Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.

BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.     

Association of RGS2 and RGS5 variants with schizophrenia symptom severity

BACKGROUND: Several lines of evidence indicate that Regulator of G Protein Signaling 4 (RGS4) contributes to schizophrenia vulnerability. RGS4 is one of a family of molecules that modulate signaling via G-protein coupled receptors. Five genes encoding members of this family (RGS2, RGS4, RGS5, RGS8 and RGS16) map to chromosome 1q23.3-1q31. Due to overlapping cellular functions and chromosomal proximity, we hypothesized that multiple RGS genes may contribute to schizophrenia severity and treatment responsiveness. METHODS: Subjects were 750 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Inferred ancestries were: 221 (30%) 'Africa only', 422 (56%) 'Europe only' and 107 (14%) 'Other'. Fifty-nine single nucleotide polymorphisms (SNPs) in or near the RGS5, RGS16, RGS8 and RGS2 genes were genotyped. Multiple linear regression was used to analyze association of markers with Positive and Negative Symptoms Scale (PANSS) total scores at baseline and throughout antipsychotic treatment. RESULTS: RGS5 marker rs10799902 was associated with altered baseline PANSS total score in both the Africa only (P=0.0440) and Europe only (P=0.0143) strata, although neither association survived multiple comparisons correction. A common five-marker haplotype of the RGS2 gene was associated with more severe baseline PANSS total score in the Europe only strata (global P=0.0254; haplotype-specific P=0.0196). In contrast to RGS4, none of the markers showed association with antipsychotic treatment response. CONCLUSIONS: RGS2 and RGS5 genotypes predicted severity of baseline symptoms in schizophrenia. Although these analyses are exploratory and replication is required, these data suggest a possible role for multiple RGS proteins in schizophrenia.     

RGS4 is not a susceptibility gene for schizophrenia in Japanese: association study in a large case-control population

The regulator of the G-protein signaling 4 (RGS4) has been implicated in the susceptibility to schizophrenia. RGS4 interacts with ErbB3 that acts as receptors for neuregulin 1 and these proteins may play a role in the pathogenesis of schizophrenia via glutamatergic dysfunction. Recently, two meta-analysis studies provided different interpretations for the genetic association between RGS4 and schizophrenia. We attempted to confirm this association in a case-control study of 1918 Japanese patients with schizophrenia and 1909 Japanese control subjects. Four widely studied single nucleotide polymorphisms (SNPs) were genotyped, and none showed association with schizophrenia. SNP 1 (rs10917670), p=0.92; SNP 4 (rs951436), p=0.91; SNP 7 (rs951439), p=0.27; and SNP 18 (rs2661319), p=0.43. A haplotype block constructed by these SNPs spans the 5' flanking region to the 5' mid-region of the RGS4 gene. Previous meta-analysis showed that both two major haplotypes of this block were risk haplotypes. The two common haplotypes were observed in the Japanese population. However, neither haplotype was significantly associated with schizophrenia. We conclude that the common haplotypes and SNPs of the RGS4 gene identified thus far are unlikely to contribute to the genetic susceptibility to schizophrenia in the Japanese population.     

Significant association between the genetic variations in the 5' end of the N-methyl-D-aspartate receptor subunit gene GRIN1 and schizophrenia.

BACKGROUND: N-methyl-D-aspartate (NMDA) receptors play important roles in many neurophysiological processes. Evidence from previous studies indicate that NMDA receptors contribute to the pathophysiology of schizophrenia. Two NMDA receptor subunit genes, GRIN1 and GRIN2A, are both good candidate genes for schizophrenia. METHOD: We genotyped five single nucleotide polymorphisms (SNPs) in GRIN1 and two in GRIN2A in 2455 Han Chinese subjects, including population- and family-based samples, and performed case-control and transmission disequilibrium test (TDT) analyses. A microsatellite in GRIN2A was genotyped in population-based samples and a Mann-Whitney U test was performed. RESULTS: A highly significant association was detected at the 5' end of GRIN1. Analyses of single variants and multiple-locus haplotypes indicate that the association is mainly generated by rs11146020 (case-control study: p = .0000013, odds ratio = .61, 95% confidence interval .50-.74; TDT: p = .0019, T/NT = 79/123). No association was found in the GRIN2A polymorphisms. CONCLUSIONS: Our results provide support for the hypothesis that NMDA receptors are an important factor in schizophrenia. Moreover, rs11146020 is located in 5' untranslated region where several functional elements have been found. Hence, the SNP is a potential candidate in altering risk for schizophrenia and worthy of further replication and functional study.     

Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia

Schizophrenia is a common psychotic mental disorder that is believed to result from the effects of multiple genetic and environmental factors. In this study, we explored gene-gene interactions and main effects in both case-control (657 cases and 411 controls) and family-based (273 families, 1,350 subjects) datasets of English or Irish ancestry. Fifty three markers in 8 genes were genotyped in the family sample and 44 markers in 7 genes were genotyped in the case-control sample. The Multifactor Dimensionality Reduction Pedigree Disequilibrium Test (MDR-PDT) was used to examine epistasis in the family dataset and a 3-locus model was identified (permuted p=0.003). The 3-locus model involved the IL3 (rs2069803), RGS4 (rs2661319), and DTNBP1 (rs2619539) genes. We used MDR to analyze the case-control dataset containing the same markers typed in the RGS4, IL3 and DTNBP1 genes and found evidence of a joint effect between IL3 (rs31400) and DTNBP1 (rs760761) (cross-validation consistency 4/5, balanced prediction accuracy=56.84%, p=0.019). While this is not a direct replication, the results obtained from both the family and case-control samples collectively suggest that IL3 and DTNBP1 are likely to interact and jointly contribute to increase risk for schizophrenia. We also observed a significant main effect in DTNBP1, which survived correction for multiple comparisons, and numerous nominally significant effects in several genes.     

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.     

Association of SNPs and haplotypes in APOL1, 2 and 4 with schizophrenia

Prior work found the APOL1, 2 and 4 genes, located on chromosome 22q12.3-q13.1, to be upregulated in brains of schizophrenic patients. We performed a family-based association study using 130 SNPs tagging the APOL gene family (APOL1-6). The subjects were 112 African-American (AA), 114 European-American (EA), 109 Chinese (Ch) and 42 Japanese (Jp) families with schizophrenia (377 families, 1161 genotyped members and 647 genotyped affected in total). Seven SNPs had p-values<0.05 in the APOL1, 2 and 4 regions for the AA, EA and combined (AA and EA) samples. In the AA sample, two SNPs, rs9610449 and rs6000200 showed low p-values; and a haplotype which comprised these two SNPs yielded a p-value of 0.00029 using the global test (GT) and the allele specific test (AST). The two SNPs and the haplotype were associated with risk for schizophrenia in African-Americans. In the combined (AA and EA) sample, two SNPs, rs2003813 and rs2157249 showed low p-values; and a three SNP haplotype including these two SNPs was significant using the GT (p=0.0013) and the AST (p=0.000090). The association of this haplotype with schizophrenia was significant for the entire (AA, EA, Ch and Jp) sample using the GT (p=0.00054) and the AST (p=0.00011). Although our study is not definitive, it suggests that the APOL genes should be more extensively studied in schizophrenia.     

A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: Association with impairment of sustained attention.

BACKGROUND: The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia. METHODS: We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia. RESULTS: Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test. CONCLUSIONS: Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.     

Association analysis of the 5-HT5A gene in depression, psychosis and antipsychotic response

The serotonergic system is targeted by both antidepressants and atypical antipsychotic drugs such as clozapine. Genetic variation in the 5-HT5A gene might be involved in susceptibility to depression, the major psychoses or in influencing clinical response to treatment. To examine this hypothesis we genotyped two polymorphisms (-19G/C; 12A/T) in the human 5-HT5A receptor gene in a sample of 269 unrelated schizophrenic patients treated with clozapine, 112 bipolar patients, 75 unipolar patients and 187 controls. After five-fold correction for multiple testing, allelic association was found with the -19G/C polymorphism and bipolar affective disorder, (p = 0.025; OR 0.56), unipolar depression (p = 0.004; OR 0.52) and schizophrenia (p = 0.036; OR 0.67) indicating a potential protective effect of the G19 allele. For the 12A/T polymorphism allelic association was observed with unipolar depression only (p = 0.004). We conclude that allelic variation in the human 5-HT5A receptor gene may be involved in susceptibility to schizophrenia and affective disorders but not in determining response to clozapine.     

