotype, or its sleep comorbidities.
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Affiliation(s)
- Karen Spruyt
- Department of Pediatrics, Comer Children's Hospital, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois 60637, USA
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Zhang R, Valenzuela RK, Lu S, Meng L, Guo T, Du X, Kang W, Ma J. Is the conserved mammalian region of ZNF804A locus associated with schizophrenia? A population-based genetics analysis. Schizophr Res 2011; 133:159-64. [PMID: 21993378 DOI: 10.1016/j.schres.2011.09.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2011] [Revised: 08/23/2011] [Accepted: 09/17/2011] [Indexed: 01/13/2023]
Abstract
Recently, several genome-wide association studies (GWASs) have reproduced the significant association of the single nucleotide polymorphism (SNP) rs1344706 (located in intron 2 of the zinc finger protein 804A (ZNF804A) on chromosome 2q32.1) with schizophrenia. Bioinformatic analysis of the chromosome segment around rs1344706 suggests that a short conserved mammalian region exists approximately 3kb downstream of rs1344706. In the present work, we studied all SNPs in this conserved mammalian region and performed genetic analyses on samples from Chinese schizophrenia patients (n = 516) and compared control subjects (n = 520). Significant association between an allele of rs13423388 and schizophrenia was found (P = 0.0012). Haplotype analysis of the three SNPs rs4666998, rs13423388, and rs56280129 showed significant associations with schizophrenia (global P = 0.00001). Furthermore, we performed a four-SNP haplotype analysis which included the SNPs from the three-SNP haplotype analysis and rs1344706 (global P = 0.0005), and found that haplotype GCCG was associated with schizophrenia (P = 0.003). In summary, the present study adds new evidence for an association between the conserved mammalian region of the ZNF804A gene and schizophrenia. Further research is needed to clarify the transcriptional regulation of ZNF804A gene and to relate this to the pathophysiology of schizophrenia.
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Affiliation(s)
- Rui Zhang
- Department of Genetics and Molecular Biology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi 710061, PR China
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Brandon NJ, Sawa A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 2011; 12:707-22. [PMID: 22095064 DOI: 10.1038/nrn3120] [Citation(s) in RCA: 331] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Recent advances in our understanding of the underlying genetic architecture of psychiatric disorders has blown away the diagnostic boundaries that are defined by currently used diagnostic manuals. The disrupted in schizophrenia 1 (DISC1) gene was originally discovered at the breakpoint of an inherited chromosomal translocation, which segregates with major mental illnesses. In addition, many biological studies have indicated a role for DISC1 in early neurodevelopment and synaptic regulation. Given that DISC1 is thought to drive a range of endophenotypes that underlie major mental conditions, elucidating the biology of DISC1 may enable the construction of new diagnostic categories for mental illnesses with a more meaningful biological foundation.
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Zhu F, Yan CX, Wang Q, Zhu YS, Zhao Y, Huang J, Zhang HB, Gao CG, Li SB. An association study between dopamine D1 receptor gene polymorphisms and the risk of schizophrenia. Brain Res 2011; 1420:106-13. [PMID: 21955727 DOI: 10.1016/j.brainres.2011.08.069] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 08/29/2011] [Accepted: 08/30/2011] [Indexed: 11/16/2022]
Abstract
Deficits in dopamine transmission at D1 receptors in the PFC are implicated in schizophrenia. Genetic polymorphisms in functional regions of DRD1 have a plausible role in modulating the risk of schizophrenia. In order to evaluate the role of DRD1 polymorphisms as a risk factor for schizophrenia, we performed a detailed analysis of possible functional single nucleotide polymorphisms (SNPs) in regulatory and coding regions of DRD1. Nine SNPs were identified by DNA sequencing in 20 patients with schizophrenia. Then 385 cases and 350 healthy control subjects were genotyped using the nine SNPs (rs4867798, rs686, rs1799914, rs4532 rs5326, rs265981, rs10078714, rs10063995, rs10078866). Statistically significant differences were observed in the allelic or genotypic frequencies of the rs686 and rs10063995 polymorphism in the DRD1 gene. A significantly lower risk of schizophrenia was associated with the G allele and AG+GG genotype of rs686 (OR (G allele)=0.632, 95%CI (G allele): 0.470-0.849; OR (AG+GG genotype)=0.578, 95%CI (AG+GG genotype): 0.416-0.803) compared with the A allele and AA genotype, respectively. And a significantly increased risk of schizophrenia was associated with the T allele of rs10063995 (OR=1.446, 95%CI: 1.125-1.859) compared with the G allele. The haplotype analysis indicated the G-T variant containing the T allele of rs10063995 is a risk for schizophrenia (P=0.005, OR=1.467, 95%CI: 1.123-1.917). These data suggest that DRD1 gene polymorphisms confer susceptibility to schizophrenia, and also support the notion that dysfunction of DRD1 is involved in the pathophysiological process of schizophrenia.
