A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia

The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).     

No association between the dopamine D3 receptor Bal I polymorphism and schizophrenia in a family‐based study of a Palestinian Arab population

Several recent meta‐analyses appear to show a weak but significant effect of both forms of the gly/ser DRD3 polymorphism in conferring risk for schizophrenia. Since most studies have employed the artifact‐prone case‐control design, we thought it worthwhile to examine the role of this polymorphism using a robust family‐based strategy in an ethnic group not previously systematically studied in psychiatric genetics, Palestinian Arabs. We failed to obtain any evidence in 129 Palestinian triads, using the haplotype relative risk (allele frequency: Pearson chi‐square = 0.009, P > 0.1, df = 1, n = 258 alleles) or transmission disequilibrium test design (chi‐square = 0.38, P > 0.1, n = 86 families) for association/linkage (or increased homozygosity) of the DRD3 Bal I polymorphism to schizophrenia in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:778–780, 2000. © 2000 Wiley‐Liss, Inc.     

Angiotensin converting enzyme gene insertion/deletion polymorphism: Case‐control association studies in schizophrenia,major affective disorder,and tardive dyskinesia and a family‐based association study in schizophrenia

Angiotensin converting enzyme (ACE) is a candidate gene for psychiatric disorders. We examined the frequency of a functional insertion/deletion (I/D) polymorphism in the 16th intron of the ACE gene (located on chromosome 17q23) in groups of patients with schizophrenia (n = 104 and 113), major depression (n = 55), and bipolar disorder (n = 87) compared to healthy control subjects (n = 87). There was no evidence for allelic or genotypic association of the polymorphism with any of the disorders or with tardive dyskinesia (TD) in patients with schizophrenia. In a sample of nuclear families (n = 61) made up of one or more patients with schizophrenia recruited with their parents, there was no evidence for biased transmission of ACE I/D alleles. Particularly in the case of schizophrenia, these findings do not support an association of the ACE I/D polymorphism with the phenotypes examined. © 2002 Wiley‐Liss, Inc.     

Lack of association of serotonin‐2A receptor gene polymorphism (T102C) with suicidal ideation and suicide

Serotonergic dysfunction has been implicated in the pathophysiology of affective disorders and suicidality. Especially the density of the 5‐HT2A receptor was claimed as being increased in suicidality, proposed as an adaptive upregulation due to reduced serotonergic transmission. Recent studies have shown an association of allele C of the 5‐HT2A‐T102C polymorphism with suicidal ideation in patients with major depression. The purpose of this study was to test whether this proposed marker indicates susceptibility not only to suicidal ideation in depressed patients but also to suicidality as a syndrome. We investigated the 5‐HT2A‐T102C polymorphism in 131 suicide victims with unknown underlying psychiatric diagnoses, 84 patients with major depression with or without suicidal ideation, and 125 healthy controls. We were unable to find any association of genotype or allele frequencies to major depression, suicidal ideation, or suicide as a syndrome. Thus, our results suggest that this polymorphism may not commonly be involved in the susceptibility to suicidality. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:831–835, 2000. © 2000 Wiley‐Liss, Inc.     

Linkage study of the α2A adrenergic receptor in attention‐deficit hyperactivity disorder families

Attention‐deficit hyperactivity disorder (ADHD) is a common childhood psychiatric disorder, characterized by marked and pervasive inattention, hyperactivity, and impulsiveness. An alteration in the expression or function of the adrenergic system has been suggested to be involved in ADHD based on animal models, pharmacological interventions, and the neural circuitry of attentional processes. The efficacy of clonidine in reducing disruptive behaviors in some children with ADHD argues for a causal role of the adrenergic system and more specifically for the α2A receptors as clonidine is an α2A agonist that inhibits release of noradrenaline into the synapse. In animal studies, α2A receptor agonists have also been shown to improve performance on working memory tasks under distracting conditions, indicating that these receptors function in the regulation of attention. We examined the possibility that the gene for the α2A adrenergic receptor (ADRA2A) is linked to ADHD by testing a polymorphism located in the promoter region of the ADRA2A gene in a sample of 94 nuclear families with an ADHD proband. We found no evidence for linkage of the ADRA2A gene with ADHD, using the transmission disequilibrium test in this set of families. © Wiley‐Liss. Inc.     