Association analysis of the glial cell line-derived neurotrophic factor (GDNF) gene in schizophrenia

The glial cell line-derived neurotrophic factor (GDNF) gene is located within a region of chromosome 5 (5p14.1-q13.3) that has been highlighted as a potential schizophrenia susceptibility locus by a number of genome scans. GDNF is neurotrophic and is also thought to be involved in differentiation of dopaminergic neurones. The GDNF gene is, therefore, a positional and functional candidate gene for schizophrenia. It is of additional interest because altered GDNF mRNA and protein expression has been reported in response to antipsychotics and the psychotomimetic phencyclidine, and two previous studies, focussed on a single variant, have reported weak support for genetic association between GDNF and schizophrenia in small samples. To test the hypothesis that GDNF is a susceptibility gene for schizophrenia, we performed a detailed association study. We chose 9 SNPs that spanned a genomic region of 40 kb and fully encompassed GDNF. SNPs were genotyped in a sample of 673 schizophrenic patients and 716 matched controls, all of Caucasian origin and all collected from the UK or Ireland. Of the 9 SNPs genotyped 2 showed nominally significant genotypic association at the P< or =0.05 level (rs2973050; OR=1.11; P-value=0.007 and rs2910702; OR=1.14; P-value=0.039). Permutation testing to allow for multiple comparisons of non-independent markers gave a corrected genotypic P-value of 0.052 for rs2973050. We also genotyped an (AGG)(n) repeat located in the 3' UTR of the GDNF but this showed no evidence for association. We conclude that our sample does not provide independent statistically significant evidence for association between GDNF and schizophrenia, nor does it replicate previous specific reports of association.     

Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia

CONTEXT: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. OBJECTIVES: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. DESIGN: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging.Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia. MAIN OUTCOME MEASURES: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping. RESULTS: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. CONCLUSIONS: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.     

Mutation screening and LD mapping in the VCFS deleted region of chromosome 22q11 in schizophrenia using a novel DNA pooling approach

We examined whether variation within six genes from the VCFS critical region at 22q11 (DGSC, Stk22A1, DGSI, Gscl, Slc25A1 and Znf74) confers susceptibility to schizophrenia. We screened the exons and flanking intronic sequence of each gene for mutations in 14 individuals with DSM-IV schizophrenia using DHPLC. All polymorphisms identified were characterised and genotyped in a sample of 184 schizophrenics and matched controls, using novel DNA pooling methods. Of the polymorphisms identified, 17 were located within exons, six were within coding sequence, and two were non-synonymous. Pooled genotyping revealed no differences in the allele frequencies for any polymorphism between cases and controls that met our pre-defined criterion (P < or = 0.1). In a complementary approach we also attempted to define the location of a schizophrenia susceptibility locus more precisely by performing association mapping using seven microsatellites spanning the VCFS region with an average inter-marker distance of 450 kb. Conventional chi(2) analysis of genotypes in 368 cases and 368 controls revealed that none of the markers was significantly associated (P < 0.05) with schizophrenia. However, evidence for significant association (P = 0.003) was obtained for D22S944 when alleles were combined. TDT analysis of D22S944 genotyped in a further 278 cases of schizophrenia and their parents failed to find any overall allele-wise significant transmission disequilibrium (chi(2) = 18.3, P = 0.17). However, individual analysis of the alleles revealed that allele 12 was excessively non-transmitted and that this almost reached significance when corrected for multiple alleles (chi(2) = 7.35, P = 0.006, P = 0.078 corrected for 13 alleles).     

Association between schizophrenia and the syntaxin 1A gene.

