Association study of polymorphisms in the GluR7, KA1 and KA2 kainate receptor genes (GRIK3, GRIK4, GRIK5) with schizophrenia

On the basis of the glutamatergic dysfunction hypothesis of schizophrenia, we have been conducting a systematic study of the association of glutamate receptor genes with schizophrenia. Here we report association studies of schizophrenia with polymorphisms in three kainate receptor genes: GRIK3, GRIK4 and GRIK5. We selected 16, 24 and 5 common single nucleotide polymorphisms (SNPs) distributed in the entire gene regions of GRIK3 (>240 kb), GRIK4 (>430 kb) and GRIK5 (>90 kb), respectively. We tested associations of the polymorphisms with schizophrenia using 100 Japanese case-control pairs (the Kyushu set). We observed no significant "single marker" associations with the disease in any of the 45 SNPs tested except for one (rs3767092) in GRIK3 showing a nominal level of significance. The significant association, however, disappeared after the application of the Bonferroni correction. We also observed significant haplotype associations in seven SNP pairs in GRIK3 and in four SNP pairs in GRIK4. None, however, remained significant after Bonferroni correction. We also failed to replicate the nominally significant haplotype associations in a second sample set, the Aichi set (106 cases and 100 controls). We conclude that SNPs in the gene regions of GRIK3, GRIK4 or GRIK5 do not play a major role in schizophrenia pathogenesis in the Japanese population.     

A case-control association study between the GRID1 gene and schizophrenia in the Chinese Northern Han population

The glutamatergic dysfunction hypothesis of schizophrenia implicates the genes involved in glutamatergic transmission as strong candidates for schizophrenia-susceptibility. Recent linkage and association studies have identified the glutamate receptor, ionotropic, delta 1 gene GRID1 on 10q22 as a strong candidate for schizophrenia. In this current association study, we genotyped five genetic variants within the GRID1 gene in 567 Chinese Han subjects recruited from Northeast of China (260 schizophrenics and 307 normal controls). Four SNPs, rs1902666 (P=0.024), rs2814351 (P=0.027), rs11591408 (P=0.0000107) and rs999383 (P=0.000093) were found to be significantly associated with schizophrenia. Haplotype analysis also revealed significance with global P values of 0.0081 and 0.00076 for SNPs 1-2 and SNPs 3-4-5 haplotypes, respectively. Our results strongly support previously reported association studies, implicating GRID1 in the etiology of schizophrenia.     

A possible association between schizophrenia and GRIK3 polymorphisms in a multicenter sample of Scandinavian origin (SCOPE)

There is considerable evidence of altered glutamatergic signalling in schizophrenia and a polymorphic variant of the GRIK3 glutamate receptor gene on 1p34-33 has previously been associated to this psychotic disorder. We therefore conducted a systematic association study with 30 HapMap-selected tagging SNPs across GRIK3 in three independent samples of Scandinavian origin from the Scandinavian Collaboration of Psychiatric Etiology (SCOPE), including a total of 839 cases with schizophrenia spectrum and 1473 healthy controls.Four markers (rs6671364, rs17461259, rs472188, and rs535620) attained nominally significant P-values in both the genotypic (0.002, 0.02, 0.03, and 0.05, respectively) and allelic (0.001, 0.006, 0.03, and 0.02, respectively) association tests for the combined sample, and 2 additional markers (rs481047and rs1160751) displayed significance for the genotype (P-values: 0.03 and 0.04). Several haplotypes, that all included at least one of the four SNPs implicated by the single marker analysis, remained significant after adjustment for multiple testing using permutations with 10,000 shuffles. In addition we observed an association for two of the four significant GRIK3 markers (rs472188 and rs535620) to scores for negative symptoms on the PANSS scale.The present results, although not robust, support the importance of more extensive investigations of GRIK3, given its potential role in mediating risk for schizophrenia.     

