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  • Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: A novel strategy for complex disorders

    • 摘要:

      Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches - the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.

    • 作者:

      Xu Q.;Jia Y. B.;Zhang B. Y.;Zou K.;Tao Y. B.;Wang Y. P.;Qiang B. Q.;Wu G. Y.;Shen Y.;Ji H. K.;Huang Y.;Sun X. Q.;Ji L.;Li Y. D.;Yuan Y. B.;Shu L.;Yu X.;Shen Y. C.;Yu Y. Q.;Ju G. Z.;Liu Shu-Zheng;Shi Jie-Ping

    • 刊名:

      Molecular Psychiatry

    • 在线出版时间:

      2004

  • An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia

    • 摘要:

      Dysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the possible involvement of these genes in the development of paranoid schizophrenia, we genotyped 80 paranoid schizophrenics from northern China and 108 matched controls by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) methods or directly sequencing of PCR product. Seven SNPs were found to be polymorphic in the population investigated. No significant differences in the genotype distributions or allele frequencies between patients and controls were found. Therefore, we conclude the polymorphisms studied in the five genes do not play major roles in pathogenesis of paranoid schizophrenia in the population investigated. © 2004 Elsevier SAS. All rights reserved.

    • 作者:

      Zhang Boyu;Jia Yanbin;Xu Qi;Shen Yan;Yuan Yanbo;Yu Xin;Shen Yucun

    • 刊名:

      European Psychiatry

    • 在线出版时间:

      2005

  • Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics

    • 摘要:

      There is accumulating evidence of altered antioxidant enzyme activities and increased levels of lipid peroxidation in schizophrenia. Free radical-mediated abnormalities may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment. However, few studies have evaluated both antioxidant enzymes and lipid peroxidation in the same schizophrenic patient groups treated with typical or atypical antipsychotics. Plasma malondialdehyde (MDA) levels and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were analyzed using established procedures in 92 medicated schizophrenia including paranoid (n = 34), disorganized (n = 18) and residual subtypes (n = 40), as well as in control subjects (n = 50). The results showed that activities of SOD and GSH-Px were decreased but levels of MDA were elevated in patients with a chronic form of schizophrenia as compared with normal controls. SOD and GSH-Px activities were found to be significantly lower in paranoid and residual subtypes compared to both disorganized subtype and the control group. MDA levels were significantly higher in all subtypes compared to the control group. There were no significant differences in any parameters measured among all three subgroups treated with clozapine (n = 44), risperidone (n = 20) and typical antipsychotics (n = 28). Additionally, a significantly higher MDA levels, but a significantly lower CAT activity was noted in female than male patients. These results suggest that oxidative stress may be implicated in the pathophysiology of all subtypes of schizophrenia, which may contribute to the increased membrane lipid peroxidation. Long-term treatments with typical and atypical antipsychotics may produce the similar effects on the antioxidant enzymes and lipid peroxidation. © 2005 Elsevier B.V. All rights reserved.

    • 作者:

      Zhang Xiang Yang;Tan Yun Long;Zhou Dong Feng;Cao Lian Yuan;Wu Gui Ying;Xu Qi;Shen Yan

    • 刊名:

      Schizophrenia Research

    • 在线出版时间:

      2006

  • Association of clozapine-induced weight gain with a polymorphism in the leptin promoter region in patients with chronic schizophrenia in a Chinese population

    • 摘要:

      Weight gain is a problem commonly encountered with antipsychotic treatment and has become more apparent with increasing use of the newer atypical antipsychotics. The adipocyte-derived hormone, leptin, has been associated with body weight and energy homeostasis, and abnormal regulation of leptin could play a role in weight gain induced by antipsychotics. We investigated whether a leptin gene promoter variant affected weight gain after long-term treatment with clozapine in chronic schizophrenia. Leptin G2548A polymorphism was genotyped in 102 Chinese Han inpatients with chronic schizophrenia treated with clozapine. Weight gains, expressed as change in body mass index (BMI), were monitored after long-term clozapine treatment. We found a significant relationship between the 3 leptin G/A genotypes and mean BMI gain (F 2,99 = 3.35, P = 0.039, r 2 = 0.09). Moreover, genotype had a strong effect on BMI gain in male (P = 0.004, r 2 = 0.16), but not in female patients (P > 0.05). Thus, variation in the leptin gene may be a risk factor for weight gain in male patients with schizophrenia on long-term clozapine treatment. © 2007 Lippincott Williams & Wilkins, Inc.