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Affiliation(s)
- Feng Zhu
- Forensic Department, Xi'an Jiaotong University Medical College, 76# West Yanta Road, Xi'an, 710061, PR China
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Kurnianingsih YA, Kuswanto CN, McIntyre RS, Qiu A, Ho BC, Sim K. Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder. J Neural Transm (Vienna) 2011; 118:1621-39. [DOI: 10.1007/s00702-011-0672-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 06/05/2011] [Indexed: 04/08/2023]
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Zhang F, Chen Q, Ye T, Lipska BK, Straub RE, Vakkalanka R, Rujescu D, St Clair D, Hyde TM, Bigelow L, Kleinman JE, Weinberger DR. Evidence of sex-modulated association of ZNF804A with schizophrenia. Biol Psychiatry 2011; 69:914-7. [PMID: 21349497 DOI: 10.1016/j.biopsych.2011.01.003] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Revised: 11/29/2010] [Accepted: 01/03/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND The single nucleotide polymorphism (SNP) rs1344706 in ZNF804A (2q32.1) has been associated with schizophrenia in a genome-wide association study (GWAS). A recent candidate gene study, which replicated the positive association with rs1344706, identified another positive SNP (rs7597593) in ZNF804A associated with schizophrenia. METHODS We performed an association study of rs7597593 in four GWAS cohorts of European ancestry. Postmortem human brain expression data of normal Caucasian individuals (n = 89) was also analyzed for examining the effect of rs7597593 on ZNF804A messenger RNA expression, using logistic regression and linear regression. RESULTS We found that rs7597593 was significantly associated with schizophrenia in the combined GWAS datasets (n = 5023, odds ratio [OR](combined) = 1.15, p = .0011). Analysis of stratification by sex showed that the association was driven by the female subjects (OR = 1.29, p = .0002) and was not significant in male subjects (OR = 1.08, p = .148) in the combined sample of four cohorts. A sex by genotype interaction was near significant in both the Genetic Association Information Network sample (p = .0532) and the combined sample of four cohorts (p(combined) = .0531). Gene expression analysis showed no main effects but a significant female-specific association (p(female) = .047, p(male) = .335) and sex by genotype interaction (p = .0166) for rs7597593. CONCLUSIONS Our data suggest a clinical and molecular modulation by sex of the association of ZNF804A SNP rs7597593 and risk of schizophrenia.
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Affiliation(s)
- Fengyu Zhang
- Genes, Cognition and Psychosis Program and Clinical, Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA
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Fine mapping of ZNF804A and genome-wide significant evidence for its involvement in schizophrenia and bipolar disorder. Mol Psychiatry 2011; 16:429-41. [PMID: 20368704 PMCID: PMC3918934 DOI: 10.1038/mp.2010.36] [Citation(s) in RCA: 210] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A recent genome-wide association study (GWAS) reported evidence for association between rs1344706 within ZNF804A (encoding zinc-finger protein 804A) and schizophrenia (P=1.61 × 10(-7)), and stronger evidence when the phenotype was broadened to include bipolar disorder (P=9.96 × 10(-9)). In this study we provide additional evidence for association through meta-analysis of a larger data set (schizophrenia/schizoaffective disorder N=18 945, schizophrenia plus bipolar disorder N=21 274 and controls N=38 675). We also sought to better localize the association signal using a combination of de novo polymorphism discovery in exons, pooled de novo polymorphism discovery spanning the genomic sequence of the locus and high-density linkage disequilibrium (LD) mapping. The meta-analysis provided evidence for association between rs1344706 that surpasses widely accepted benchmarks of significance by several orders of magnitude for both schizophrenia (P=2.5 × 10(-11), odds ratio (OR) 1.10, 95% confidence interval 1.07-1.14) and schizophrenia and bipolar disorder combined (P=4.1 × 10(-13), OR 1.11, 95% confidence interval 1.07-1.14). After de novo polymorphism discovery and detailed association analysis, rs1344706 remained the most strongly associated marker in the gene. The allelic association at the ZNF804A locus is now one of the most compelling in schizophrenia to date, and supports the accumulating data suggesting overlapping genetic risk between schizophrenia and bipolar disorder.