Case control and family‐based studies of tryptophan hydroxylase gene A218C polymorphism and suicidality in adolescents

The association of suicidality with polymorphism A218C in intron 7 of tryptophan hydroxylase (TPH) gene remains controversial. The aim of this study was to use family‐based methods to examine this association in adolescents in order to eliminate the difficulty of sampling a control group from the same ethnic population. Eighty‐eight inpatient adolescents who recently attempted suicide were assessed by structured interview for detailed clinical history, diagnoses, suicide intent, suicide risk, impulsivity, aggression, and depression. DNA samples were collected from all subjects, from both biological parents of 40 subjects and from one parent of 9 subjects; TPH allele frequencies were calculated and tested for association to phenotype, stratified by severity, using the haplotype relative risk (HRR) and transmission disequilibrium test (TDT) methods (n = 49). The frequencies were also compared for all the Jewish subjects (n = 84) to the known frequencies of these alleles in healthy Jewish populations. There was no significant allelic association of A218C polymorphism with suicidal behavior or other phenotypic measures according to the HRR method (chi‐square = 0.094; P = 0.76), the TDT (chi‐square = 0.258; P = 0.61), or association analysis to known population frequencies (chi‐square = 1.667, P = 0.19 for Ashkenazi, and chi‐square = 0.810, P = 0.37 for non‐Ashkenazi). Analysis of variance with the Scheffè test demonstrated a significant difference between CC and AA genotypes in suicide risk and depression among the patients (n = 88). The findings suggest that polymorphism A218C has no major relevance to the pathogenesis of adolescent suicidal behavior, but may have a subtle effect on some related phenotypes. © 2001 Wiley‐Liss, Inc.     

Association study of schizophrenia and the IL-2 receptor β chain gene

A case-control association study was conducted in Caucasian patients with schizophrenia (DSM-III-R, n = 42) and unaffected controls (n = 47) matched for ethnicity and area of residence. Serum interleukin-2 receptor (IL-2R) concentrations, as well as a dinucleotide repeat polymorphism in the IL-2Rβ chain gene, were examined in both groups. No significant differences in IL-2R concentrations or in the distribution of the polymorphism were noted. This study does not support an association between schizophrenia and the IL-2Rβ gene locus, contrary to the suggestive evidence from linkage analysis in multicase families. © 1995 Wiley-Liss, Inc.     

Investigation of the human serotonin 6 (5‐HT6) receptor gene in bipolar affective disorder and schizophrenia

Serotonin (5‐hydroxytryptamine, 5‐HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5‐HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5‐HT₆ receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0.023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family‐based association design. Fifty‐one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5‐HT₆ gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217–221, 2000. © 2000 Wiley‐Liss, Inc.     

Lack of an association between 5‐HT1A receptor gene structural polymorphisms and suicide victims

A serotonergic dysfunction in the brain has been reported to be involved in suicidal behavior independently of the presence of a specific psychiatric disorder. Serotonin 1A (5‐HT_1A) receptors are known to be located on serotonergic nerve terminals and to be involved in the presynaptic regulation of serotonin release. Genetic factors partly explain the risks for suicide, and a suicide completion group is thought to be more uniform than a suicide attempt group. To explore the hypothesis that the 5‐HT_1A receptor‐induced serotonergic dysfunction is implicated genetically in suicide, we focused on the structural polymorphisms, Pro16Leu and Gly272Asp, of the 5‐HT_1A receptor gene, and examined the association between suicide victims who completed suicide and these two polymorphisms. In both polymorphisms, we found no significant difference in genotype distribution or allele frequencies between suicide victims and controls. These findings suggest that neither of these two polymorphisms is associated with suicide victims and it is unlikely that the 5‐HT_1A receptor gene is implicated in the susceptibility to suicide. © 2002 Wiley‐Liss, Inc.     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

Novel and previously reported single‐nucleotide polymorphisms in the human 5‐HT1B receptor gene: No association with cocaine or alcohol abuse or dependence

Evidence from animal self‐administration and human genetics studies suggests that the serotonin_1B (5‐HT_1B) receptor may be involved in modulating responses to cocaine or alcohol. We hypothesize that polymorphisms, including single‐nucleotide polymorphisms (SNPs), in the human 5‐HT_1B receptor gene, may be associated with individual differences in vulnerability to cocaine or alcohol abuse or dependence. A total of 210 subjects were studied, including individuals with a primary diagnosis (DSM‐IV criteria) of cocaine abuse or dependence, alcohol abuse or dependence, and controls with no history of previous or current illicit drug or alcohol abuse or dependence. Genomic DNA samples were isolated from each individual. For 157 of the subjects, polymerase chain reaction (PCR) was used to amplify the entire coding region of the 5‐HT_1B receptor gene as well as parts of the 5′ and 3′ untranslated regions. PCR products were sequenced in forward and reverse directions on an automated sequencer. Amplified DNA from an additional 53 subjects was sequenced in the 5′ untranslated region to gain additional data on the frequency of one identified SNP. Seven polymorphisms were identified: one novel SNP in the 5′ untranslated region (UTR) of the gene (A‐161T); one SNP not reported in any published scientific communication (but found to be recorded in GenBank) in the 3′ UTR (A1180G); two novel dinucleotide deletions at positions ? 184/? 183 and ? 182/? 181; and three previously identified SNPs (T‐261G, C129T, G861C). Data were stratified by ethnicity and pooled Relative Risk was calculated for combined alcohol abuse and dependence cases and controls, and also for combined cocaine abuse and dependence cases and controls. No significant differences between cases and controls were found. © 2001 Wiley‐Liss, Inc.     