Association between the ionotropic glutamate receptor kainate3 (GRIK3) Ser310Ala polymorphism and schizophrenia in the Indian population

Various studies have been done to check the status of glutamate receptor gene in the pathogenesis of schizophrenia. The T928G (Ser310Ala) polymorphism of ionotropic glutamate receptor kainate 3 gene (GRIK3) and its positive association with schizophrenia was reported in Caucasians, whereas no association of this polymorphism with schizophrenia was shown in two other populations, Chinese and Japanese. However, no literature is available regarding the prevalence of this polymorphism and its association with schizophrenia in the Indian population. As genetic susceptibility profiles in India are often different from those of white Caucasians or Orientals, we investigated the status of Ser310Ala polymorphism of GRIK3 in 100 schizophrenic patients and 100 healthy controls in the Indian population by the PCR-RFLP (restriction fragment length polymorphism) method. A statistically significant difference in the genotype and allelic distributions (P<0.000001 and P=0.01, respectively) of Ser310Ala polymorphism was found in schizophrenics than in control, considering Ala-allele as being associated with the disease (OR=1.7, 95% CI=1.137–2.540). Our study suggests a potential role for GRIK3 for susceptibility to schizophrenia in Indian population.     

The Human MSI2 Gene is Associated with Schizophrenia in the Chinese Han Population

It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia,so genes impacting on neurogenesis could be potential candidates for schizophrenia.A member of the Musashi family,the human MSI2 gene plays a substantial role in stem-cell maintenance,asymmetric division,and differentiation during neurogenesis.Our previous genome-wide association study(GWAS)implied an association of MSI2 with schizophrenia in a Han Chinese population.To further explore this association,three single-nucleotide polymorphisms(SNPs),rs9892791,rs11657292,and rs1822381,were selected for a replication study involving 921 schizophrenia cases and 1244 controls.After rigorous Bonferroni correction,two of the SNPs(rs9892791 and rs11657292) displayed significant differences in allele and genotype distribution frequencies between the case and control groups.When our GWAS and replication samples were combined,the three MSI2 SNPs were all strongly associated with schizophrenia(rs9892791:allelic P = 1.07E-5;rs11657292:allelic P = 1.95E-12;rs1822381:allelic P = 1.44E-4).These results indicate that the human MSI2 gene might be a susceptibility gene forschizophrenia and encourage future research on the functional relationship between this gene and schizophrenia.     

Association study of a new schizophrenia susceptibility locus of 10q24.32-33 in a Han Chinese population

Recently, a new schizophrenia susceptibility locus 10q24.32-q24.33, containing two single-nucleotide polymorphisms (SNPs: rs7914558 and rs11191580), was identified in a genome-wide association study. To examine if this locus is associated with schizophrenia in the Han Chinese population, we analyzed six SNPs, including two SNPs within the region of interest. The sample consisted of 1430 schizophrenia cases and 1570 controls from genetically independent members of the Han population. Single-SNP association, haplotype association and sex-specific association analyses were performed. Three SNPs, rs7914558 (p=1.41×10(-4); OR=1.11; 95% CI 1.05-1.17), rs12220375 (p=1.18×10(-4); OR=1.06; 95% CI 1.03-1.09) and rs11191580 (p=3.03×10(-4); OR=1.05; 95% CI 1.02-1.10), mapped to the locus and were significantly associated in our sample set. Further genotype and haplotype association analyses suggested a similar pattern. Similar to results from European populations, our results provide further evidence that this region associated with schizophrenia in Han Chinese. Results also confirm previous reports suggesting that 10q24.32-q24.33 offers an intriguing new insight into the pathogenesis of schizophrenia and may play an important role in its etiology.     

Association study of polymorphisms in the GluR6 kainate receptor gene (GRIK2) with schizophrenia

The glutamatergic dysfunction hypothesis of schizophrenia suggests genes involved in glutamatergic transmission as candidates for schizophrenia-susceptibility genes. The GluR6 kainate receptor gene GRIK2 is located on chromosome 6q16.3-q21, a schizophrenia susceptibility region, as suggested by multiple linkage studies. We examined 15 SNPs evenly distributed in the entire GRIK2 region (>700 kb) in Japanese patients with schizophrenia (n=100) and controls (n=100). Neither genotype nor allele frequency showed a significant association with the disorder. We constructed 2-SNP haplotypes from the 15 SNPs. Although we observed three long linkage disequilibrium blocks (>150 kb) within the GRIK2 region, none of the pairwise haplotypes showed a significant association with the disorder. Therefore, we conclude that GRIK2 does not play a major role in the pathogenesis of schizophrenia in the Japanese population.     