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Kopsida E, Mikaelsson MA, Davies W. The role of imprinted genes in mediating susceptibility to neuropsychiatric disorders. Horm Behav 2011; 59:375-82. [PMID: 20403360 DOI: 10.1016/j.yhbeh.2010.04.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Revised: 03/31/2010] [Accepted: 04/09/2010] [Indexed: 11/25/2022]
Abstract
Imprinted genes, which are thought to comprise <1% of the mammalian genome, are defined by their parent-of-origin specific monoallelic expression arising as a consequence of differential epigenetic marking of alleles in the paternal and maternal germlines. Such genes are highly represented in the brain and placental transcriptomes, and have been shown to exert significant influence on fundamental developmental processes in these organs. Converging evidence from work in man and animal models has shown that imprinted genes can influence a variety of brain and behavioral endophenotypes. In this article, we review the current evidence that imprinted gene dysfunction is associated with vulnerability to several common psychiatric disorders. We also discuss how studying imprinted gene (dys)function may provide mechanistic insights into two important areas in modern psychiatry: first, how environmental factors (especially in utero) interact with genetic liability via epigenetic mechanisms to predispose to later mental illness, and second, the molecular underpinnings of sex-specific vulnerability to psychiatric disorders.
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Deep-Soboslay A, Benes FM, Haroutunian V, Ellis JK, Kleinman JE, Hyde TM. Psychiatric brain banking: three perspectives on current trends and future directions. Biol Psychiatry 2011; 69:104-12. [PMID: 20673875 PMCID: PMC3105380 DOI: 10.1016/j.biopsych.2010.05.025] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2010] [Revised: 05/12/2010] [Accepted: 05/14/2010] [Indexed: 12/31/2022]
Abstract
Postmortem human brain tissue is critical for advancing neurobiological studies of psychiatric illness, particularly for identifying brain-specific transcripts and isoforms. State-of-the-art methods and recommendations for maintaining psychiatric brain banks are discussed in three disparate collections, the National Institute of Mental Health Brain Tissue Collection, the Harvard Brain Tissue Resource Center, and the Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank. While the National Institute of Mental Health Brain Tissue Collection obtains donations from medical examiners and focuses on clinical diagnosis, toxicology, and building life span control cohorts, the Harvard Brain Tissue Resource Center is designed as a repository to collect large-volume, high-quality brain tissue from community-based donors across a nationwide network, placing emphasis on the accessibility of tissue and related data to research groups worldwide. The Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank has shown that prospective recruitment is a successful approach to tissue donation, placing particular emphasis on clinical diagnosis through antemortem contact with donors, as well as stereological tissue sampling methods for neuroanatomical studies and frozen tissue sampling approaches that enable multiple assessments (e.g., RNA, DNA, protein, enzyme activity, binding) of the same tissue block. Promising scientific approaches for elucidating the molecular and cellular pathways in brain that may contribute to schizophrenia are briefly discussed. Despite different perspectives from three established brain collections, there is consensus that varied networking strategies, rigorous tissue and clinical characterization, sample and data accessibility, and overall adaptability are integral to the success of psychiatric brain banking.