BACKGROUND: Both microarray and candidate molecule studies have demonstrated that protein and mRNA expression of syntaxin and other genes involved in synaptic function are altered in the cerebral cortex of patients with schizophrenia. METHODS: Genetic association between polymorphic markers in the syntaxin 1A gene and schizophrenia was assessed in a matched case-control sample of 192 pairs, and in an independent sample of 238 nuclear families. RESULTS: In the family-based sample, a significant genetic association was found between schizophrenia and one of the four single nucleotide polymorphisms (SNPs) tested: an intron 7 SNP (transmission disequilibrium test [TDT] chi(2) = 5.898; df = 1; p =.015, family-based association test [FBAT] z = 2.280, p =.023). When the results for the TDT and case-control analyses were combined, the association was stronger (n = 430; z(c) = 2.859; p =.004). Haplotype analysis supported the association with several significant values that appear to be driven by the intron 7 SNP. Conclusions: The results should be treated with caution until replicated, but this is the first report of a genetic association between syntaxin 1A and schizophrenia.     

Positive association between ALDH1A2 and schizophrenia in the Chinese population

Vitamin A (retinol), in the biologically active form of retinoic acid (RA), has been proposed as involved in the pathogenesis of schizophrenia. We hypothesized that genetic basis of genes encoding RA metabolism enzymes, which control the cellular RA level, might be associated with this disease. This cascade genetic association model, using markers in genes of synthesis and degradation enzymes within the retinoid cascade, would better fit the biological character of the retinoid hypothesis than the single gene strategy. In the present study we chose to investigate 7 genes involved in the synthesis, degradation and transportation of RA, ALDH1A1, ALDH1A2, ALDH1A3, CYP26A1, CYP26B1, CYP26C1 and Transthyretin (TTR), for their roles in the development of schizophrenia. We genotyped 18 single nucleotide polymorphisms (SNPs) in the regulatory and coding regions of these 7 genes using LDR technology in the 617 Chinese Han subjects. Case–control analyses were performed to detect association of these 7 genes with schizophrenia. Association analyses using both allelic and genotypic single-locus tests revealed no significant association between the risk for each of investigated gene and schizophrenia. However, analyses of multiple-locus haplotypes indicated that the overall frequency of rs4646642–rs4646580 of ALDH1A2 gene showed significant difference between patients and control subjects (p = 0.0055). We also employed multifactor dimensionality reduction method to detect multilocus effects. In summary, in this work we show multiple candidate genes involved in retinoid cascade in schizophrenics. In addition, our results suggest a positive association between ALDH1A2 and schizophrenics in the Chinese population and support the retinoid hypothesis of schizophrenia.     

Genome scan for susceptibility loci for schizophrenia

OBJECTIVE: Schizophrenia is a relatively common, often chronic and debilitating mental illness. Evidence from various studies has clearly demonstrated that genetic factors contribute substantially to the etiology. The goal of this study was to identify chromosomal regions likely to contain schizophrenia susceptibility genes. METHODS: A genome-wide map of 388 microsatellite DNA markers was genotyped in 5 schizophrenia families. Nonparametric linkage analysis (Genehunter) was used to assess the pattern of allele sharing at each marker locus relative to the presence of disease. RESULTS: Nonparametric linkage scores did not reach a genome-wide level of statistical significance (p < 0.00002) or a p value suggestive of linkage (p < 0.007) for any marker; however, one p value suggested replicated linkage (p < 0.01) at chromosome 6p24 in region D6S309 (p = 0.0047). Furthermore, 11 markers resulted in p < 0.05 at chromosomes 6p, 6q, 10q, 12q and 14q. CONCLUSIONS: Despite the differences in diagnostic schemes, in markers used and methods of analyses between studies published so far, we think that our result supports the notion that there is possibly some consistent evidence for replicated linkage of a schizophrenia susceptibility locus around the region of D6S309 at chromosome 6p24.     

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.     