No genetic association between NCAM1 gene polymorphisms and schizophrenia in the Chinese population

Background

The neural cell adhesion molecule 1(NCAM1, aliases NCAM and CD56) is a cell-surface molecule which makes homophilic adhesion between neural cells involved in cell migration, axon outgrowth and synaptic plasticity. Recent studies reported that NCAM1 might act as a candidate schizophrenia susceptibility gene.

Method

We genotyped five SNPs (rs1943620, rs1836796, rs1821693, rs686050, rs584427) within the NCAM1 gene and conducted a case-control study in 288 schizophrenic patients and 288 healthy subjects in the Chinese Han population. We compared allele and genotype frequencies and haplotype distributions between cases and controls.

Result

No significant differences in allele and genotype frequencies were found for each single SNP between schizophrenic patients and healthy subjects. Moreover, there were no significant differences in haplotype distributions between cases and controls (global χ² = 1.318, P = 0.725, df = 3).

Conclusion

Our study suggests that the five SNPs within NCAM1 gene we studied may not play a major role in the schizophrenia susceptibility in the Chinese Han population.     

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

In the search for the biological causes of schizophrenia and bipolar disorder, glutamate neurotransmission has emerged as one of a number of candidate processes and pathways where underlying gene deficits may be present. The analysis of chromosomal rearrangements in individuals diagnosed with neuropsychiatric disorders is an established route to candidate gene identification in both Mendelian and complex disorders. Here we describe a set of genes disrupted by, or proximal to, chromosomal breakpoints (2p12, 2q31.3, 2q21.2, 11q23.3 and 11q24.2) in a patient where chronic schizophrenia coexists with mild learning disability (US: mental retardation). Of these disrupted genes, the most promising candidate is a member of the kainate-type ionotropic glutamate receptor family, GRIK4 (KA1). A subsequent systematic case-control association study on GRIK4 assessed its contribution to psychiatric illness in the karyotypically normal population. This identified two discrete regions of disease risk within the GRIK4 locus: three single single nucleotide polymorphism (SNP) markers with a corresponding underlying haplotype associated with susceptibility to schizophrenia (P=0.0005, odds ratio (OR) of 1.453, 95% CI 1.182-1.787) and two single SNP markers and a haplotype associated with a protective effect against bipolar disorder (P=0.0002, OR of 0.624, 95% CI 0.485-0.802). After permutation analysis to correct for multiple testing, schizophrenia and bipolar disorder haplotypes remained significant (P=0.0430, s.e. 0.0064 and P=0.0190, s.e. 0.0043, respectively). We propose that these convergent cytogenetic and genetic findings provide molecular evidence for common aetiologies for different psychiatric conditions and further support the 'glutamate hypothesis' of psychotic illness.     

Family-based association studies of CAPON and schizophrenia in the Chinese Han population

Although there is evidence pointing to CAPON as a susceptible gene for schizophrenia, the results of independent association studies have so far been inconsistent. A recent case-control study by Zheng et al. supported CAPON as a susceptible site for the disease in the Chinese Han population. In their study both the single polymorphism (rs348624) and individual haplotypes showed significant association with schizophrenia. Our study further investigates this relationship this time using a family-based association. We selected 5 SNPs including rs348624 and performed a Transmission Disequilibrium Test (TDT) in 319 Chinese Han trios. Our results identified no single marker nor haplotype associated with schizophrenia, which did not suggest that CAPON was a susceptible site in the Chinese Han population, or it appeared unlikely that the CAPON played a major role in the aetiology of schizophrenia. Since there is consistent evidence pointing to 1q21-22 as a positional candidate region for schizophrenia, we suggest that further research should focus on other genes located in this region.     

