1Psychiatry Res 2001 Sep 103: 147-55
PMID11549403
TitleLinked polymorphisms (-333G>T and -286A>G) in the promoter region of the CCK-A receptor gene may be associated with schizophrenia.
AbstractCholecystokinin A receptors (CCKAR) modulate CCK-stimulated dopamine release, and mutations in the CCKAR gene may predispose affected individuals to schizophrenia. Our previous study suggested that -286A>G polymorphism (previously named 201A>G) in the CCKAR gene promoter is associated with schizophrenia. In the present study, we carried out a further investigation of the promoter and intron 1 of the CCKAR gene. In addition to polymorphisms reported previously (-333G>T, -286A>G, -241G>A, 773A>T, and 779T>C), two novel polymorphisms (-388(GT)(8)>(GT)(9) and -85C>G) were identified. These polymorphisms were in a linkage disequilibrium. Association analyses between schizophrenic patients and controls revealed that the frequencies of the A allele and AA genotype at the -286 loci, as well as the frequency of the GG genotype at the -333 loci, were significantly higher in patients than in controls. Furthermore, patients with paranoid type schizophrenia, auditory hallucinations, or a positive family history had a significantly higher frequency of the -286A allele than the control group. The results supported our previous data, and suggest the possible involvement of the -333G>T and the -286A>G polymorphisms in the promoter region of the CCKAR gene in the predisposition to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
2Psychiatry Res 2001 Sep 103: 147-55
PMID11549403
TitleLinked polymorphisms (-333G>T and -286A>G) in the promoter region of the CCK-A receptor gene may be associated with schizophrenia.
AbstractCholecystokinin A receptors (CCKAR) modulate CCK-stimulated dopamine release, and mutations in the CCKAR gene may predispose affected individuals to schizophrenia. Our previous study suggested that -286A>G polymorphism (previously named 201A>G) in the CCKAR gene promoter is associated with schizophrenia. In the present study, we carried out a further investigation of the promoter and intron 1 of the CCKAR gene. In addition to polymorphisms reported previously (-333G>T, -286A>G, -241G>A, 773A>T, and 779T>C), two novel polymorphisms (-388(GT)(8)>(GT)(9) and -85C>G) were identified. These polymorphisms were in a linkage disequilibrium. Association analyses between schizophrenic patients and controls revealed that the frequencies of the A allele and AA genotype at the -286 loci, as well as the frequency of the GG genotype at the -333 loci, were significantly higher in patients than in controls. Furthermore, patients with paranoid type schizophrenia, auditory hallucinations, or a positive family history had a significantly higher frequency of the -286A allele than the control group. The results supported our previous data, and suggest the possible involvement of the -333G>T and the -286A>G polymorphisms in the promoter region of the CCKAR gene in the predisposition to schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
3Schizophr. Res. 2006 Jun 84: 253-71
PMID16632332
TitleGene regulation by hypoxia and the neurodevelopmental origin of schizophrenia.
AbstractNeurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.
SCZ Keywordsschizophrenia, schizophrenic
4Mol. Psychiatry 2007 Nov 12: 1011-25
PMID17457313
TitleAssociation analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia.
AbstractSeveral independent linkage studies have identified chromosome 4p15-p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15-p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 Mb, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control individuals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (PCCKAR and DKFZp761B107 overlapped with these regions. This study has identified significant associations between BP and SCZ within the chromosome 4p linkage region, resulting in candidate regions worthy of further investigation.
SCZ Keywordsschizophrenia, schizophrenic
5Acta Psychiatr Scand 2009 Oct 120: 281-7
PMID19753663
TitleAn intron 1 polymorphism in the cholecystokinin-A receptor gene associated with schizophrenia in males.
AbstractTo identify whether a genetic variation (rs1800857; IVS1-5T>C) in the neuropeptide cholecystokinin-A receptor (CCKAR) gene is a risk factor in the pathogenesis of schizophrenia.
The variation was analysed in a case-control design comprising 508 patients with schizophrenia and 1619 control subjects. A possible functional impact of this variant on CCKAR protein synthesis through alterations in splicing was analysed in an exon-trapping assay.
In males only, the risk variant, IVS1-5C, was associated with a significantly increased risk of schizophrenia. Carrying one risk allele was associated with an increased risk of 1.74 (Odds Ratio, OR) and homozygosity (CC) was associated with an OR of 3.19. The variation had no impact on protein synthesis of CCKAR.
This is the first report associating the CCKAR gene variant with schizophrenia specifically in men. Our study strengthens the conclusion that a CCKAR dysfunction could be involved in the aetiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
6Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Sep 159B: 741-7
PMID22825913
TitleInvestigation of allelic heterogeneity of the CCK-A receptor gene in paranoid schizophrenia.