自杀未遂与5-羟色胺2A受体基因的关联分析

目的 探讨5-羟色胺（5-HT）2A受体基因A-1438G和T102C两种多态性与自杀未遂之间的关系。方法 以149例自杀未遂者为研究对象。190名正常人为对照,采用聚合酶链反应-限制性片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)方法,分析5-HT2A受体基因A-1438G和T102C多态性。结果 PCR-RFLP分析发现,男性自杀未遂与5-HT2A受体基因A-1438G多态性的基因型GG关联。结论 5-HT2A受体基因A-1438G多态性可能与男性的自杀易感性相关。     

The 5‐HT2A receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5‐HT_2A‐C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5‐HT_2A‐102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5‐HT_2A receptor gene was analyzed in 159 patients with major depression (DSM‐IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi‐square = 4.13, df = 1, P = 0.04) and genotype (chi‐square = 6.19, df = 2, P = 0.04) distributions were found between non–suicide attempters and suicide attempters. Moreover, those patients carrying 5‐HT_2A‐C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18–35.20, P = 0.01). Our results replicate the proposed association between 5HT_2A‐C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5‐HT_2A‐C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself. © 2001 Wiley‐Liss, Inc.     

Further evidence of no association between Ser9Gly polymorphism of dopamine D3 receptor gene and schizophrenia

Dopamine D3 receptor (DRD3) was demonstrated to have important implications in schizophrenia, because it binds antipsychotic drugs and is abundant in the limbic system of the brain. Several groups attempted to find an association between a serine-to-glycine polymorphism at codon 9 of the DRD3 gene (Ser9Gly) and schizophrenia; however, the results were inconsistent. We conducted a case-control association study in Han Chinese schizophrenic patients from Taiwan, to examine the relationship of this serine-to-glycine polymorphism and schizophrenia. We noted no significant differences of genotype distribution, allele frequencies, or homozygosity proportion of this polymorphism between schizophrenic patients (N = 178) and controls (N = 100). When patients were divided according to sex, or presence or absence of family history, the differences were still not significant. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia. Am. J. Med. Genet. 74:40–43, 1997. © 1997 Wiley-Liss, Inc.     

Neuregulin 1基因多态性与中国汉族精神分裂症关联分析

目的 探讨Neuregulin 1(NRG1)基因多态性与精神分裂症的关联.方法 在258个中国汉族精神分裂症核心家系(患者及其亲生父母)中,应用实时定量PCR技术检测位于NRGl基因5'端的4个单核苷酸多态(single nucleotide polymorphism,SNP)位点:rs221533(C/T)、rs7820838(C/T)、433E1006 (A/G)和rs3924999(C/T),进行基因分型,应用传递不平衡检测(transmission disequilibrium test,TDT)分析等位基因传递情况,分析该基因与精神分裂症易感性的关联.结果 在258个中国汉族核心家系中,rs221533、433E1006、rs3924999三个SNP均存在有统计学意义的传递不平衡,优先传递的等位基因分别是:C、A、T(rs221533:X2=27.45,P=0.000;433E1006:X2=56.08,P=0.000;rs3924999:X2=10.53,P=0.001).rs7820838未检到不平衡传递(X2=3.31,P=0.081).频率大于1%单倍型进行分析,rs221533-rs7820838-433E1006联合分析,单倍型C/C/G和C/C/A优先传递(C/C/G:X2=5.26,P=45.08;C/C/A:X2=0.026,P=0.000);rs221533-rs7820838-433E1006-rs3924999联合分析,单倍型C/C/G/T、C/C/A/C和C/C/A/T优势传递(C/C/G/T:X2=10.71,P=0.001;C/C/A/C:.)X2=8.83,P=0.006、C/C/A/T:X2=27.00,P=0.000).213个阳性亚型的精神分裂症核心家系中传递不平衡得出基本一致的结果 .结论 Nrg1基因多态性与中国汉族人群精神分裂症存在关联,尤其是支持与阳性亚型精神分裂症存在关联.     