Family-based association studies of the TCP1 gene and schizophrenia in the Chinese Han population

Summary. A previous case-control study by Yang et al. indicated that the TCP1 gene in 6q25 was associated with schizophrenia in the Han population. To replicate this result, we selected eight SNPs (rs2273828, rs3818298, rs1547094, rs1547093, rs2295898, rs2295899, rs4832, rs15982) spanning the whole gene and performed a family-based study using 325 trios samples. Our transmission disequilibrium test showed neither allele nor haplotype association with schizophrenia, and suggests that the TCP1 locus is not associated with schizophrenia in the Chinese population. Since 6q25 has consistently been found to be a susceptible region for schizophrenia, we suggest that other genes within this region should be the focus of attention. The first and second authors contributed equally to this work     

Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort

OBJECTIVE: An initial pharmacogenetic study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial reported an association between genetic variation in the HTR2A gene and outcome of citalopram treatment. By design, the study analyzed only those markers that showed reproducible association in the first wave of genotypes (comprising 1,297 patients) in the complete cohort of patients. The purpose of the present study was to utilize a second wave of genotype results, for a more powerful analysis, in the complete cohort of patients with available deoxyribonucleic acid (DNA) samples. METHOD: The authors tested the association between treatment response and 768 markers that were genotyped in the full set of 1,816 eligible patients from the STAR*D cohort. In order to control for multiple testing, the subjects were divided into two study groups: discovery and replication. RESULTS: In addition to the previously identified marker in the HTR2A gene, a new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, was observed. The effect size of the GRIK4 marker alone was modest, but homozygote carriers of the treatment-response-associated marker alleles of both the GRIK4 and HTR2A genes were 23% less likely to experience nonresponse to treatment relative to participants who did not carry any of these marker alleles. CONCLUSIONS: The findings demonstrate that genetic variation in a kainic acid-type glutamate receptor is reproducibly associated with response to the antidepressant citalopram. This finding suggests that the glutamate system plays an important role in modulating response to selective serotonin reuptake inhibitors (SSRIs).     

Genetic analysis of the human ENTH (Epsin 4) gene and schizophrenia

Numerous linkage studies suggest that chromosome 5q may be one of the important cytogenetic regions containing risk loci for schizophrenia susceptibility. Recently, genetic variations (rs254664 and rs10046055) in the intron 1 and 5' flanking regions of the ENTH (also known as Epsin 4) gene, which is located in 5q 33.3, have been demonstrated to be significantly associated with schizophrenia. The present study investigates whether this finding could be replicated in a population of Han Chinese, consisting of 269 patients with schizophrenia and 236 normal controls, by analyzing 9 single nucleotide polymorphisms (SNPs) ranging from the 5' upstream region to intron 8 of the ENTH gene and covering 96 kb. The results showed that we failed to identify the associations of rs1186922 and rs10046055 with schizophrenia. Although another genetic variation (rs1186922) showed a weak association with schizophrenia (uncorrected p value for alleles = 0.038), the significance did not survive after Bonferroni correction. This study thus fails to support an association of genetic variations in the ENTH gene and schizophrenia.     

The CMYA5 gene confers risk for both schizophrenia and major depressive disorder in the Han Chinese population

Objectives. A recent genome-wide association study (GWAS) of the European population implicated the CMYA5 gene in schizophrenia. Previous functional studies showed that the CMYA5 protein can interact with DTNBP1 and PKA, providing further support for a role of CMYA5 in the pathogenesis of schizophrenia. However, this association requires additional validation in independent populations. Methods. To validate the association between CMYA5 and schizophrenia and major depressive disorder, we genotyped 16 SNPs within the CMYA5 gene and performed case–control studies in 1330 schizophrenia patients, 1045 patients with major depressive disorder, and 1235 normal controls. All patients were of Han Chinese origin. Results. rs6883197 and rs259127 were significantly associated with schizophrenia, and rs12514461, rs259127, and rs7343 were associated with major depressive disorder. Additionally, one risk haplotype of rs16877109–rs3828611 (G–G) was associated with both schizophrenia (P = 0.0000784, after correction) and major depressive disorder (P = 0.00230, after correction). Conclusions. Our findings support the idea that specific alleles and haplotype in the CMYA5 confer genetic risk for both schizophrenia and major depressive disorder in the Han Chinese population.     

