同胞精神分裂症与5-羟色胺2A受体基因的关联分析

目的 探讨慢性精神分裂症患者的受累同胞和散发性精神分裂症与5-羟色胺2A受体基因(5-HT2A)T102C多态性的关联。方法 先用严格的纳入标准收集共患慢性精神分裂症的同胞60对(120例)和散发性精神分裂症120例,分别与正常同胞60对(120名)和120名正常人对照,采用聚合酶链反应(PCR)扩增及MspI内切酶酶切技术,检测各组的5-HT2A受体基因的基因型和等位基因的频率分布。结果 60对共患慢性精神分裂症的受累同胞组5-HT2A受体基因A1／A1基因型频率显著高于正常同胞组(X2=5.58,P<0.05),经配对比较,患者同胞组共有A1／A1基因型也显著多于正常同胞组(X2=3.94,P<0.05),而散发性精神分裂症与正常人对照组各基因型和等位基因的构成差异均无显著性意义。结论 共患慢性精神分裂症的同胞与5-HT2A受体基因A1／A1型关联,A1／A1纯合子易患精神分裂症,散发性精神分裂症可能与5-HT2A受体基因无关联。     

No linkage between D2 dopamine receptor gene region and schizophrenia

The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.     

Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility--T102C(3) and his452tyr(4) in the coding region and A-1438G(5) in the promoter--in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. There was a significant excess of 102C and -1438G alleles (62.7%) in the SCZ-TD-Y patients compared to SCZ-TD-N patients (41.1%) and controls (45.9%; chi(2) = 12.8, df = 2, P = 0.002; SCZ-TD-Y vs SCZ-TD-N, chi(2) = 11.4, df = 1, P = 0.0008, OR 2.41, 95% CI 1.43-3.99) and of 102CC and -1438GG genotypes (SCZ-TD-Y 42.4%, SCZ-TD-N, 16.1%, controls 20.8%, chi(2) = 13.3, df = 4, P = 0.01). The 102CC and the -1438GG genotypes were associated with significantly higher AIMS trunk dyskinesia scores (F = 3.9; df = 2, 116; P = 0.02) and more incapacitation (F = 5.0; df = 2, 115; P = 0.006). The his452tyr polymorphism showed no association with TD. These findings suggest that the 5-HT2A receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia. Previously reported association of the T102C and A-1438G polymorphisms with schizophrenia(6) may reflect association of a sub-group of patients with a susceptibility to abnormal involuntary movements related to antipsychotic drug exposure.     

5-羟色胺2A受体基因多态性与精神分裂症的相关性研究

目的探讨５－羟色胺２Ａ受体基因多态性与精神分裂症的相关性。方法采用Ａｍｐ－ＲＦＬＰ方法对精神分裂症患者和各对照组的５－羟色胺２Ａ受体（简称５－ＨＴ２ＡＲ）基因的相关性进行了研究。结果精神分裂症患者５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子基因型频率及等位基因Ａ２频率均高于对照组（χ２＝８．９９，８３８Ｐ均＜０．０１），对发生精神分裂症的５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子相对危险度是２３６。结论本实验结果提示５－ＨＴ２ＡＲ基因的变异与精神分裂症有密切相关性。     

Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia

We have shown a decrease in cortical serotonin_2A receptors using tissue sections, but not with washed membranes, from the same cohort of subjects. These discrepant findings led us to determine if we could obtain similar results using samples from the same tissue block. Our studies used single-point saturation analyses to estimate the total number of [³H]ketanserin binding sites in tissue sections, crude homogenate, membrane-enriched and cytosol-enriched tissue samples from Brodmann's area 9. There were significant decreases in the levels of [³H]ketanserin binding using tissue sections (mean ± SD: 38 ± 16 vs. 56 ± 16 fmol/mg ETE; p = 0.008) and crude tissue homogenates (131 ± 53 vs. 168 ± 38 fmol/mg protein; p < 0.05) from subjects with schizophrenia compared to that in controls. By contrast, there was no significant difference in radioligand binding to the membrane-enriched (155 ± 95 vs. 145 ± 48 fmol/mg protein; p = 0.72) or cytosol-enriched (8.6 ± 14 vs. 7.5 ± 10 mol/mg protein; p = 0.85) tissue fraction. Significantly, adding 10^{− 5} M risperidone or chlorpromazine, as surrogates for residual antipsychotic drugs in the CNS, to crude homogenate from control subjects did not alter [³H]ketanserin binding. Our data therefore is consistent with the hypothesis that apparent decreases in serotonin_2A receptors in schizophrenia are due to altered levels of a regulatory factor(s) that modulates the binding of ligands to the serotonin_2A receptor and that separating the membrane and cytosol removes this regulatory control.     

Association and linkage disequilibrium between a functional polymorphism of the dopamine-2 receptor gene and schizophrenia in a genetically homogeneous Portuguese population

A functional polymorphism in the promoter region of the DRD2 gene has been found to be associated with schizophrenia in Japanese(1,2) and Swedish populations.(3) We attempted to replicate these findings in a genetically homogeneous Portuguese population using a family-based study design. Analysis of 78 trios revealed evidence for association between the -141 C Ins allele and schizophrenia using the haplotype relative risk (HRR) method (chi(2) = 9.30, P = 0.0023). Further examination of this sample using an alternative family-based association analysis method, the transmission disequilibrium test (TDT), of 33 informative matings from the Portuguese trios provided evidence for an allelic association and linkage disequilibrium between the insertion allele and schizophrenia (chi(2) = 8.76, P = 0.0031). These consistent results using two alternative family-based association analysis methods replicate the findings of previous reports, and thus further implicate a potential role for the dopamine-2 receptor in the genetic etiology of schizophrenia.     

5-羟色胺2A受体基因多态性与精神分裂症患者迟发性运动障碍的关联分析

目的　探讨5- 羟色胺2A( 5- HT2A)受体基因A 1 4 38G、T1 0 2C多态性与精神分裂症伴迟发性运动障碍(TD)的相关性。方法　先用异常不自主运动量表(AIMS)评定精神分裂症男性患者有无TD及其严重程度,有4 2例符合TD(AIMS总分≥3分)者和51例与TD组严格相匹配的非TD者入组,采用简明精神病评定量表(BPRS)评定精神症状,应用聚合酶链反应 限制性片段长度多态性方法分析5 HT2A受体基因的A 1 4 38G、T1 0 2C多态性位点的多态性。结果　①5- HT2A受体基因A 1 4 38G和T1 0 2C两位点多态性呈完全连锁不平衡,TD组与非TD组的两多态性位点的基因型总体分布无显著性差异( χ2 =4 37,v =2 ,P >0 . 0 5) ,在TD组有更高的C/A等位基因频率,与非TD组有显著性差异( χ2 =4 . 36 ,v =1 ,P <0. 0 5)。②不同基因型间的人口学和临床学资料(如:病程、服药总时间、日服抗精神病药物剂量、AIMS和BPRS的评分)间无显著性差异(P >0. 0 5)。结论　5 -HT2A受体基因的A 1 4 38G、T1 0 2C多态性可能与男性精神分裂症患者的TD相关联。     

Clinical polydiagnostic studies in a large Swedish pedigree with schizophrenia

Summary A polydiagnostic computerized diagnostic system for psychosis was used in a Swedish family complex, and 51 patients with psychiatric symptomatology were examined with eight main diagnostic systems for schizophrenia and three systems for schizophrenic subgroups. All patients fulfilled the criteria for schizophrenia according to Taylor et al., 50 according to Carpenter, 41 according to RDC, and 31 of the 51 according to DSM-III and DSM-III-R. The hypothesis that the patients in the Swedish family complex differ from other phenotypes of schizophrenia must be refuted based on the data of the present study.     

Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia.

Genetic factors and dopamine receptor dysfunction have been implicated in the pathophysiology of schizophrenia. Recently, an association between a putative functional promoter polymorphism (-141C Ins/Del) in the dopamine D2 receptor gene and schizophrenia was reported. We investigated unrelated Swedish schizophrenic patients (n = 129) and control subjects (n = 179) for the same polymorphism. Similarly to a previous Japanese report, the - 141C Del allele frequency was significantly lower in patients than controls (chi2=4.4, 1 df, p<0.05; odds ratio 0.49, 95% confidence interval 0.26-0.91). The present and previous results may indicate that the -141C Ins/Del dopamine D2 receptor gene polymorphism affects susceptibility to schizophrenia.     