Chromosome 7q21-22 and multiple sclerosis: evidence for a genetic susceptibility effect in vicinity to the protachykinin-1 gene

Chromosome 7q21-22 and, in particular, the region surrounding D7S554 emerged from the recent American genome screen in multiple sclerosis (MS) as the most promising region genome-wide for harboring a disease susceptibility gene. We tested association between D7S554 and MS in 217 Sardinian trio MS families by the transmission disequilibrium test (TDT), and in a Northern Irish case-control study comprising 542 individuals. In both populations, we found evidence for significant allelic association (P(c)=0.04 and P(c)=0.0002, respectively). In a second stage, we analysed five microsatellite markers in a 4 megabase interval on chromosome 7q21-22 in the same set of Sardinian families. Parental transmission of a single allele of one of these markers, i.e. D7S3126, was significantly distorted (P(c)=0.008). D7S554 and D7S3126 are located at distances of, respectively, 40 and 81 kb 5' from the startcodon of the protachykinin-1 gene (TAC1), and occur in strong linkage disequilibrium (P<10(-7)). Our study indicates that the previous finding of linkage with D7S554 refers possibly to the presence of an MS susceptibility effect in vicinity to TAC1. In addition, a second independent association was uncovered between a microsatellite polymorphism in the plasminogen activator inhibitor-1 gene, i.e. D7S477, and MS. Overall, the analysis presented here may contribute to the increasingly refined genomic map of MS and underscores the requirement for a further high-resolution screening of chromosome 7q21-22.     

Association between chromogranin b gene polymorphisms and schizophrenia in the Japanese population.

BACKGROUND: We found in previous work a significant association between schizophrenia and D20S95 on chromosome 20p12.3. In this study, we analyzed 10 microsatellite markers and found an association of schizophrenia with D20S882 and D20S905 that flank D20S95. The chromogranin B gene (CHGB) is 30 kb from D20S905. The chromogranin B (secretogranin I) belongs to a series of acidic secretory proteins that are widely expressed in endocrine and neuronal cells, and its cerebrospinal fluid levels have been reported to decrease in patients with chronic schizophrenia. METHODS: We screened for polymorphisms in CHGB with polymerase chain reaction direct sequencing methods in 24 Japanese schizophrenic patients and identified a total of 22 polymorphisms. Allelic and genotypic distributions of detected polymorphisms were compared between unrelated Japanese schizophrenic patients (n = 192) and healthy control subjects (n = 192). RESULTS: Statistically significant differences in the allelic distributions were found between schizophrenic patients and control subjects for 1058C/G (A353G) (corrected p = 7.7 x 10(-5)) and 1104A/G (E368E) (corrected p = 8.1 x 10(-6)). The 1058C/G and 1104A/G alleles were in almost complete linkage disequilibrium and were in linkage disequilibrium with D20S95. CONCLUSIONS: Results suggest that the CHGB variations are involved in the susceptibility to schizophrenia in our study population.     

An association study between PPP1R1B gene and schizophrenia in the Chinese population

Schizophrenia has been linked with dysfunctions of glutamatergic, dopaminergic, and serotonergic neurotransmission. Dopamine- and cAMP-regulated phosphoprotein of relative molecular mass 32 kDa (DARPP-32), encoded by PPP1R1B (protein phosphatase 1, regulatory/inhibitor subunit 1B) gene, is enriched in neostriatal medium spiny neurons. It plays a key regulator role in dopaminergic and glutamatergic signaling pathways. The combined evidence from reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients and from abnormalities in mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32 suggested that it would be worthwhile to investigate the association between DARPP-32 and schizophrenia. In the present study, we genotyped five single nucleotide polymorphisms (SNPs) in the PPP1R1B gene and conducted a case-control study involving 520 schizophrenic patients and 386 healthy subjects drawn from the Chinese population. No allelic, genotypic or haplotypic association was found. However, our results do not preclude the possibility that the PPP1R1B is a susceptibility gene for schizophrenia in the Chinese population, since, as a central molecular switch, PPP1R1B may contribute to schizophrenia by interacting with other genes. Further functional analysis and genetic association studies are needed to determine the potential roles of PPP1R1B and other related genes in the pathophysiology of schizophrenia.     

Strong evidence for association between the dystrobrevin binding protein 1 gene (DTNBP1) and schizophrenia in 488 parent-offspring trios from Bulgaria.

BACKGROUND: The gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent-proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47). METHODS: We genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects. RESULTS: A significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p =.0009 and.0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p <.001. CONCLUSIONS: These results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies.