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1.
Psychiatry Res ; 275: 276-282, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952071

RESUMO

EGR1, involved in the regulation of synaptic plasticity, learning, and memory, is considered a candidate gene for schizophrenia. We resequenced the exonic regions of EGR1 in 516 patients with schizophrenia and conducted a reporter gene assay. We found two mutations including a rare mutation (c.-8C>T, rs561524195) and one common SNP (c.308-42C>T, rs11743810). The reporter gene assay showed c.-8C>T mutant did not affect promoter activity. Gene expression analyses showed that the average EGR1 mRNA and protein levels in lymphoblastoid cell lines of schizophrenia in male, but not female, were significantly higher than those in controls. We conducted in vitro DNA methylation reaction, luciferase activity assay, and pyrosequencing to assess DNA methylation of EGR1 expression underlying the pathophysiology of schizophrenia. DNA methylation of the EGR1 promoter region attenuated reporter activity, suggesting that DNA methylation regulates EGR1 expression. There were no statistically significant differences in DNA methylation levels of 17 CpG sites at the EGR1 promoter region between 64 patients with schizophrenia compared with 64 controls. These results suggest that the exonic mutations in EGR1 and DNA methylation regulating EGR1 expression might not be associated with schizophrenia. However, the gender-specific association of elevated EGR1 expression might be involved in the pathophysiology of schizophrenia.


Assuntos
Metilação de DNA , Proteína 1 de Resposta de Crescimento Precoce/genética , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Linhagem Celular , Ilhas de CpG/genética , Éxons , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Mutação , Regiões Promotoras Genéticas/genética , RNA Mensageiro/metabolismo , Esquizofrenia/fisiopatologia , Fatores Sexuais
2.
Psychiatry Res ; 265: 246-248, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29763843

RESUMO

Aberrant WNT signaling has been implicated in the pathophysiology of schizophrenia. WNT7A, a member of the WNT gene family, is considered a potential candidate of schizophrenia. All exons of WNT7A in 570 schizophrenic patients and 563 controls were sequenced, and protein functional analysis was conducted. Five common variants were identified, but none were noted to be associated with schizophrenia. Nevertheless, nine rare mutations, including one schizophrenia-specific missense mutation (c.305G > A), were discovered. However, immunoblot analysis findings revealed that the c.305G > A mutation did not affect protein expression. These results suggest that WNT7A is unlikely to be associated with susceptibility to schizophrenia.


Assuntos
Análise Mutacional de DNA/métodos , Mutação/genética , Esquizofrenia/genética , Proteínas Wnt/genética , Estudos de Coortes , Éxons/genética , Feminino , Células HEK293 , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Esquizofrenia/diagnóstico
3.
Schizophr Res ; 190: 28-31, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28341002

RESUMO

Autoimmune encephalopathy caused by autoantibodies against neuronal cell-surface proteins in the brain is a newly discovered disease category associated with psychiatric disorders. Correct diagnosis of this condition relies on the detection of specific autoantibodies in the blood or cerebral spinal fluid in addition to the clinical presentations. The study aimed to understand the seroprevalence of selective anti-neuronal autoantibodies in our patients with schizophrenia. First, we screened for six anti-neuronal autoantibodies in an archived blood sample collected from patients with the first-episode schizophrenia. The six autoantibodies including antibodies against N-methyl-d-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors 1 and 2, γ-butyric acid receptor type B1 (GABARB1), leucine-rich glioma inactivated-1 (LGI1) protein, and contactin-associated protein-like 2 (CASPR2) protein. A total of 78 plasma samples (46 males and 32 females) were investigated; however, no positive case was identified. In this second study, we screened anti-NMDA receptor autoantibodies in a blood sample of 234 patients with chronic schizophrenia (133 females and 101 males) including 48 patients defined as treatment resistance. None of this sample was detected as positive. The negative findings in this study suggest that the seroprevalence of autoantibodies against neuronal surface proteins might be low in patients diagnosed with schizophrenia.