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Affiliation(s)
- Amy Deep-Soboslay
- Section on Neuropathology, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Francine M. Benes
- Harvard Brain Tissue Resource Center, Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA, USA
| | - Vahram Haroutunian
- The Mount Sinai School of Medicine Alzheimer's Disease and Schizophrenia Brain Bank, New York, NY, USA
| | - Justin K. Ellis
- Section on Neuropathology, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Joel E. Kleinman
- Section on Neuropathology, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Thomas M. Hyde
- Section on Neuropathology, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
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Collins A, Politopoulos I. The genetics of breast cancer: risk factors for disease. APPLICATION OF CLINICAL GENETICS 2011; 4:11-9. [PMID: 23776363 PMCID: PMC3681174 DOI: 10.2147/tacg.s13139] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The genetic factors known to be involved in breast cancer risk comprise about 30 genes. These include the high-penetrance early-onset breast cancer genes, BRCA1 and BRCA2, a number of rare cancer syndrome genes, and rare genes with more moderate penetrance. A larger group of common variants has more recently been identified through genome-wide association studies. Quite a number of these common variants are mapped to genomic regions without being firmly associated with specific genes. It is thought that most of these variants have gene regulatory functions, but their precise roles in disease susceptibility are not well understood. Common variants account for only a small percentage of the risk of disease because they have low penetrance. Collectively, the breast cancer genes identified to date contribute only ~30% of the familial risk. Therefore, there is much interest in accounting for the missing heritability, and possible sources include loss of information through ignoring phenotype heterogeneity (disease subtypes have genetic differences), gene–gene and gene–environment interaction, and rarer forms of variation. Identification of these rarer variations in coding regions is now feasible and cost effective through exome sequencing, which has already identified high-penetrance variants for some rare diseases. Targeting more ‘extreme’ breast cancer phenotypes, particularly cases with early-onset disease, a strong family history (not accounted for by BRCA mutations), and with specific tumor subtypes, provides a route to progress using next-generation sequencing methods.
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Affiliation(s)
- Andrew Collins
- Genetic Epidemiology and Bioinformatics Research Group, Human Genetics Research Division, Southampton General Hospital, School of Medicine, University of Southampton, Southampton, UK
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Varma V, Wise C, Kaput J. Carbohydrate metabolic pathway genes associated with quantitative trait loci (QTL) for obesity and type 2 diabetes: identification by data mining. Biotechnol J 2010; 5:942-9. [PMID: 20845384 DOI: 10.1002/biot.201000067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Increasing consumption of refined carbohydrates is now being recognized as a primary contributor to the development of nutritionally related chronic diseases such as obesity and type 2 diabetes mellitus (T2DM). A data mining approach was used to evaluate the role of carbohydrate metabolic pathway genes in the development of obesity and T2DM. Data from public databases were used to map the position of the carbohydrate metabolic pathway genes to known quantitative trait loci (QTL) for obesity and T2DM and for examining the pathway genes for the presence of sequence and structural genetic variants such as single nucleotide polymorphisms (SNPs) and copy number variants (CNS), respectively. The results demonstrated that a majority of the genes of the carbohydrate metabolic pathways are associated with QTL for obesity and many for T2DM. In addition, some key genes of the pathways also encode non-synonymous SNPs that exhibit significant differences in population frequencies. This study emphasizes the significance of the metabolic pathways genes in the development of disease phenotypes, its differential occurrence across populations and between individuals, and a strategy for interpreting an individuals' risk for disease.
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Affiliation(s)
- Vijayalakshmi Varma
- Division of Personalized Nutrition and Medicine, National Center for Toxicological Research, Jefferson, AR 72079, USA.