    • 作者:

      Zhang Xiang Yang;Tan Yun Long;Zhou Dong Feng;Cao Lian Yuan;Kosten Therese A.;Kosten Thomas R.;Haile Colin N.;Xu Qi;Shen Yan

    • 刊名:

      Journal of Clinical Psychopharmacology

    • 在线出版时间:

      2007

  • Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics

    • 摘要:

      Several lines of evidence suggest that central brain-derived neurotrophic factor (BDNF) modulates food intake, metabolism, and increases in body weight. Reports have also shown that serum BDNF is altered in schizophrenic patients treated with antipsychotics. This study aimed to determine if there was a relationship between BDNF and antipsychotic-induced weight gain in patients with chronic schizophrenia. Serum BDNF was measured in 124 schizophrenia patients chronically treated with clozapine (n = 57), risperidone (n = 23) or typical antipsychotics (n = 44) and 50 healthy control subjects. To further assess group differences in serum BDNF, additional analyses were performed in a subset of patients and controls individually matched for body mass index (BMI). BDNF levels were lower in patients with schizophrenia than normal controls. However, this difference was not present when controlling for current BMI. In the individually BMI-matched sample, no differences in serum BDNF levels were observed in schizophrenic patients compared to BMI-matched healthy controls. BDNF levels negatively correlated with BMI gain in female but not in male patients when gender was considered. Antipsychotic class exerted differential effects over BDNF levels and BMI gain. Our findings suggest that decreased BDNF levels may be associated with weight gain in female schizophrenic patients on long-term antipsychotic treatment. © 2006.

    • 作者:

      Zhang Xiang Yang;Wu Gui Ying;Haile Colin N.;Kosten Therese A.;Kosten Thomas R.;Tan Yun Long;Zhou Dong Feng;Cao Lian Yuan;Xu Qi;Shen Yan

    • 刊名:

      Journal of Psychiatric Research

    • 在线出版时间:

      2007

  • An association study between paranoid schizophrenia and four genes involved in dopamine metabolism

    • 摘要:

      Schizophrenia is a complex disease caused by interactions among multiple genes. Reports of one of its susceptibility genes, ethyltracatechol-O-mnsferase (COMT) have been conflicting. In the present study on paranoid schizophrenia, we have performed a multilocus association study to analyze the interactions among 4 genes that are involved in dopamine metabolism. Result supports the hypothesis that COMT-136-BclI regulates Val108/158Met. When the genotype of the former is CC, Met (A) is the genotype of susceptibility allele Val108/158Met; and when the genotype of the former is GG, Val (G) is the genotype of susceptibility allele Val108/158Met. This new hypothesis may explain the conflicting results about Val108/158Met (COMT) obtained by single-locus analyses. It also illustrates that multilocus analysis is necessary for the research of complex diseases.