N-甲基-D-天冬氨酸受体2A亚单位基因与精神分裂症的连锁分析

目的了解N-甲基-D-天冬氨酸受体2A亚单位基因(NR2A)与精神分裂症的连锁关系。方法选取NR2A亚单位基因所在区域的3个微卫星标志[D16s407、D16s3075及NR2A启动子区的1个(GT)重复序列]，对中国汉族81个独立精神分裂症受累同胞对及其家系成员共324个个体作基因分型，其中男166名，女158名，患病同胞对81个162例。采用受累同胞对法对分型资料进行非参数连锁分析。结果324人的两点、多点非参数分析最大LOD值均位于D16s407，分别为2．643(P=0．004)，2．504(P=0．005)，均大于2．2。结论NR2A基因微卫星标志与精神分裂症存在提示性连锁关系，NR2A基因可能为精神分裂症的易感基因之一。     

Association analysis of serotonin 2A receptor gene T102c polymorphism and schizophrenia.

The serotonin neurotransmitter has been associated with the pathogenesis of mood disorders and schizophrenia. Serotonin receptors genes may therefore be candidate genes for the study of the genetics of these disorders. In this study, patients with schizophrenia (n=235) and controls (n=344) were analysed to determine the correlation between the 5HT(2A) receptor gene T102C polymorphism and schizophrenia. No association was found between the studied polymorphism and schizophrenia (p=0.854 for alleles and p=0.945 for genotypes). Results were also not significant when analysed by gender (for male p=0.861-allele frequency and p=0.467-genotype frequency, for female p=0.857-allele frequency and p=0.833-genotype frequency). Subgroups with regard to schizophrenia subtypes, age of onset and clinical course of schizophrenia were analysed with negative results.     

Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred

We studied a seven-generation kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess linkage relationships to multiple human leukocyte antigen (HLA) loci on the short arm of chromosome 6. Age at onset, clinical features, and course of the disease are described. Although the mean age of onset was 34 years in this family, in 6 of 41 affected individuals onset was below 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage studies were performed on 93 individuals, and the results show strong evidence for linkage of the SCA locus to the HLA loci. A maximum logarithm of the odds score of 5.83 was found at a recombination fraction of 0.12. This is the first documentation of childhood onset in the HLA-linked form of SCA.     

Molecular analysis of a chromosome 4 inversion segregating in a large schizophrenia kindred from Hong Kong

The present study looks at a paracentric inversion on chromosome 4 [inv(4)(q13;q25)] in members of a large schizophrenia kindred from Hong Kong, and the possibility of a susceptibility gene for schizophrenia at one of the inversion breakpoints. Fluorescence in situ hybridization with BAC and fosmid clones was used to determine the location of the 4q13 and 4q25 breakpoints, however bioinformatic analysis indicated that no known genes are directly disrupted by the breakpoints. We identified several putative genes and expressed sequence tags (ESTs) from around the breakpoint regions, and have characterized them further in order to determine whether they may represent full-length mRNAs that are disrupted by the inversion. Overall, it appears that, while no known genes are disrupted, an as yet undiscovered gene, or indeed, a known gene, may be present near one of the breakpoints and may be disrupted by position effect. We hypothesized that either the 4q13 or 4q25 breakpoint region may contain a common susceptibility gene for schizophrenia. We genotyped 117 schizophrenia families for several short tandem repeat polymorphisms close to the breakpoints. Family based association testing showed no association at the 4q13 breakpoint region, but showed significant allelic association for marker D4S2989 at the 4q25 breakpoint region (p=0.016). This study suggests that the 4q breakpoint regions may harbour a gene that contributes to the illness in the large Hong Kong pedigree, and this 4q25 region should be examined further in other schizophrenia samples.     

