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Liao H.-M.,National Tsing Hua University | Chao Y.-L.,Tzu Chi University | Huang A.-L.,Yuli Veterans Hospital | Cheng M.-C.,Yuli Mental Health Research Center | And 7 more authors.
Schizophrenia Research | Year: 2012

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 ~. 4.4. Mb at chromosome 6q12-q13, a microduplication of ~. 1. Mb at chromosome 18q12.3, and an interstitial duplication of ~. 5. Mb 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. © 2012 Elsevier B.V. Source


Chen C.-H.,Chang Gung Memorial Hospital Linkou | Chen C.-H.,Chang Gung University | Chen C.-H.,National Taiwan University Hospital | Huang C.-C.,Tzu Chi University | And 7 more authors.
Molecular Autism | Year: 2014

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. © 2014 Chen et al.; licensee BioMed Central Ltd. Source


Liao D.-L.,Bali Psychiatric Center | Cheng M.-C.,Yuli Mental Health Research Center | Lai C.-H.,National Health Research Institute | Tsai H.-J.,National Health Research Institute | And 3 more authors.
Addiction Biology | Year: 2014

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. 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. © 2011 Society for the Study of Addiction. Source


Li J.-M.,Taoyuan Armed Forces General Hospital | Lu C.-L.,Hualien Armed Forces General Hospital | Cheng M.-C.,Yuli Mental Health Research Center | Luu S.-U.,Taoyuan Armed Forces General Hospital | And 4 more authors.
Psychiatry Research | Year: 2013

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. © 2012 Elsevier Ireland Ltd. Source


Li J.-M.,Taoyuan Armed Forces General Hospital | Lu C.-L.,Hualien Armed Forces General Hospital | Cheng M.-C.,Yuli Mental Health Research Center | Luu S.-U.,Taoyuan Armed Forces General Hospital | And 4 more authors.
Psychiatry Research | Year: 2013

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. © 2012 Elsevier Ireland Ltd. Source

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