AbstractThe cholecystokinin type A receptor (CCKAR) gene has been found to be associated with positive symptoms in patients with schizophrenia but the results reported to date are inconsistent. Considering the involvement of allelic heterogeneity in poor replication of the CCKAR finding, we genotyped five single nucleotide polymorphisms (SNPs) located in the 5' putative regulatory region of the CCKAR gene in a Chinese case-control sample and then applied the 5-SNP haplotype analysis to extract allelic heterogeneity information. The results showed that three individual haplotypes were strongly associated with increased risk of schizophrenia (corrected P = 2.9 10(-4), P = 2.5 10(-5), and P = 1.4 10(-5), respectively) and their combination gave an odds ratio (OR) of 6.12 with 95% CI 3.67-10.21 (P = 6.7 10(-15)). The haplotypes were also associated with some clinical symptoms including hallucination, suspiciousness, and hostility. Our work provided further evidence in support of the CCKAR hypothesis of schizophrenia and also suggested that haplotype-based association analysis may be a powerful approach for identification of allelic heterogeneity of a disease-underlying gene, which is very likely to be attributable to poor replication of an initial finding due to the reduction of sample power and the complexity of genetic architectures.
SCZ Keywordsschizophrenia, schizophrenic
7PLoS ONE 2013 -1 8: e53643
PMID23341962
TitleCholecystokinin A receptor (CCKAR) gene variation is associated with language lateralization.
Abstractschizophrenia is a psychiatric disorder associated with atypical handedness and language lateralization. However, the molecular mechanisms underlying these functional changes are still poorly understood. Therefore, the present study was aimed at investigating whether variation in schizophrenia-related genes modulates individual lateralization patterns. To this end, we genotyped 16 single nucleotide polymorphisms that have previously been linked to schizophrenia on a meta-analysis level in a sample of 444 genetically unrelated healthy participants and examined the association of these polymorphisms with handedness, footedness and language lateralization. We found a significant association of the cholecystokinin-A receptor (CCKAR) gene variation rs1800857 and language lateralization assessed using the dichotic listening task. Individuals carrying the schizophrenia risk allele C of this polymorphism showed a marked reduction of the typical left-hemispheric dominance for language processing. Since the cholecystokinin A receptor is involved in dopamine release in the central nervous system, these findings suggest that genetic variation in this receptor may modulate language lateralization due to its impact on dopaminergic pathways.
SCZ Keywordsschizophrenia, schizophrenic
8Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2014 Oct 36: 466-9
PMID25360641
Title[Deep sequencing for cholecystokinin a receptor gene to get loci associated with schizophrenia].
AbstractTo find the risk loci on cholecystokinin A receptor gene (CCKAR) - a schizophrenia candidate gene by using the deep sequencing and then analyze the variations.
In the present study, 8 schizophrenia patients and 8 healthy controls were recruited. After DNA extraction from peripheral blood, we conducted deep sequencing on CCKAR region by HaloPlex Target Enrichment System (Agilent). We used Unphased software to exclude the false positive.
After deep sequencing, we got 103 loci, among which 30 were located in CCKAR gene. Besides, the SNP rs191275118 was found to be associated with schizophrenia.
A new variation that may be associated with schizophrenia was found. The deep sequencing is effective to find genetic variation.
SCZ Keywordsschizophrenia, schizophrenic
9Biomed Rep 2014 Sep 2: 729-736
PMID25054019
TitleMeta-analyses of 10 polymorphisms associated with the risk of schizophrenia.
Abstractschizophrenia (SCZ) is a severe complex psychiatric disorder that generates problems for the associated family and society and causes disability with regards to work for patients. The aim of the present study was to assess the contribution of 10 genetic polymorphisms to SCZ susceptibility. Meta-analyses were conducted using the data without a limitation for time or language. A total of 27 studies with 7 genes and 10 polymorphisms were selected for the meta-analyses. Two polymorphisms were found to be significantly associated with SCZ. SNAP25 rs3746544 was shown to increase the SCZ risk by 18% [P=0.01; odds ratio (OR), 1.18; 95% confidence interval (CI), 1.05-1.34] and GRIK3 rs6691840 was found to increase the risk by 30% (P=0.008; OR, 1.30; 95% CI, 1.07-1.58). Significant results were found under the dominant (P=0.001; OR, 1.36; 95% CI, 1.13-1.65) and additive (P=0.02; OR, 1.45; 95% CI, 1.06-1.98) model for the SNAP25 rs3746544 polymorphism and under the additive model for the GRIK3 rs6691840 polymorphism (P=0.03; OR, 1.73; 95% CI, 1.04-2.85). There were no significant results observed for the other eight polymorphisms, which were CCKAR rs1800857, CHRNA7 rs904952, CHRNA7 rs6494223, CHRNA7 rs2337506, DBH Ins>Del, FEZ1 rs559668, FEZ1 rs597570 and GCLM rs2301022. In conclusion, the present meta-analyses indicated that the SNAP25 rs3746544 and GRIK3 rs6691840 polymorphisms were risk factors of SCZ, which may provide valuable information for the clinical diagnosis of SCZ.
SCZ Keywordsschizophrenia, schizophrenic