FXYD6基因遗传多态性在精神分裂症患者核心家系中的传递不平衡检验

目的 探讨FXYD6基因单核苷酸多态性(single nucleotide polymorphisms,SNP)和精神分裂症(schizophrenia)之间的相关性.方法 采用等位基因特异性PCR的方法对FXYD6基因6个SNPs(rs10790212、rs11544201、rs555577、rs1815774、rs4938446和rs497768)位点的基因型在101个三口之家中进行传递不平衡检验(transmission disequilibrium test,TDT).结果 遗传标记rs10790212和rs11544201显示了显著的传递不平衡(P＜0.05),而单倍型分析的结果表明单倍型rs10790212-rs11544201与精神分裂症显著性关联(P＜0.05).结论 FXYD6基因与中国汉族人群精神分裂症遗传易感性相关,有必要进一步开展对FXYD6基因的功能学研究.     

5-HT 102T/C多态性与Tourette综合征的病例对照及核心家系关联分析

目的 研究5－羟色胺受体102T／C多态性是否与Tourette综合征（TS）相关联,方法对157个核心家系样本采用病例－对照关联分析,传递不平衡检验方法,聚合酶链反应及RFLP等技术,根据TS与强迫症（obsessive compulsive disorder,OCD)的同病现象,将TS划分亚组进行与5－羟色胺受体102T／C多态性的关联分析。结果 合并OCD的TS与该位点的基因型102C／C（X2＝8．38,P＝0．004）及等位基因102C／（X2＝4．84,P＝0．028）存在关联,进一步采用传递不平衡分析,发现合并（美国精神疾病诊断和统计手册IV》论断标准的OCD的TS与该位点存在关联或连锁不平衡（X2＝5．12,,P＝0．02）,而在TS总体样本及单纯TS样本中未发现与该位点的关联,结论 5－羟色胺受体102T／C多态性与中国人群合并OCD的TS存在关联,合并OCD的TS可能是TS中相对独立的一个亚型。     

网状内皮素4受体基因多态性与中国汉族精神分裂症关联分析

目的:分析网状内皮素4受体(RTN4R)基因上的5个单核苷酸多态性(SNP)与中国汉族精神分裂症关联,探讨RTN4R基因单核苷酸多态性与精神分裂症易感性的关系。方法:收集符合美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)诊断的528名偏执型精神分裂症患者,在同一地域招募健康体检者528名作为对照,并采用阳性与阴性症状量表(PANSS)评估234例首次发病患者的临床症状,采用基因分型芯片对RTN4R基因上的5个功能单核苷酸多态性位点进行基因分型,分析多态性与疾病的关联性,以及PANSS因子分与RTN4R多态性的关联。结果:成功检测5个单核苷酸多态性位点的基因型,关联分析显示这些位点基因型和等位基因频率分布病例和对照之间差异无统计学意义。与携带rs696880位点GG基因型患者相比,携带AA基因型患者PANSS阳性分[(23.5±5.6)vs.(25.1±7.6),P0.05]、一般精神病理症状分[(42.6±9.9)vs.(46.0±13.4),P0.05]均较低,携带AA基因型患者发病年龄晚于携带GG型患者[(24.9±8.1)岁vs.(22.2±6.2)岁,P0.05]。结论:在中国汉族人群中,RTN4R基因多态性与精神分裂症可能不存在关联,但可能影响疾病表现。     

Activation of central 5HT2A receptors reduces the craniofacial nociception of rats

We assessed the contribution of central 5HT2A receptors to the craniofacial tissue nociception in naïve male rats. First, we tested whether activation of central 5HT2A receptors affected nociceptive neural activities recorded from superficial laminae of the trigeminal subnucleus caudalis (Vc)/upper cervical spinal cord junction (Vc/C2) region. Two types of units, such as deep-nociceptive or skin–wide dynamic range (WDR) units were identified from extracellular recordings. Topical administration of 5HT2A receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) onto the Vc/C2 region significantly reduced deep-nociceptive unit discharges evoked by formalin injection into the masseter muscle. Noxious pinch stimulation to the facial skin-evoked skin–WDR unit discharges was significantly reduced by topical administration of 0.1 mg/rat DOI onto the Vc/C2 region. Second, we tested whether i.c.v. administration of DOI affected Fos-like immunoreactivity (-LI) evoked by formalin injection into the masseter muscle. Fos-LI was significantly induced mainly at the ventrolateral (vl) area of trigeminal subnucleus interpolaris (Vi)/Vc junction (vl-Vi/Vc) region and Vc/C2 region in vehicle-treated rats. Formalin-evoked Fos-LI was significantly reduced in laminae I–II of the Vc/C2, but not vl-Vi/Vc region after i.c.v. administration of DOI. Finally, orofacial nocifensive behavioral activities evoked by formalin injection into the masseter muscle were significantly reduced by intracisternal administration of DOI. These results suggest that 5HT2A receptors in the Vc/C2 region mediate antinociceptive effects in the craniofacial nociception.