Assuntos
Autoanticorpos/sangue , Proteínas do Tecido Nervoso/imunologia , Esquizofrenia/epidemiologia , Esquizofrenia/imunologia , Doença Aguda , Adulto , Doença Crônica , Resistência a Medicamentos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Esquizofrenia/sangue , Estudos Soroepidemiológicos , Adulto Jovem
4.
Psychiatry Res ; 251: 115-117, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28199908

RESUMO

DNA methylation has been implicated in the pathogenesis of schizophrenia. EGR3 is considered as a potential candidate gene for schizophrenia. We conducted in vitro DNA methylation reaction, Lucia luciferase activity assay, and pyrosequencing assay to assess the DNA methylation of the EGR3 expression underlying the pathophysiology of schizophrenia. We found that DNA methylation of the putative EGR3 regulatory regions attenuated Lucia luciferase activity. There was no difference in the DNA methylation pattern of EGR3 between in 50 schizophrenic patients and 47 controls. Our data suggest that DNA methylation regulated the expression of EGR3 might not be associated with schizophrenia.


Assuntos
Metilação de DNA/genética , Proteína 3 de Resposta de Crescimento Precoce/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Feminino , Humanos , Masculino , Regiões Promotoras Genéticas/genética
5.
Genes (Basel) ; 7(11)2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27879657

RESUMO

A higher-than-expected frequency of schizophrenia in patients with 22q11.2 deletion syndrome suggests that chromosome 22q11.2 harbors the responsive genes related to the pathophysiology of schizophrenia. The TBX1 gene, which maps to the region on chromosome 22q11.2, plays a vital role in neuronal functions. Haploinsufficiency of the TBX1 gene is associated with schizophrenia endophenotype. This study aimed to investigate whether the TBX1 gene is associated with schizophrenia. We searched for mutations in the TBX1 gene in 652 patients with schizophrenia and 567 control subjects using a re-sequencing method and conducted a reporter gene assay. We identified six SNPs and 25 rare mutations with no association with schizophrenia from Taiwan. Notably, we identified two rare schizophrenia-specific mutations (c.-123G>C and c.-11delC) located at 5' UTR of the TBX1 gene. The reporter gene assay showed that c.-123C significantly decreased promoter activity, while c.-11delC increased promoter activity compared with the wild-type. Our findings suggest that the TBX1 gene is unlikely a major susceptible gene for schizophrenia in an ethnic Chinese population for Taiwan, but a few rare mutations in the TBX1 gene may contribute to the pathogenesis of schizophrenia in some patients.

6.
Schizophr Res ; 176(2-3): 106-113, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27464451

RESUMO

Activity-regulated cytoskeleton-associated protein (ARC), which interacts with the N-methyl-d-aspartate receptor (NMDAR) complex, is a critical effector molecule downstream of multiple neuronal signaling pathways. Dysregulation of the ARC/NMDAR complex can disrupt learning, memory, and normal brain functions. This study examined the role of ARC in susceptibility to schizophrenia. We used a resequencing strategy to identify the variants of ARC in 1078 subjects, including patients with schizophrenia and normal controls. We identified 16 known SNPs and 27 rare mutations. SNP-based analysis showed no association of ARC with schizophrenia. In addition, the rare mutations did not increase the burden in patients compared with controls. However, one patient-specific allele in the putative ARC promoter region and seven patient-specific mutants in ARC exon regions significantly reduced the reporter gene activity compared with ARC wild-type. Methylation of a putative ARC promoter attenuated reporter activity in vitro, suggesting that ARC expression is regulated by DNA methylation. Pyrosequencing revealed eight hypermethylated CpG sites in the putative ARC promoter region in 64 schizophrenic patients compared with 63 controls. Taken together, our results suggest that both rare variants and epigenetic regulation of ARC contribute to the pathogenesis of schizophrenia in some patients.


Assuntos
Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Metilação de DNA , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Grupo com Ancestrais do Continente Asiático/genética , Linhagem Celular Tumoral , Ilhas de CpG , Éxons , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Taiwan
7.
Brain Res ; 1629: 126-34, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26496011

RESUMO

Methamphetamine (METH) is a highly addictive psychostimulant that may cause long-lasting synaptic dysfunction and abnormal gene expression. We aimed to explore the differential expression of synaptic plasticity genes in chronic METH-treated mouse brain. We used the RT(2) Profiler PCR Array and the real-time quantitative PCR to characterize differentially expressed synaptic plasticity genes in the frontal cortex and the hippocampus of chronic METH-treated mice compared with normal saline-treated mice. We further used pyrosequencing to assess DNA methylation changes in the CpG region of the five immediate early genes (IEGs) in chronic METH-treated mouse brain. We detected six downregulated genes in the frontal cortex and the hippocampus of chronic METH-treated mice, including five IEGs (Arc, Egr2, Fos, Klf10, and Nr4a1) and one neuronal receptor gene (Grm1), compared with normal saline-treated group, but only four genes (Arc, Egr2, Fos, and Nr4a1) were confirmed to be different. Furthermore, we found several CpG sites of the Arc and the Fos that had significant changes in DNA methylation status in the frontal cortex of chronic METH-treated mice, while the klf10 and the Nr4a1 that had significant changes in the hippocampus. Our results show that chronic administration of METH may lead to significant downregulation of the IEGs expression in both the frontal cortex and the hippocampus, which may partly account for the molecular mechanism of the action of METH. Furthermore, the changes in DNA methylation status of the IEGs in the brain indicate that an epigenetic mechanism-dependent transcriptional regulation may contribute to METH addiction, which warrants additional study.


Assuntos
Encéfalo/metabolismo , Metilação de DNA/fisiologia , Epigênese Genética/fisiologia , Genes Precoces/fisiologia , Metanfetamina/administração & dosagem , Plasticidade Neuronal/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Regulação da Expressão Gênica , Genes Precoces/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Plasticidade Neuronal/efeitos dos fármacos
8.
Psychiatry Res ; 228(3): 958-60, 2015 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-26119399

RESUMO

Abnormal myelination is considered as part of the pathophysiology of schizophrenia. We resequenced the genomic DNA of the EGR2, which has a specific function in the myelination of peripheral nervous system, in 543 schizophrenic patients and 554 non-psychotic controls. We identified six known SNPs, which were not associated with schizophrenia. Nevertheless, we discovered 24 rare mutations, some of them were patient-specific, including a recurrent mutation (p.P173_Y174insP), which might be associated with the pathogenesis of schizophrenia.


Assuntos
Proteína 2 de Resposta de Crescimento Precoce/genética , Mutação/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Análise de Sequência de DNA/métodos , Adulto , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
9.
Mol Autism ; 5: 36, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24999380

RESUMO

BACKGROUND: GABRB3 is a position candidate gene at chromosome 15q12 that has been implicated in the neurobiology of autism spectrum disorders (ASD). The aim of this study was to examine the genetic association of GABRB3 with ASD. METHODS: The sample consisted of 356 patients with clinical diagnosis of ASD according to the DSM-IV diagnostic criteria and confirmed by the Autism Diagnostic Interview-Revised and 386 unrelated controls. We searched for mutations at all the exonic regions and 1.6 Kb of the 5' region of GABRB3 in the genomic DNA of all the participants using the Sanger sequencing. We implemented a case-control association analysis of variants detected in this sample, and conducted a reporter gene assay to assess the functional impact of variants at the 5' regulatory region. RESULTS: We detected six known common SNPs; however, they were not associated with ASD. Besides, a total of 22 rare variants (12 at 5' regulatory, 4 at intronic, and 6 at exonic regions) were detected in 18 patients and 6 controls. The frequency of rare variants was significantly higher in the patient group than in the control group (18/356 versus 6/386, odds ratio = 3.37, P = 0.007). All the 12 rare variants at the 5' regulatory region were only detected in 7 patients, but not in any of the controls (7/356 versus 0/386, Fisher's exact test, P = 0.006). Two patients carried multiple rare variants. Family studies showed that most of these rare variants were transmitted from their parents. Reporter gene assays revealed that four rare variants at the 5' regulatory region and 1 at exon 1a untranslated region had elevated reporter gene activities compared to two wild type alleles. CONCLUSIONS: Our data suggest rare variants of GABRB3 might be associated with ASD, and increased GABRB3 expression may contribute to the pathogenesis of ASD in some patients. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION IDENTIFIER: NCT00494754.

