Association study between Disrupted-in-Schizophrenia-1 (DISC1) and Japanese patients with treatment-resistant schizophrenia (TRS)

Treating the 20-30% of patients with schizophrenia whose symptoms are resistant to antipsychotic treatment, a condition known as treatment-resistant schizophrenia (TRS), can be problematic. Recently, an association between Disrupted-in-Schizophrenia-1 (DISC1), a candidate susceptibility gene for schizophrenia, and TRS was reported. Associations between three missense SNPs, rs3738401 (Q264R), rs6675281 (L607F), and rs821616 (S704C) in DISC1, especially rs3738401, showed strong significance. Thus, the main aim of our current study was to examine if the reported possible functional polymorphisms in DISC1 were related to Japanese TRS. First, DISC1 was re-investigated in 485 Japanese patients with schizophrenia and 660 healthy controls with a case-control study using four candidate SNPs, rs751229, rs3738401, rs821597, and rs821616. DISC1 was not associated with schizophrenia in the Japanese population. Second, we investigated whether these SNPs contributed to TRS in 127 inpatients with schizophrenia (35 patients; TRS and 92 patients; non-TRS). The genotypic distributions of these four SNPs were not significantly different between TRS and non-TRS in either genotypic or recessive models of minor alleles. In addition, clinical variables, such as improvement in clinical symptoms, duration of hospitalization, and total antipsychotics dose amounts, were not different among the genotypes of these SNPs. Taken together, results showed that DISC1 had no apparent degree of association with Japanese patients with schizophrenia as a candidate susceptibility gene for disease per se or TRS.     

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.     

GRIA1、GRM3、TCF4基因单核苷酸多态性与精神分裂症的关联研究

目的 探讨GRIA1、GRM3和TCF4基因单核苷酸多态性与精神分裂症的关联,为精神分裂症的遗传学研究提供参考。 方法 选取昆明医科大学第一附属医院精神科的663例符合《精神障碍诊断与统计手册（第4版）》（DSM-IV）诊断标准的精神分裂症患者为病例组,以昆明市第一人民医院体检中心的690例健康人为对照组,使用SNaPshot基因分型方法对受试者GRIA1、GRM3、TCF4三个候选基因12个SNPs进行基因分型,并进行遗传学分析。 结果 GRM3多态性位点rs6465084的A等位基因频率与对照组相比差异有统计学意义（P=0.027）;以性别特异性做相关分析,表明多态性位点rs6465084 A等位基因频率在男性精神分裂症患者与正常对照组中差异有统计学意义（P=0.02）。 结论 GRM3多态性位点rs6465084可能与精神分裂症存在关联,其等位基因A可能增加精神分裂症的发病风险。     

转化生长因子β1基因29T >C单核苷酸多态性与脊柱融合的相关性

背景：影响脊柱融合的因素很多,但对转化生长因子β1基因变化与脊柱融合相关关系的报道较为少见。 目的：探讨转化生长因子β1基因第一外显子29T>C单核苷酸多态性与脊柱融合的相关关系。 设计、时间及地点：基因多态性观察实验,2007-07/2008-05在青岛大学医学院附属医院分子中心实验室完成。 对象：山东半岛汉族人200名正常人和210例颈腰椎植骨的手术患者。 方法：采用等位基因特异性多聚酶链反应和基因测序方法,检测210例脊柱融合患者和200名正常对照组外周血中转化生长因子β1基因29T >C单核苷酸多态性情况,并根据影像学的表现对植骨融合状况进行分级,分析其与脊柱术后植骨融合疗效之间的关系。 主要观察指标：转化生长因子β1基因29T >C单核苷酸多态与脊柱植骨融合是否有相关性。 结果：脊柱融合患者和正常对照组均存在转化生长因子β1基因29T >C单核苷酸多态性,其多态性在脊柱融合组和正常对照组的分布无显著性差异(P=0.707),但转化生长因子β1基因29T >C单核苷酸多态性的分布差异与颈椎前路自体髂骨椎间植骨融合程度之间存在相关性(P=0.001),与腰椎横突间植骨融合程度之间不存在相关性(P=0.647)。 结论：转化生长因子β1基因29T > C单核苷酸多态性中TT基因型可能是促进颈椎前路自体髂骨椎间植骨融合的一个重要遗传因素;而腰椎横突间植骨融合影响因素较多,需要进一步深入研究。     

Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies

OBJECTIVE: There is strong evidence for a genetic contribution to schizophrenia, but efforts to identify susceptibility genes have been largely unsuccessful because of the low power of individual studies. The authors' goal was to evaluate the collective evidence for an association between the Val158/108Met polymorphism of the catechol O-methyltransferase (COMT) gene and schizophrenia. METHOD: They performed separate meta-analyses of existing case-control and family-based association studies. RESULTS: Overall, case-control studies showed no indication of an association between either allele and schizophrenia, and family-based studies found modest evidence implicating the Val allele in schizophrenia risk. The pooled analyses of studies from diverse geographical regions may have obscured ethnic differences in patterns of genetic risk for schizophrenia. Stratification of the studies by ethnicity of the subjects yielded evidence for an association with the Val allele in case-control studies of European samples and, especially, in family-based studies of European samples. Case-control and family-based studies of Asian samples produced mixed results and, overall, little evidence for association. CONCLUSIONS: The results of the two types of association studies diverged somewhat, but the evidence from the family-based studies, although based on fewer reports, may be more accurate. The Val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry, but the influence of this polymorphism on risk in Asian populations remains unclear. These results call for more family-based studies to confirm the association between COMT and schizophrenia in European samples and to clarify its contribution to risk in Asian samples. They also suggest that case-control studies should use methods of genomic control to avoid being confounded by population stratification.     

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 of schizophrenia with the rs821633 polymorphism in the DISC1 gene among Han Chinese

Background

Previous studies report that various single nucleotide polymorphisms (SNP) in the Disrupted-in Schizophrenia 1 (DISC1) gene are closely associated with schizophrenia, but there are no studies that assess the relationship of age of onset of schizophrenia with these SNPs.

Objective

Investigate the relationship between the rs821633 SNP in the DISC1 gene and the occurrence and age of onset of schizophrenia in Han Chinese.

Methods

We used the TaqMan genotyping technology to examine the rs821633 SNP in the DISC1 gene among 315 individuals who developed schizophrenia prior to 19 years of age (‘early-onset’), 407 individuals who developed schizophrenia when 19 years of age or older (‘late-onset’), and 482 healthy controls. We used survival analyses to investigate the relationship between the rs821633(C) risk allele and the age of onset of schizophrenia.

Results

Compared to the prevalence in healthy controls, the prevalence of the C/C genotype of rs821633 and of the C allele in rs821633 were significantly greater in individuals with early-onset schizophrenia (X²=7.17, df=1, p=0.007; X²=7.20, df=2, p=0.032) and significantly greater in individuals with late-onset schizophrenia (X²=5.36, df=1, p=0.022; X²=6.58, df=2, p=0.041). However, there were no significant differences in the prevalence of the C/C genotype or the C allele between individuals with early-onset and late-onset schizophrenia. Kaplan-Meier survival analyses found no significant association between the rs821633(C) risk allele and age of onset in schizophrenia.

Conclusion

We confirm the association of polymorphism in the rs821633 SNP in the DISC1 gene with schizophrenia among Han Chinese, but we found no association between the rs821633(C) risk allele and the age of onset in individuals with schizophrenia.     

Association study of dopamine transporter gene and schizophrenia in Korean population using multiple single nucleotide polymorphism markers

Inherited or acquired dysfunction of the dopamine system is believed to underlie the core symptoms of schizophrenia, and there are some evidences that dopamine transporter activity may be altered in schizophrenic patients. Therefore, dopamine transporter gene (DAT1) has been traditionally considered a probable candidate gene for the association study of schizophrenia. Until now, association studies of the dopamine transporter gene (DAT1) with schizophrenia have yielded largely negative results. However, these results cannot be regarded as conclusive in that they were all obtained from just a single marker, that is, 3' untranslated region variable number of tandem repeat (VNTR). We have therefore tried to find other single nucleotide polymorphisms (SNPs) in DAT1 gene and to use them as additional markers for the association study of schizophrenia. Searching for the SNPs had been done with 50 Korean schizophrenic patients. DNA sequences encompassing the whole exon and flanking exon-intron junctions were amplified and searched for the presence of SNPs. Total of five SNPs were found. Among these, three SNPs (1215A>G, 1398C>T, IVS11+14G>A) as well as the 3' untranslated region VNTR were selected as the markers to be genotyped. The allelic and genotypic frequencies of these markers were determined in 252 schizophrenic patients and 271 controls and compared between them. The frequencies of algorithmically derived haplotypes were also compared. No evidence of association was found between any of these markers and schizophrenia. The result using haplotypes was also negative. However, when the patient subgroup with verified familial history and the subgroup with early age of onset were re-analyzed, weak trend of association between 1398C>T SNP marker with schizophrenia was found in both cases. In accordance with the previous literature, we could not find any evidence of association between DAT1 gene and schizophrenia. This result acquired more certainty because not only the VNTR but several SNPs present in DAT1 gene and newly constructed haplotypes were also used as additional markers. However, the finding of weak association between one of the SNP markers (1398C>T) and the specific subgroups of schizophrenia patients added further support to the importance of defining more homogenous subgroups in association studies.     

精神分裂症与儿茶酚邻位甲基转移酶基因多态性的关联分析

目的：探讨精神分裂症与儿茶酚邻位甲基转移酶（COMT）基因Val158Met多态性的关系。方法：采用聚合酶链反应技术检测符合诊断 标准的476例精神分裂症患者（病例组）和207例名正常对照者（对照组）的COMT基因Val158Met多态性，并进行关联分析，结果：（1）病例组与对照组基因型及等位基因分布频率的差异无显著性（P＞0．05）；（2）首次起病以阳性症状为主的患者Val158Val基因型（56．5％）高于非阳性症状为主型者（45．5％；P＝0．07）；（3）在男性患者中，不吸烟患者的Met 158Met基因型分布频率（11．9％）高于吸烟患者（4．1％；P＜0．05），OR＝3．137）；两者等基因分布的差异无显著性（P＞0．05）。结论：COMT基因多态性可能与精神分裂症某些临床特点存在关联。     

Association between schizophrenia and genetic variation in DCC: a case-control study

Schizophrenia is a highly heritable neurodevelopmental disorder associated with alterations in synaptic connectivity. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, plays a pivotal role in organizing neuronal circuitry by guiding growing axons and dendrites to their correct targets and by influencing synaptic connectivity. Results from experiments we previously conducted in dcc-heterozygous mice show that DCC plays a critical role in the developmental organization of the mesocorticolimbic dopamine (DA) circuitry. Furthermore we have shown that reduced expression of DCC during development and/or throughout life confers resilience to the development of schizophrenia-like DA and behavioural abnormalities. Importantly, this "protective" phenotype only emerges after puberty. Here we assess whether DCC may contribute to the risk of schizophrenia. We examined single nucleotide polymorphisms (SNPs) located in the DCC gene for association with schizophrenia using a case-control sample consisting of 556 unrelated schizophrenic patients and 208 healthy controls. We found one SNP, rs2270954, to be nominally associated with schizophrenia; patients were less likely to be heterozygous at this locus and more likely to be homozygous for the minor allele (χ(2)=9.84, df=2, nominal p=0.0071). Intriguingly, this SNP is located within the 3' untranslated region, an area known to contain a number of regulatory sequences that determine the stability and translation efficacy of mRNA. These results, together with our previous findings from studies in rodents, point at DCC as a promising novel candidate gene that may contribute to the genetic basis behind individual differences in susceptibility to schizophrenia.     

Association between a serotonin transporter promoter polymorphism (5HTTLPR) and personality disorder traits in a community sample

Background

The serotonin transporter (SERT) polymorphism (5HTTLPR) has been reported to be associated with several psychiatric conditions. Specific personality disorders could be intermediate factors in the known relationship between 5HTTLPR and psychiatric disorders. This is the first study to test the association between this polymorphism and dimensions of all DSM-IV personality disorders in a community sample.

Methods

374 white participants were assessed by clinical psychologists using the International Personality Disorder Examination (IPDE). Associations between dimensions of each DSM-IV personality disorder and the long (l) and short (s) alleles of the 5HTTLPR were evaluated using non-parametric tests and regression models.

Results

The s allele of the 5HTTLPR polymorphism was significantly associated with higher avoidant personality trait scores in the whole sample. Males with the s allele had a significantly lower likelihood of higher obsessive-compulsive personality disorder (OCPD) trait scores, whereas females with the s allele were likely to have higher OCPD personality trait scores.

Conclusion

This paper provides preliminary data on the relationship between personality disorders and the 5HTTLPR polymorphism. The relationship of the s allele and avoidant PD is consistent with findings of a nonspecific relationship of this polymorphism to anxiety and depressive disorders. Concerning the unusual sexual dimorphic result with OCPD, several hypotheses are presented. These findings need further replication, including a more detailed study of additional variants in SERT.     

精神分裂症与G72基因多态性的关联

目的：探讨在云南省汉族人群中D-氨基酸氧化酶激活基因（G72）多态性与精神分裂症的关联性。方法：采用聚合酶链式反应-限制性片段长度多态（PCR-RFLP）方法,在云南汉族276例精神分裂症患者和312例健康对照者中进行G72基因3个多态位点（rs9558562,rs45476401,rs3918341）的分型。结果：各位点在病例组和对照组中基因型分布均符合Hardy-Weinberg平衡。无论在男女混合样本,还是分别在男性、女性样本中,rs9558562,rs45476401,rs3918341在病例组和对照组间的等位基因频率分布差异均无显著性（P均〉0.05）。结论：G72基因rs9558562,rs45476401和rs3918341多态与云南汉族精神分裂症发病无显著相关。     

Association study between glutathione S-transferase P1 polymorphism and schizophrenia in the Korean population

This study is aimed to test the association between the coding sequence functional polymorphism (Ile105Val) of glutathione S-transferase P gene (GSTP1) and schizophrenia in the Korean population. Two hundred fourteen patients with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria and 110 healthy controls were enrolled in this study. Patients and controls were biologically unrelated age and sex-matched native Koreans. Genotyping for GSTP1 polymorphism was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). Genotype and allele distributions of GSTP1 polymorphism in patients with schizophrenia were not significantly different from those of the controls. Comparisons of clinical variables including Positive and Negative Syndrome Scale (PANSS), change of Brief Psychiatric Rating Scale (BPRS), number of admission, and onset age also were not different according to genotype distribution. The present study suggests that GSTP1 polymorphism may not confer susceptibility to development of schizophrenia in the Korean population.     

Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population

Disrupted-in-Schizophrenia-1 (DISC1), identified by cytogenetic approaches in a pedigree with familial psychosis, is considered a candidate susceptibility gene for schizophrenia in some populations. In the pedigree, the TRAX gene, located adjacent to DISC1 on the disrupted chromosome 1, may also contribute to the pathophysiology of the familial schizophrenia. We studied association of the DISC1 and TRAX genes with schizophrenia in 338 Japanese by analyzing 15 single nucleotide polymorphisms (SNPs), including 12 SNPs in DISC1 and three in TRAX, respectively. No significant difference was observed between the patients and controls in allelic frequencies or genotypic distributions of 15 SNPs. A weak trend for the association in genotypic distribution of one SNP in TRAX (major homo/hetero/minor homo: 0.324/0.431/0.245 vs. 0.293/0.526/0.181 for patients vs controls, p = 0.039 in the 2 x 3 comparison) turned out to be insignificant after Bonferroni correction. Haplotype analysis did not support the association between the patients and controls. The present study suggests that the DISC1/TRAX locus may not have a major role in Japanese schizophrenia.     

DISC1 and neurocognitive function in schizophrenia

We recently reported an association between DISC1 and schizophrenia, schizoaffective disorder, and bipolar disorder. Convergent evidence suggests that DISC1 has a direct effect on central nervous system functioning. However, there is a paucity of data investigating the effects of DISC1 on neurocognition. Thus, we analyzed the relationship between five single-nucleotide polymorphisms that influenced risk for schizophrenia in our previous study and neurocognition in 250 patients with schizophrenia. DISC1 genotype was related to neurocognitive performance on measures of rapid visual search and verbal working memory, when controlling for age and premorbid intellectual capacity, and explained 3%-4% of the variance. These data suggest that DISC1 is associated with neurocognitive functioning in schizophrenia.     

Association between Taq1 a dopamine D2 receptor polymorphism and psychopathology of schizophrenia in Japanese patients

1. Previous reports showed that the A1 allele of Taq1 A dopamine D2 receptor polymorphism was associated with lowered density and diminished function of dopamine D2 receptor. In this study, association between Taq1 A dopamine D2 receptor polymorphism and psychopathology of schizophrenia was investigated. 2. The subjects were 61 acutely exacerbated schizophrenic patients who were all Japanese descent and had received no medication for at least one month before this study. Pretreatment psychotic symptoms were assessed by the Brief Psychiatric Rating Scale (BPRS). The Taq1 A genotypes, the A1 and A2 alleles, were determined by polymerase chain reaction method. 3. The patients were divided into three genotype groups; i.e., the patients with A1/A1 allele (n=6), those with A1/A2 allele (n=32) and those with A2/A2 allele (n=23). 4. There was no significant difference in total BPRS, subgrouped symptoms (positive, negative, anxiety-depression, excitement and cognitive symptoms) or any scores of BPRS items among the three Taq1 A genotype groups. 5. The present study suggests that Taq1 A dopamine D2 receptor polymorphism does not play an important role in psychopathological symptoms of schizophrenia.     

Association analysis of AKT1 and schizophrenia in a UK case control sample

AKT1 (V-akt murine thyoma viral oncogene homolog 1) is involved in intracellular signalling pathways postulated as of aetiological importance in schizophrenia. Markers in the AKT1 gene have also recently been associated with schizophrenia in two samples of European origin and in Japanese and Iranian samples. Aiming to replicate these findings, we examined ten SNPs spanning AKT1 in a UK case-control sample (schizophrenia cases n=673, controls n=716). These included all SNPs previously reported to be associated in European, Japanese and Iranian samples, alone or in haplotypes, as well as additional markers defined by the Haploview Tagger program (pair-wise tagging, minimum r(2)=0.8, minor allele frequency=0.02). We found no association with single markers (min p=0.17). We found weak evidence for association (p=0.04) with a four marker haplotype reported as significant in the original positive European sample of Emamian et al. [Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M., Gogos, J.A., 2004. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat. Genet. 36, 131-137] and also an overlapping three marker haplotype (p=0.016) that had previously been reported as significant in a Japanese sample. Nominal p-values for these haplotypes did not survive correction for multiple testing. Our study provides at best weak support for the hypothesis that AKT1 is a susceptibility gene for schizophrenia. Examination of our own data and those of other groups leads us to conclude that overall, the evidence for association of AKT1 as a susceptibility gene for schizophrenia is weakly positive, but not yet convincing.     

儿童青少年精神分裂症与NCAM1基因的关联研究

目的 对通过Affymetrix Genome-Wide SNP Array 6.0全基因组芯片扫描发现,国外曾经报道与精神分裂症关联的NCAM1基因在儿童青少年精神分裂症家系中进行验证.方法 选择了100例儿童青少年发病的精神分裂症患者及其父母,通过5个NCAM1基因内的单核甘酸多态性位点(rs10891495,rs1245133,rs1821693,rs686050,rs12794326)经高分辨率溶解曲线(High Resolution Melting,HRM)进行基因分型后,用HaploView4.1软件进行统计分析.结果 未证实上述位点及所构建的单倍型与精神分裂症关联(P>0.05).结论 (1)不支持NCAM1基因与精神分裂症病因关联;(2)Affymetrix6.0全基因组SNP芯片关联分析产生的假阳性结果可经家系连锁不平衡分析验证.