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Dwyer S, Williams H, Holmans P, Moskvina V, Craddock N, Owen MJ, O'Donovan MC. No evidence that rare coding variants in ZNF804A confer risk of schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2010; 153B:1411-6. [PMID: 20862696 DOI: 10.1002/ajmg.b.31117] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Accepted: 07/27/2010] [Indexed: 01/27/2023]
Abstract
Strong evidence that rare variants of relatively high penetrance are involved in the etiology of schizophrenia is currently restricted to the data from studies investigating copy number variants and major structural re-arrangements in that disorder. Global tests of the hypothesis of the involvement of fairly high penetrance rare single nucleotide changes or small insertion deletion events await the genesis of data from large-scale sequencing studies, meanwhile, a pragmatic approach to trying to detect such alleles is to target sequencing efforts on genes for which there is compelling evidence from other sources for their involvement in this disorder. We have undertaken a study, which aimed to identify whether rare (frequency ∼0.001%) coding variants in the schizophrenia susceptibility gene ZNF804A are involved in this disorder. We screened the coding regions of the gene in 517 schizophrenic cases and 501 controls, and genotyped rare non-synonymous variants in a case-control sample powered to detect association to rare alleles with an effect size (odds ratio) of 5. No single rare variant was associated with schizophrenia, nor was the burden of rare, or even fairly common, non-synonymous variants. Our results do not support the hypothesis that moderately rare non-synonymous variants at the ZNF804A locus are involved in schizophrenia susceptibility. © 2010 Wiley-Liss, Inc.
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Affiliation(s)
- S Dwyer
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
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Tormoehlen K, Lessick M. Schizophrenia in women: implications for pregnancy and postpartum. Nurs Womens Health 2010; 14:482-495. [PMID: 21122083 DOI: 10.1111/j.1751-486x.2010.01595.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
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Genetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34:1375-80. [PMID: 20600464 DOI: 10.1016/j.pnpbp.2010.06.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2010] [Revised: 06/17/2010] [Accepted: 06/18/2010] [Indexed: 12/21/2022]
Abstract
There is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes.
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Stergiakouli E, Thapar A. Fitting the pieces together: current research on the genetic basis of attention-deficit/hyperactivity disorder (ADHD). Neuropsychiatr Dis Treat 2010; 6:551-60. [PMID: 20856918 PMCID: PMC2938304 DOI: 10.2147/ndt.s11322] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a highly disruptive childhood-onset disorder that often persists into adolescence and adulthood. Comorbidity with other problems, such as autism, dyslexia and conduct disorder (CD) is very common. Although little is known about the pathophysiology of ADHD, family, twin and adoption studies have shown that it is highly heritable. Whole genome linkage studies suggest there are no common susceptibility genes of moderate effect size. Most published research has been based on functional candidate gene studies. The most consistent evidence for association with ADHD relates to a dopamine D4 receptor (DRD4) gene variable number tandem repeat (VNTR), a dopamine D5 receptor (DRD5) gene microsatellite and a dopamine transporter (DAT1) gene VNTR. In addition, the catechol-O-methyltransferase (COMT) val158/108 met variant has been shown to increase risk for associated antisocial behavior. The first genome-wide association studies (GWAS) of ADHD have been completed and although larger studies are still required to detect common risk variants, novel risk pathways are being suggested for ADHD. Further research on the contribution of rare variants, larger genome-wide association and sequencing studies and ADHD phenotype refinement is now needed.
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Affiliation(s)
- Evangelia Stergiakouli
- Department of Psychological, Medicine and Neurology, MRC Centre, for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff, University, United Kingdom
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Shen YC, Liao DL, Lu CL, Chen JY, Liou YJ, Chen TT, Chen CH. Resequencing of the vesicular glutamate transporter 2 gene (VGLUT2) reveals some rare genetic variants that may increase the genetic burden in schizophrenia. Schizophr Res 2010; 121:179-86. [PMID: 20541370 DOI: 10.1016/j.schres.2010.05.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 04/01/2010] [Accepted: 05/16/2010] [Indexed: 11/27/2022]
Abstract
OBJECTIVES Vesicular glutamate transporters (VGLUT1-3) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. In mesencephalic dopamine neuron culture, the majority of isolated dopamine neurons express VGLUT2, but not VGLUT1 or 3, have been demonstrated. As related to the dysregulated glutamatergic hypothesis of schizophrenia, the gene encoding VGLUT2 is the most plausible candidate involved in the pathogenesis of this illness. METHODS We searched for genetic variants in the promoter region and 12 exons (including UTR ends) of the VGLUT2 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=375) and non-psychotic controls (n=366) from Taiwan, and conducted a case-control association study. RESULTS We identified 8 common SNPs in the VGLUT2 gene. SNP and haplotype-based analyses showed no association with schizophrenia. Besides, we identified 9 rare variants in 13 out of 375 patients, including 3 variants located at the promoter region, 2 synonymous variants located at protein coding regions, and 4 variants located at UTR ends. No rare variants were found in the control subjects. Collectively, these rare variants were significantly overrepresented in the patient group (3.5% versus 0, p value of Fisher's exact test=2.3x10(-5)), suggesting they may contribute to the pathogenesis of schizophrenia. CONCLUSION Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutations hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.