10.
Psychiatr Genet ; 24(4): 125-50, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24912047

RESUMO

The XXI World Congress of Psychiatric Genetics (WCPG), sponsored by the International Society of Psychiatric Genetics (ISPG), took place in Boston, Massachusetts, on 17-21 October 2013. Approximately 900 participants gathered to discuss the latest findings in this rapidly advancing field. The following report was written by student travel awardees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported.


Assuntos
Transtornos Mentais/genética , Biomarcadores/metabolismo , Boston , Endofenótipos , Redes Reguladoras de Genes , Testes Genéticos , Estudo de Associação Genômica Ampla , Genômica , Humanos , Mutação/genética , Estatística como Assunto , Células-Tronco/metabolismo
11.
Psychiatr Genet ; 24(4): 151-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24865167

RESUMO

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.


Assuntos
Cromossomos Humanos Par 15/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de GABA-A/genética , Esquizofrenia/genética , Adulto , Feminino , Frequência do Gene/genética , Genes Reporter , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
12.
PLoS One ; 9(1): e85373, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24416398

RESUMO

Aberrant synaptic dysfunction is implicated in the pathogenesis of schizophrenia. The DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 (SAPAP2) located at the post-synaptic density of neuronal cells is involved in the neuronal synaptic function. This study aimed to investigate whether the DLGAP2 gene is associated with schizophrenia. We resequenced the putative promoter region and all the exons of the DLGAP2 gene in 523 patients with schizophrenia and 596 non-psychotic controls from Taiwan and conducted a case-control association analysis. We identified 19 known SNPs in this sample. Association analysis of 9 SNPs with minor allele frequency greater than 5% showed no association with schizophrenia. However, we found a haplotype (CCACCAACT) significantly associated with schizophrenia (odds ratio:2.5, p<0.001). We also detected 16 missense mutations and 1 amino acid-insertion mutation in this sample. Bioinformatic analysis showed some of these mutations were damaging or pathological to the protein function, but we did not find increased burden of these mutations in the patient group. Notably, we identified 5 private rare variants in 5 unrelated patients, respectively, including c.-69+9C>T, c.-69+13C>T, c.-69+47C>T, c.-69+55C>T at intron 1 and c.-32A>G at untranslated exon 2 of the DLGAP2 gene. These rare variants were not detected in 559 control subjects. Further reporter gene assay of these rare variants except c.-69+13C>T showed significantly elevated promoter activity than the wild type, suggesting increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia. Our results indicate that DLGAP2 is a susceptible gene of schizophrenia.


Assuntos
Predisposição Genética para Doença , Mutação , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adulto , Alelos , Estudos de Casos e Controles , Éxons , Feminino , Frequência do Gene , Haplótipos , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Esquizofrenia/diagnóstico , Análise de Sequência de DNA , Taiwan
13.
Addict Biol ; 19(1): 102-10, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21995595

RESUMO

Heroin dependence is a complex mental disorder resulting from interactions between genetic and environmental factors. Identifying the susceptibility genes of heroin dependence is the basis for understanding the pathogenesis of heroin dependence. Using a total gene expression microarray, we detected 924 differentially expressed gene transcripts in lymphoblastoid cell lines (LCLs) between 19 male heroin-dependent individuals and 20 male control subjects, including 279 upregulated and 645 downregulated gene transcripts in heroin-dependent individuals. We verified the reduced expression of the neuron-specific enolase gene (ENO2) in heroin-dependent individuals using real-time quantitative polymerase chain reaction and Western blot analysis. We further compared the allele and genotype frequencies of three single nucleotide polymorphisms (SNPs, rs11064464, rs3213433 and rs10849541) of the ENO2 gene between 532 male heroin-dependent individuals and 369 male controls. No significant differences in the allele or genotype frequencies of these three SNPs were detected between these two groups. Nevertheless, we identified a haplotype (T-C-G) derived from these three SNPs significantly underrepresented in heroin-dependent individuals compared with the control group (72.7% versus 75.9%, P<0.032), while two other rare haplotypes (C-A-G and T-C-A) significantly overrepresented in heroin-dependent individuals compared with the control group (P<0.001). Further study, however, did not detect significant differences of the plasma concentration of neuron-specific enolase between these two groups. Our data suggest that the ENO2 gene might be associated with heroin dependence, and reduced ENO2 gene expression may confer increased risk to heroin dependence.