    • 作者:

      Li Jun-Ning;Xu Q.;Shen Yan;Ji Liang

    • 刊名:

      Yi Chuan Hereditas Zhongguo Yi Chuan Xue Hui Bian Ji

    • 在线出版时间:

      2006

  • Association between monoamine oxidase A gene and major depression in Chinese Han population

    • 摘要:

      Objective: To explore the association between monoamine oxidase A (MAOA) variable number tandem repeat (VNTR) polymorphism and major depression in Chinese Han population. Methods: Polymerase chain reaction was used to genotype MAOA VNTR polymorphism. A total of 512 major depression patients and 566 normal controls were recruited in our study. These patients were also assessed using the 14-item Hamilton anxiety scale. Results: The allele frequency of MAOA VNTR was not significantly different between the male/female major depression patients and the normal controls. Compared with the normal controls, MAOA VNTR genotype was significantly more frequent in female major depression patients (P = 0.002), but not in male patients (P = 0.17). MAOA VNTR-L carrier was also associated with "fear" symptom in female patients (P = 0.0056). Conclusion: MAOA gene is associated with the major depression in Chinese Han population, especially among female patients.

    • 作者:

      Zhang Jie-Xu;Chen Yan-Bo;Xu Qi;Shen Yan;Zhang Ke-Rang

    • 刊名:

      Acta Academiae Medicinae Sinicae

    • 在线出版时间:

      2009

  • Association between copy number variants within metabotropic glutamate receptors 7 gene and schizophrenia

    • 摘要:

      Objective: To investigate whether genomic copy number variants (CNVs), within metabotropic glutamate receptors 7 (GRM7) gene are associated with schizophrenia. Methods: We examined CNVs in conserved region of GRM7 using real time quantitative PCR among 180 Chinese schizophrenia cases and 33 normal controls. Products of real time quantitative PCR were sequenced bilaterally. Results: Real time quantitative PCR found that a biallelic deletion existed at the 200 bps up-stream of exon 2 in a schizophrenia patient and a monoallelic deletion existed at this site in another 13 schizophreina patients and a control subject. However, sequencing results showed a substitution of C to G at the 5bp up-stream of 3′ end of reverse primer for real time PCR (GRM7-SV-1R). In addition, samples with this variant were exactly those having biallelic or monoallelic deletions, indicating that the results of the real time PCR were caused by the substitution variant at the 3′ end of the primer rather than a bona fide genome deletion. Conclusions: Real-time quantitative PCR combined with sequencing can avoid false positive deletions and therefore is effective in detecting CNVs. According to our results, CNVs in GRM7 gene is not associated with schizophrenia in the Han Chinese population. However, some potential rare CNVs may still have such relationship, and require further study.

    • 作者:

      Zhao Ya-Li;Xu Qi;Shen Yan;Zhang Ke-Rang

    • 刊名:

      Acta Academiae Medicinae Sinicae

    • 在线出版时间:

      2009

  • Association between the epidermal growth factor gene and intelligence in major depression patients

    • 摘要:

      Objective: To study the association between the epidermal growth factor (EGF) gene and intelligence in patients with major depression. Methods: Intelligence measurement using Wechsler Adult Intelligence Scale (WAIS) was performed on 120 unrelated patients with major depression and 46 control subjects. Blood was collected from all subjects for extraction of genomic DNA. Four single nucleotide polymorphisms (SNPs) in the EGF gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Results: Mean scores of both score lang and score task, two subtests in WAIS, differed significantly between major depression patients and controls (P<0.0001). Quantitative trait analysis showed that the genetype of rs2250724 was closely associated with score lang and score task in major depression patients. The associations were still significant after 10 000 permutations. Conclusions: Although preliminary, our results provide evidence for association between the EGF gene and intelligence in patients with major depression. Genetic variation in the EGF gene may increase the susceptibility of major depression.

    • 作者:

      Tian Wen-Min;Zhang Juan;Shen Yan;Xu Qi;Zhang Ke-Rang

    • 刊名:

      Chinese Medical Sciences Journal

    • 在线出版时间:

      2010

  • γ-secretase gene mutations in familial acne inversa

    • 摘要:

    • 作者:

      Wang Baoxi;Su Bin;Ma Donglai;Qu Tao;Yang Wei;Sun Jing;Lv Dan;Wen Yaran;Sun Miao;Shen Yan;Zhang Xue;Wen Wen;Liu Bo;Chen Min

    • 刊名:

      Science

    • 在线出版时间:

      2010

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