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Case–control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population

Laboratory for Cardiovascular Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Journal of Human Genetics (Impact Factor: 2.53). 02/2009; 54(2):98-107. DOI: 10.1038/jhg.2008.14
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ABSTRACT The development of molecular psychiatry in the last few decades identified a number of candidate genes that could be associated with schizophrenia. A great number of studies often result with controversial and non-conclusive outputs. However, it was determined that each of the implicated candidates would independently have a minor effect on the susceptibility to that disease. Herein we report results from our replication study for association using 255 Bulgarian patients with schizophrenia and schizoaffective disorder and 556 Bulgarian healthy controls. We have selected from the literatures 202 single nucleotide polymorphisms (SNPs) in 59 candidate genes, which previously were implicated in disease susceptibility, and we have genotyped them. Of the 183 SNPs successfully genotyped, only 1 SNP, rs6277 (C957T) in the DRD2 gene (P=0.0010, odds ratio=1.76), was considered to be significantly associated with schizophrenia after the replication study using independent sample sets. Our findings support one of the most widely considered hypotheses for schizophrenia etiology, the dopaminergic hypothesis.

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Available from: Vihra Milanova, Dec 20, 2014
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    • "Collectively, this body of evidence suggests that the rs1800497 polymorphism may alter the function of D2 receptor and confer susceptibility to schizophrenia. This supposition is not entirely implausible, as several linkage and association studies reported that the rs1800497 polymorphism may be a risk factor for schizophrenia among certain populations [Comings et al., 1991; Dubertret et al., 2001; Dubertret et al., 2004; Parsons et al., 2007; Dubertret et al., 2010], but such associations did not always survive replications in other studies or among other populations [Sanders et al., 1993; Campion et al., 1994; Nothen et al., 1994; Dollfus et al., 1996; Jonsson et al., 1996; Vijayan et al., 2007; Behravan et al., 2008; Lafuente et al., 2008a; Lafuente et al., 2008b; Monakhov et al., 2008; Betcheva et al., 2009; Aslan et al., 2010; Srivastava et al., 2010]. "
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    ABSTRACT: One functional polymorphism (rs1800497) within the ankyrin repeat and kinase domain containing-1 gene (ANKK1) was reported to be associated with schizophrenia, but results among different studies vary and conclusions remain controversial. The present study sought to clarify this potential association among a population of Han Chinese with early onset schizophrenia using a case-control (396 patients and 399 controls) and family based study (103 trios). We then performed a meta-analysis (comprising 11 case-control and 2 family-based studies) based on the present literature. Results of the association study revealed no significant difference in allele and genotype frequencies between the cases and controls, and no significant transmission distortion was detected. Kaplan–Meier survival analysis showed that age at onset in schizophrenia was significantly associated with the rs1800497 polymorphism in female patients, but not in males. Female T allele carriers had a lower age at onset than those without T allele (log rank statistic χ2 = 5.16, P = 0.023; corrected P = 0.046). Meta-analysis results indicated that rs1800497 is not associated with schizophrenia in the overall population (P = 0.77 for the case-control studies; P = 0.06 for the family-based studies). Our results support the hypothesis that rs1800497 polymorphism is likely to have a modifying rather than causative effect on schizophrenia. These findings may represent a significant genetic clue for the etiology of schizophrenia in females, but further investigation is required to clarify the exact role of ANKK1 in the development of schizophrenia. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 10/2014; 165(7). DOI:10.1002/ajmg.b.32259 · 3.27 Impact Factor
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    • "An association between the NRGN gene and schizophrenia has previously been reported in a small population of male Portuguese and Brazilians [Ruano et al., 2008], although the associated SNP in the study, rs7113041, was not tightly correlated with the genome-wide supported SNP, rs12807809 (HapMap CEU r 2 ¼ 0.07, JPT r 2 ¼ 0.01). In addition, two separate studies reported no association between the genetic variants of NRGN and schizophrenia in Bulgarian [Betcheva et al., 2009] and Chinese populations [Li et al., 2010]. The genome-wide supported SNP and other SNPs in the NRGN gene were not genotyped in the GWAS of schizophrenia in Japanese populations because of a difference in the genotyping chips used among the separate GWAS, which the Illumina HumanHap 300 or 550 BeadChips, Affymetrix Genome- Wide Human SNP Array 5.0 and Affymetrix GeneChip Mapping 100 K microarrays [Stefansson et al., 2009; Ikeda et al., 2011; Yamada et al., 2011] were used. "
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    ABSTRACT: Genome-wide association and follow-up studies have reported an association between schizophrenia and rs12807809 of the NRGN gene on chromosome 11q24.2. We investigated the association of five linkage disequilibrium-tagging SNPs and haplotypes that cover the NRGN gene with schizophrenia in a Japanese sample of 2,019 schizophrenia patients and 2,574 controls to determine whether rs12807809 is the most strongly associated variant for schizophrenia in the vicinity of the NRGN gene. We found that the rs12807809-rs12278912 haplotype of the NRGN gene was associated with schizophrenia (global P = 0.0042). The frequencies of the TG and TA haplotypes of rs12807809-rs12278912 in patients were higher (OR = 1.14, P = 0.0019) and lower (OR = 0.85, P = 0.0053), respectively, than in the controls. We did not detect any evidence of association of schizophrenia with any SNPs; however, two nominal associations of rs12278912 (OR = 1.10, P = 0.057) and rs2075713 (OR = 1.10, P = 0.057) were observed. Furthermore, we detected an association between the rs12807809-rs12278912 haplotype and NRGN expression in immortalized lymphoblasts derived from 45 HapMap JPT subjects (z = 2.69, P = 0.007) and confirmed the association in immortalized lymphoblasts derived from 42 patients with schizophrenia and 44 healthy controls (z = 3.09, P = 0.002). The expression of the high-risk TG haplotype was significantly lower than the protective TA haplotype. The expression was lower in patients with schizophrenia than in controls; however, this difference was not statistically significant. This study provides further evidence of the association of the NRGN gene with schizophrenia, and our results suggest that there is a link between the TG haplotype of rs12807809-rs12278912, decreased expression of NRGN and risk of developing schizophrenia.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2012; 159B(4):405-13. DOI:10.1002/ajmg.b.32043 · 3.27 Impact Factor
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    • "We have previously reported the 957C-allele of a DRD2 polymorphism (rs6277) to be significantly associated with schizophrenia (Lawford et al., 2005). Several studies have confirmed this association (Hanninen et al., 2006; Hoenicka et al., 2006; Betcheva et al., 2009; Dubertret et al., 2010; Fan et al., 2010) including a meta-analysis (Monakhov et al., 2008). The T-allele of rs6277 polymorphism has been shown to be associated with decreased DRD2 mRNA translation and stability as well as reduced dopamine-induced up-regulation of D2 receptors (Duan et al., 2003). "
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    ABSTRACT: Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain, which is known to be important in the etiology of schizophrenia. It is, therefore, not surprising that most antipsychotic medication acts on DRD2. DRD2 is widely expressed in the brain; levels are reduced in the brains of patients with schizophrenia, and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single-nucleotide polymorphisms (SNPs) in DRD2 by using a multiplex mass spectrometry method. SNPs were chosen by using a haplotype block-based gene-tagging approach; so, the entire DRD2 gene was represented. Results: One polymorphism, rs2734839 was found to be significantly asso-ciated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared with controls. Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor of age of onset.
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