母女同患精神分裂症与5-羟色胺2A受体基因的关联分析

目的探讨母女精神分裂症患者和女性散发性精神分裂症患者与5-羟色胺2A受体基因(5-HT2A)T102C多态性的关联。方法先用严格的纳入标准收集共患精神分裂症的母女120例和女性散发性精神分裂症250例,分别与200名女性健康者做对照比较,采用聚合酶链反应(PCR)扩增及Mspl内切酶酶切技术,检测各组的5-HT2A受体基因的基因型和等位基因的频率分布。结果120例共患精神分裂症的母女组5-HT2A受体基因各组基因型频率均显著高于女性散发性精神分裂症组及正常女性对照组,经配对比较,女性散发性精神分裂症与女性正常人对照组各基因型和等位基因的构成差异均无显著性意义。结论母女共患精神分裂症的患者与5-HT2A受体基因的各组基因型均有关联,但A1/A2型杂合子可能更易患精神分裂症,女性散发性精神分裂症可能与5-HT2A受体基因无关联。     

Spinocerebellar ataxia in a large kindred: age at onset, reproduction, and genetic linkage studies

We studied a large kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess reproductive performance, the impact of genetic counseling, and linkage relationships of the SCA locus. Reproduction was not lower in those with SCA than in unaffected sibs or first cousins. Genetic counseling reduced reproduction during the risk period for development of SCA. Given autosomal dominant transmission of a single gene, we found strong evidence that the locus for SCA in this kindred is linked to the HLA loci.     

Decrease of serotonin receptor 2C in schizophrenia brains identified by high-resolution mRNA expression analysis.

BACKGROUND: RNA expression profiling can provide hints for the selection of candidate susceptibility genes, for formulation of hypotheses about the development of a disease, and/or for selection of candidate gene targets for novel drug development. We measured messenger RNA expression levels of 16 candidate genes in brain samples from 55 schizophrenia patients and 55 controls. This is the largest sample so far used to identify genes differentially expressed in schizophrenia brains. METHODS: We used a sensitive real-time polymerase chain reaction methodology and a novel statistical approach, including the development of a linear model of analysis of covariance type. RESULTS: We found two genes differentially expressed: monoamine oxidase B was significantly increased in schizophrenia brain (p =.001), whereas one of the serotonin receptor genes, serotonin receptor 2C, was significantly decreased (p =.001). Other genes, previously proposed to be differentially expressed in schizophrenia brain, were invariant in our analysis. CONCLUSIONS:The differential expression of serotonin receptor 2C is particularly relevant for the development of new atypical antipsychotic drugs. The strategy presented here is useful to evaluate hypothesizes for the development of the disease proposed by other investigators.     

精神分裂症与5—HT2c受体基因的关系

目的探讨上海地区汉族人５－ＨＴ２ｃ受体基因Ｃｙｓ２３Ｓｅｒ多态性的发生率及其与精神分裂症之间的关系。方法随机抽取２７４例精神分裂症患者作研究,以１８７例正常人作对照。用多聚酶链式反应（ＰＣＲ）扩增及单链构橡多态性（ＳＳＣＰ）分析、限制性片段长度多态性（ＲＦＬＰｓ）技术检测所研究对象的５－ＨＴ２ｃ受体基因Ｃｙｓ２３Ｓｅｒ多态性。结果仅在１个正常个体发现Ｃｙｓ－２３－Ｓｅｒ突变,精神分裂症患者中均未见     

Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

Prefrontal serotonin 2A receptors (5‐HT_2ARs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5‐HT_2AR at clinical relevant doses, and activation of 5‐HT_2A receptors by lysergic acid diethylamide (LSD) and LSD‐like drugs induces a schizophrenia‐like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well‐established model for schizophrenia‐like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5‐HT_2ARs. As a measure of 5‐HT_2AR functionality, we used the 5‐HT_2AR agonist 2,5‐dimethoxy‐4‐iodoamphetamine (DOI)‐induced head‐twitch response (HTR) and mRNA expression of the immediate‐early genes (IEGs) activity‐related cytoskeletal associated‐protein (Arc), c‐fos, and early growth response protein 2 (egr‐2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5‐day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5‐HT_2AR binding. Also, binding of the 5‐HT_1AR and the 5‐HT transporter was unaffected. Finally, basal mRNA level of Arc was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5‐HT_2AR could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc.     

No evidence for linkage between COMT and schizophrenia in a French population

Catechol-O-methyltransferase is a candidate in the predisposition to schizophrenia both because of its function and the position of its gene. A multipoint non-parametric linkage analysis and a transmission disequilibrium test were performed on 42 multiplex families genotyped for Pml I and Bcl I polymorphisms using two definitions of the affected phenotype. Neither linkage nor preferential transmission of any allele or haplotype was detected, failing to replicate previous positive findings.