Assuntos
Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Dependência de Heroína/genética , Fosfopiruvato Hidratase/genética , RNA Mensageiro/genética , Western Blotting , Estudos de Casos e Controles , Linhagem Celular , Frequência do Gene , Interação Gene-Ambiente , Estudos de Associação Genética , Haplótipos/genética , Hemoglobinas/metabolismo , Humanos , Linfócitos/citologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fosfopiruvato Hidratase/sangue , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único/genética , Taiwan
14.
Psychiatry Res ; 208(1): 84-7, 2013 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-23414653

RESUMO

We resequenced the exonic regions of the DLGAP3 gene, which encodes SAP90/PSD95-associated protein 3, in 215 schizophrenic patients and 215 non-psychotic controls. Seven known single-nucleotide polymorphisms (SNPs) were identified, but not associated with schizophrenia. Nevertheless, we identified several rare missense mutations and some of them might be associated with the pathogenesis of schizophrenia.


Assuntos
Éxons/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto/genética , Polimorfismo de Nucleotídeo Único/genética
15.
Psychiatry Res ; 205(1-2): 13-7, 2013 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-22940546

RESUMO

Schizophrenia is a severe chronic mental disorder with high genetic components in its etiology. Several studies indicated that synaptic dysfunction is involved in the pathophysiology of schizophrenia. Postsynaptic synapse-associated protein 90/postsynaptic density 95-associated proteins (SAPAPs) constitute a part of the N-methyl-d-aspartate receptor-associated postsynaptic density proteins, and are involved in synapse formation. We hypothesized that genetic variants of the SAPAPs might be associated with schizophrenia. Thus, we systemically sequenced all the exons of the discs, large (Drosophila) homolog-associated protein 1 (DLGAP1) gene that encodes SAPAP1 in a sample of 121 schizophrenic patients and 120 controls from Taiwan. We totally identified six genetic variants, including five known SNPs (rs145691437, rs3786431, rs201567254, rs3745051 and rs11662259) and one rare missense mutation (c.1922A>G) in this sample. SNP- and haplotype-based analyses showed no association of these SNPs with schizophrenia. The c.1922A>G mutation that changes the amino acid lysine to arginine at codon 641 was found in one out of 121 patients, but not in 275 control subjects, suggesting it might be a patient-specific mutation. Nevertheless, bioinformatic analysis showed this mutation does not affect the function of the DLGAP1 gene and appears to be a benign variant. Hence, its relationship with the pathogenesis remains to be investigated.


Assuntos
Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Transmissão Sináptica/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Proteínas Associadas SAP90-PSD95 , Esquizofrenia/etnologia , Taiwan
16.
Prog Neuropsychopharmacol Biol Psychiatry ; 39(1): 149-55, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22691714

RESUMO

OBJECTIVE: Early growth response genes (EGR1, 2, 3, and 4) encode a family of nuclear proteins that function as transcriptional regulators. They are involved in the regulation of synaptic plasticity, learning, and memory, and are implicated in the pathogenesis of schizophrenia. METHODS: We conducted a genetic association analysis of 14 SNPs selected from the EGR1, 2, 3, and 4 genes of 564 patients with schizophrenia and 564 control subjects. We also conducted Western blot analysis and promoter activity assay to characterize the EGR genes associated with schizophrenia RESULTS: We did not detect a true genetic association of these 14 SNPs with schizophrenia in this sample. However, we observed a nominal over-representation of C/C genotype of rs9990 of EGR2 in female schizophrenia as compared to female control subjects (p=0.012, uncorrected for multiple testing). Further study showed that the average mRNA level of the EGR2 gene in the lymphoblastoid cell lines of female schizophrenia patients was significantly higher than that in female control subjects (p=0.002). We also detected a nominal association of 4 SNPs (rs6747506, rs6718289, rs2229294, and rs3813226) of the EGR4 gene that form strong linkage disequilibrium with schizophrenia in males. Reporter gene assay showed that the haplotype T-A derived from rs6747506 and rs6718289 at the promoter region had significantly reduced promoter activity compared with the haplotype A-G. CONCLUSION: Our data suggest a tendency of gender-specific association of EGR2 and EGR4 in schizophrenia, with an elevated expression of EGR2 in lympoblastoid cell lines of female schizophrenia patients and a reduced EGR4 gene expression in male schizophrenia patients.


Assuntos
Fatores de Transcrição de Resposta de Crescimento Precoce/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Genes Reporter/genética , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Genótipo , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Caracteres Sexuais
17.
Schizophr Res ; 139(1-3): 229-36, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22682706

RESUMO

Schizophrenia is a complex mental disorder with high degree of genetic influence in its etiology. Several recent studies revealed that copy number variations (CNVs) of genomic DNA contributed significantly to the genetic architecture of sporadic schizophrenia. This study aimed to investigate whether CNVs also contribute to the familial forms of schizophrenia. Using array-based comparative genomic hybridization technology, we searched for pathogenic CNV associated with schizophrenia in a sample of 60 index cases from multiplex schizophrenia families. We detected three inherited CNVs that were associated with schizophrenia in three families, including a microdeletion of ~4.4Mb at chromosome 6q12-q13, a microduplication of ~1Mb at chromosome 18q12.3, and an interstitial duplication of ~5Mb at chromosome 15q11.2-q13.1. Our data indicate that CNVs contribute to the genetic underpinnings of the familial forms of schizophrenia as well as of the sporadic form. As 15q11-13 duplication is a well-known recurrent CNV associated with autism in the literature, the detection of the 15q11.2-q13.1 duplication in our schizophrenia patients provides additional support to other studies reporting that schizophrenia is part of the clinical spectrum of 15q11-q13 duplication syndrome.


Assuntos
Variações do Número de Cópias de DNA/genética , Saúde da Família , Predisposição Genética para Doença , Esquizofrenia/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 6/genética , Hibridização Genômica Comparativa , Análise Citogenética , Análise Mutacional de DNA , Feminino , Dosagem de Genes , Genômica , Humanos , Masculino , Taiwan , Trissomia/genética
18.
Schizophr Res ; 137(1-3): 7-13, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22306195

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Neurogranina/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Taiwan/epidemiologia , Taiwan/etnologia
19.
Schizophr Res ; 134(2-3): 239-45, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22138049

RESUMO

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.


Assuntos
Proteína GAP-43/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Idoso , Linhagem Celular Tumoral , Éxons/genética , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Neuroblastoma/patologia , Escalas de Graduação Psiquiátrica , Transfecção
20.
Hum Mol Genet ; 20(15): 3042-51, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21551456

RESUMO

Schizophrenia is a severe chronic mental disorder with a high genetic component in its etiology. Several lines of study have suggested that synaptic dysfunction may underlie the pathogenesis of schizophrenia. Neuroligin proteins function as cell-adhesion molecules at post-synaptic membrane and play critical roles in synaptogenesis and synaptic maturation. In this study, we systemically sequenced all the exons and promoter region of neuroligin-2 (NLGN2) gene in a sample of 584 schizophrenia patients and 549 control subjects from Taiwan. In total, we identified 19 genetic variants, including six rare missense mutations such as R215H (one patient), V510M (two patients), R621H (one patient), A637T (two patients), P800L (one patient and one control) and A819S (one patient and one control). In silico analysis predicted that two patient-specific missense mutations, R215H and R621H, had damaging effect, whereas the other missense mutations were benign. Importantly, functional analysis with immunocytochemistry and electrophysiological recordings identified the R215H mutant as a loss-of-function mutant in inducing GABAergic synaptogenesis. Mechanistically, the synaptogenic deficiency of R215H mutant was due to its retention inside the endoplasmic reticulum and inability to be transported to cell membrane. Our study suggests that defects in GABAergic synapse formation in the brain may be an important contributing factor for the onset of schizophrenia. In the family study of this mutation, we found his elder brother also carried this mutation but did not have psychiatric symptoms, indicating that this mutation has incomplete penetrance, and thus the clinical relevance of this mutation should be interpreted with caution.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Proteínas do Tecido Nervoso/genética , Esquizofrenia/genética , Adulto , Western Blotting , Agregação Celular/genética , Agregação Celular/fisiologia , Linhagem Celular , Eletrofisiologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Mutação , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição/genética
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