No association found between the promoter variations of QKI and schizophrenia in the Chinese population

BackgroundSchizophrenia is a chronic psychiatric disorder with a strong genetic component. Several recent published studies have reported that the mRNA expression level of quaking homolog, KH domain RNA binding (QKI) is down regulated in individuals diagnosed with schizophrenia.MethodsWe were interested in the genetic variants around the promoter region of QKI and selected seven variants in this region, namely rs4263561, rs3904720, rs387504, rs3763197, rs7772756, rs7758706 and rs4709716. For the study we recruited 288 individuals diagnosed with schizophrenia and 288 control subjects. All the recruits were from Shanghai and were Han Chinese in origin.ResultsNo individual SNP nor any haplotype was found to be associated with schizophrenia.ConclusionsThese results suggest that the variants within the promoter region of QKI gene are unlikely to play a major role in susceptibility to schizophrenia in the Chinese population.     

Association Between Polymorphisms in GRIK2 Gene and Obsessive‐Compulsive Disorder: A Family‐Based Study

Several studies support a genetic influence on obsessive‐compulsive disorder (OCD) etiology. The role of glutamate as an important neurotransmitter affecting OCD pathophysiology has been supported by neuroimaging, animal model, medication, and initial candidate gene studies. Genes involved in glutamatergic pathways, such as the glutamate receptor, ionotropic, kainate 2 (GRIK2), have been associated with OCD in previous studies. This study examines GRIK2 as a candidate gene for OCD susceptibility in a family‐based approach. Probands had full DSM‐IV diagnostic criteria for OCD. Forty‐seven OCD probands and their parents were recruited from tertiary care OCD specialty clinics from France and USA. Genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes were analyzed using Haploview and FBAT software. The polymorphism at rs1556995 (P= 0.0027; permuted P‐value = 0.03) was significantly associated with the presence of OCD. Also, the two marker haplotype rs1556995/rs1417182, was significantly associated with OCD (P= 0.0019, permuted P‐value = 0.01). This study supports previously reported findings of association between proximal GRIK2 SNPs and OCD in a comprehensive evaluation of the gene. Further study with independent samples and larger sample sizes is required.     

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: III. Lack of association of CYP3A4 and CYP2D6 gene polymorphisms

Recent studies of the association between the metabotropic glutamate receptor 3 gene (GRM3) and schizophrenia have produced conflicting results, although GRM3 is a promising candidate gene. Fujii et al. found a single nuclear polymorphism (SNP) for within this gene, rs1468412 to have a positive association to schizophrenia in Japanese patients. To investigate this further, we genotyped 7 SNPs around GRM3 including rs1468412, in 752 Chinese patients with schizophrenia and 752 controls using Taqman technology. We did not detect any association between rs1468412 and schizophrenia, however we found differences in the allele frequency distribution of SNP rs2299225 (p=0.0297, odds ration [OR]=1.44, 95% confidence interval 1.05-1.99) between cases and controls. Moreover, the overall frequency of haplotypes constructed from three SNPs including rs2299225 showed significant differences between cases and controls (p=0.0017). Our results partially support the previous studies in other ethnic groups and indicate that the GRM3 gene may play an important role in the etiology of schizophrenia in the Han Chinese.     

No association of GRIP1 gene polymorphisms with schizophrenia in Chinese population

Disturbance in glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Since glutamate receptor interacting protein 1 (GRIP1), a modular protein that enables anchoring of AMPA receptors via its PDZ (postsynaptic density-95/discs large/zona occludens-1) domain and modulates d-serine release, plays an important role in glutamatergic function, this study tests the hypothesis that GRIP1 genetic variants confer susceptibility to schizophrenia. This study investigated whether GRIP1 genetic polymorphisms (rs1038923 and rs4913301) cause a predisposal to schizophrenia. Two GRIP1 polymorphisms were studied in a sample population of 252 people with schizophrenia and 207 normal controls. Significant linkage disequilibrium was obtained between the two polymorphisms. Results demonstrated that neither single marker nor haplotype analysis revealed an association between variants at the GRIP1 locus and schizophrenia, suggesting that it is unlikely that the GRIP1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia. However, association between schizophrenia and other polymorphisms in the GRIP1 gene cannot be totally ruled out as the whole gene was not covered by the two polymorphisms studied.     

