Betcheva, E.T., Mushiroda, T., Takahashi, A., Kubo, M., Karachanak, S.K., Zaharieva, I.T. et al. 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. J. Hum. Genet. 54, 98-107

Laboratory for Cardiovascular Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Tokyo, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 02/2009; 54(2):98-107. DOI: 10.1038/jhg.2008.14
Source: PubMed


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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    • "Albeit we aim to avoid overhasty conclusions regarding directional selection on DRD2, the three SNPs detected by BayeScan under positive selection—and that are found by LOSITAN just below significance—could be of interest. This is particularly the case for rs6277, with its known phenotypic associations: rs6277 has been associated with schizophrenia in Han Chinese in Taiwan (Glatt et al., 2009), in Russians (Monakhov et al., 2008) and in Bulgarians (Betcheva et al., 2009). "
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    ABSTRACT: Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. Schizophrenia, for example, is treated by blocking the dopamine receptors type 2. Shaner, Miller & Mintz (2004) stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2) underwent any selection processes. We acquired genotype data of the 1,000 Genomes project (phase I), which contains 1,093 individuals from 14 populations. We included single nucleotide polymorphisms (SNPs) with two minor allele frequencies (MAFs) in the analysis: MAF over 0.05 and over 0.01. This is equivalent to 151 SNPs (MAF > 0.05) and 246 SNPs (MAF > 0.01) for DRD2. We used two diVerent approaches (an outlier approach and a Bayesian approach) to detect loci under selection. The combined results of both approaches yielded nine (MAF > 0.05) and two candidate SNPs (MAF > 0.01), under balancing selection. We also found weak signs for directional selection on DRD2, but in our opinion these were too weak to draw any final conclusions on directional selection in DRD2. All candidates for balancing selection are in the intronic region of the gene and only one (rs12574471) has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible eVects.
    Full-text · Article · Aug 2015 · PeerJ
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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.
    Full-text · Article · Oct 2014 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "In the Chinese study investigating two KPNA3 polymorphisms, 238 family trios consisting of mother, father and affected offspring showed association with schizophrenia [41] and rs3782929 but not rs3736830. In a Bulgarian population, association between KPNA3 and schizophrenia was not found [6]. As well as being associated with schizophrenia, KP- NA3 may also be associated with other psychiatric conditions as chromosome 13 overlaps a few psychiatric disorders. "
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    ABSTRACT: KPNA3 is a gene that has been linked to schizophrenia susceptibility. In this study we investigated the possible association between KPNA3 variation and schizophrenia. To investigate a wider role of KPNA3 across psychiatric disorders we also analysed major depression, PTSD, nicotine dependent, alcohol dependent and opiate dependent cohorts. Using a haplotype block-based gene-tagging approach we genotyped six KPNA3 single nucleotide polymorphisms (SNPs) in 157 schizophrenia patients, 121 post-traumatic stress disorder patients, 120 opiate dependent patients, 231 alcohol dependent patients, 147 nicotine dependent patients and 266 major depression patients. One SNP rs2273816 was found to be significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level. Major depression was also associated with rs2273816 but only at the allele level. Our study suggests that KPNA3 may contribute to the genetic susceptibility to schizophrenia as well as other psychiatric disorders.
    Full-text · Article · Nov 2012 · Disease markers
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