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Affiliation(s)
- Yu-Chih Shen
- Department of Psychiatry, Tzu Chi General Hospital and University, Hualien, Taiwan
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Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain. Biol Psychiatry 2010; 68:33-40. [PMID: 20434134 DOI: 10.1016/j.biopsych.2010.03.015] [Citation(s) in RCA: 104] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 02/10/2010] [Accepted: 03/03/2010] [Indexed: 01/25/2023]
Abstract
BACKGROUND The combined analysis of several large genome-wide association studies identified the basic helix-loop-helix (bHLH) transcription factor TCF4 as one of the most significant schizophrenia susceptibility genes. Its function in the adult brain, however, is not known. TCF4 belongs to the E-protein subfamily known to be involved in neurodevelopment. The messenger RNA expression of Tcf4 is sustained in the adult mouse brain, suggesting a function in the adult nervous system. Tcf4 null mutant mice die perinatally, and haploinsufficiency of TCF4 in humans causes severe mental retardation. METHODS To investigate the possible function of TCF4 in the adult central nervous system, we generated transgenic mice that moderately overexpress TCF4 postnatally in the brain to reduce the risk of developmental effects possibly interfering with adult brain functions. Tcf4 transgenic mice were characterized with molecular, histological, and behavioral methods. RESULTS Tcf4 transgenic mice display profound deficits in contextual and cued fear conditioning and sensorimotor gating. Furthermore, we show that TCF4 interacts with the neurogenic bHLH factors NEUROD and NDRF in vivo. Molecular analyses revealed the dynamic circadian deregulation of neuronal bHLH factors in the adult hippocampus. CONCLUSIONS We conclude that TCF4 likely acts in concert with other neuronal bHLH transcription factors contributing to higher-order cognitive processing. Moderate transcriptional deregulation of Tcf4 in the brain interferes with cognitive functions and might alter circadian processes in mice. These observations provide insight for the first time into the physiological function of TCF4 in the adult brain and its possible contributions to neuropsychiatric disease conditions.
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Abstract
Schizophrenia is a major debilitating psychiatric disorder affecting approximately 1% of the population worldwide. A tremendous amount of effort has been expended in the last two decades to identify genes influencing susceptibility to this disorder. Although there is a strong trend toward integrating data obtained from various genetic studies and their related biological information into a comprehensive resource for many complex diseases, we were unable to find such an effort for schizophrenia or for any other psychiatric disorder yet. In this study, we present Schizophrenia gene resource (SZGR), a comprehensive database with user-friendly web interface. SZGR deposits genetic data from all available sources, including those from association studies, linkage scans, gene expression, literature, gene ontology (GO) annotations, gene networks, cellular and regulatory pathways, as well as microRNAs and their target sites. Moreover, SZGR provides online tools for data browse and search, data integration, custom gene ranking and graphical presentation. This system can be easily applied to other complex diseases, especially to other psychiatric disorders. The SZGR database is available at http://bioinfo.mc.vanderbilt.edu/SZGR/.
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Affiliation(s)
- P Jia
- Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37203, USA,Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - J Sun
- Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37203, USA,Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - AY Guo
- Virginia Institute for Psychiatric and Behavioral Genetics and Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Z Zhao
- Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37203, USA,Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203, USA,Virginia Institute for Psychiatric and Behavioral Genetics and Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA,Vanderbilt-Ingram Cancer Center, Nashville, TN 37211, USA
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Singh SM, Castellani C, O'Reilly R. Autism meets schizophrenia via cadherin pathway. Schizophr Res 2010; 116:293-4. [PMID: 19861233 DOI: 10.1016/j.schres.2009.09.031] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Accepted: 09/22/2009] [Indexed: 11/28/2022]
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