Transmission of NOTCH4 and GRIK2 in a population of Han Chinese with schizophrenia and affective disorder*★

BACKGROUND： Increasing evidence suggests overlapped genetic susceptibility across traditional classification systems that divided psychotic disorders into schizophrenia or affective disorder. OBJECTIVE： This study aimed to explore whether schizophrenia and affective disorder share genetic susceptibility in NOTCH4 and GRIK2 loci in a population of Han Chinese. DESIGN： Repetitive measurements. SETTING： The experiment was carried out at Shanghai Mental Health Center and Hongkou Mental Health Center of Shanghai between January 2001 and June 2004. PARTICIPANTS： Sixty-five mixed pedigrees （suffering from various diseases, in combination with schizophrenia and affective disorder）, composed of 45 completed trios and 20 single-parent families, were selected from Shanghai Mental Health Center and Hongkou Mental Health Center of Shanghai between January 2001 and June 2004. Probands received clinical diagnosis according to ICD-10; an independent clinician used identical criteria to review all diagnoses. All subjects were Han Chinese in origin and provided informed consent. There were 65 probands and 110 parents among the subjects. The probands comprised 30 males and 35 females： 33 with schizophrenia, 32 with affective disorder, mean age of （30.9 ± 9.8） years, mean age of onset （24.3 ± 8.8） years, mean duration （6.6 ± 7.0） years, and mean age of parents （58.8 ±10.9） years. METHODS： DNA samples from probands and their biological parents were extracted from peripheral blood according to standard methods. Four polymorphisms, -1725T/G and -25T/C in NOTCH4, rs6922753T/C and rs2227283G/A in GRIK2, were amplified and genotyped with PCR-RFLP techniques. MAIN OUTCOME MEASURES： Association between NOTCH4, GRIK2 polymorphism, and schizophrenia was analyzed by transmission disequilibrium test （TDT）. RESULTS： Sixty-five probands and 110 parents were included in the result analysis, with no dropouts. The results showed that the -25T/C polymorphism of NOTCH4 associated significantly with affecti     

Association of MB-COMT polymorphisms with schizophrenia-susceptibility and symptom severity in an African cohort

The catechol-O-methyltransferase (COMT) gene is an attractive schizophrenia candidate gene, encoding a catabolic dopamine enzyme. The enzyme exists as two distinct isoforms, with the membrane bound enzyme (i.e. MB-COMT) being predominantly expressed in the brain. Since African populations remain underrepresented in genetic/genomic research, we performed an association study to determine whether MB-COMT genetic variants are associated with schizophrenia-susceptibility and symptom severity in the South African Xhosa population. Fourteen candidate polymorphisms were selected by means of a literature search and in silico analyses and were subsequently genotyped in a cohort of 238 Xhosa schizophrenia patients and 240 healthy Xhosa controls. Genetic association was tested with schizophrenia-susceptibility as well as symptom severity within the patient group. Polymorphisms of interest were also analysed using functional assays. Two SNPs, rs2020917 (OR=0.54, 95% CI 0.37-0.79; P=0.0011) and rs737865 (OR=0.52, 95% CI 0.36-0.74; P=0.0002), in the P2 promoter region were significantly associated with schizophrenia as well as an increase (increase=11.2%, 95% CI 3.7%-19.2%; P=0.0031) in reporter gene expression. The minor alleles of these SNPs were underrepresented in the schizophrenia cohort, indicating a possible protective effect. The P2 region also formed part of a haplotype found to be associated with the severity of the negative symptoms of the disorder. The data generated by this study indicate that genetic variation of MB-COMT could be associated with schizophrenia and negative symptom severity in the Xhosa population and may therefore be one of the genomic loci contributing towards the disorder in the South African community. Future large-scale studies in other African schizophrenia populations are required to further elucidate the significance of these findings.