多巴胺D4受体基因多态性与注意缺陷多动障碍的关联分析

目的探讨注意缺陷多动障碍(ADHD)与多巴胺D4受体(DRD4)基因第3外显子48bp可变数目顺向重复(VNTR)多态性的关系.方法对176例ADHD患儿(病例组)、98个ADHD核心家系(家系组,共294人)及119名正常对照(对照组)进行ADHD与DRD4基因48bpVNTR多态性的关联分析.结果所测人群中的48bpVNTR多态性表现为2～6次重复(分别为407、bp、455bp、503bp、551bp及599bp);其中以4次重复(73.9%)和2次重复(21.8%)最为常见;尚未发现7次重复序列.病例组2/2基因型(6.3%)显著低于对照组(14.3%;P=0.02),这种差异主要表现在ADHD混合型.对98个家系的精确多等位基因不平衡传递检验,未发现等位基因与ADHD存在连锁不平衡(x2=5.119,v=4,P＞0.05).结论DRD4基因48bpVNTR多态性主要集中于4次重复序列片段上;48bp片段的重复次数可能与ADHD相关,重复2次时可以减少ADHD的易患性.     

多巴胺转运体基因与注意缺损多动障碍

目的　探讨注意缺损多动障碍（ＡＤＨＤ） 与多巴胺转运体（ＤＡＴ１） 基因间的关系。方法　分别采用基于单体型和基于基因型的单体型相对风险分析方法,在上海地区汉族人群中对ＡＤＨＤ 与ＤＡＴ１ 基因微卫星多态性进行遗传关联分析。结果　①上海地区汉族人中,ＤＡＴ１ 基因多态以４８０ ｂｐ 重复片段为主,其基因频率为９２％ 。②以父母双亲为对照,经ＧＨＲＲ 和ＨＨＲＲ 分析,ＤＡＴ１ 基因与ＡＤＨＤ 均无关联。结论　上海地区汉族人群中ＤＡＴ１ 基因多态与ＡＤＨＤ 无关。     

儿茶酚氧位甲基转移酶基因与注意缺陷多动障碍患儿认知功能的关联研究

目的 探讨儿茶酚氧位甲基转移酶(COMT)基因Va1108/158Met(rs4680)多态性对注意缺陷多动障碍(ADHD)患儿认知功能的影响.方法 对203例中国汉族ADHD患儿进行韦氏记忆测查、Stroop测验及数字划消测查,评定记忆力、反应抑制能力和注意力,并检测COMT基因Va1158Met多态性.按照基因型将样本分为高活性基因型组(92例,ValVal)和中低活性基因型组(111例,ValMet和MetMet),比较两组间各项测查结果的异同.结果 高活性基因型组图片分测验[(11.7±3.1)分]和Stroop测验C部分错误数(0个)的成绩好于中低活性基因型组[分别为(10.8±2.9)分和1个;P＜0.05～0.01].两组其他方面的差异均无统计学意义.结论 COMT基因Val158Met多态性与ADHD患儿的认知功能中的记忆力、反应抑制能力和注意力相关.     

5-羟色胺转运体基因多态与共患学习困难的儿童注意缺陷多动障碍的相关性

目的探讨共患学习困难(LD)的注意缺陷多动障碍(ADHD)患儿与5-羟色胺转运体(5-HTT)基因连锁多态区(5-HTTLPR)和第2内含子17 bp数目可变的顺向重复(stin2.VNTR)的关联关系。方法对126例共患LD的ADHD患儿和198例不共患LD的ADHD患儿的5-HTTLPR和stin2.VNTR两种多态进行检测,并采用传递不平衡检测(TDT)和单体型分析方法进行关联分析。结果(1)TDT检测:5-HTTLPR多态的S等位基因在共患LD的ADHD和ADHD混合型(ADHD-C)核心家系中优先传递(X2=5.831和5.281,P=0.015和0.020);所有家系均未观察到stin2.VNTR多态中的任何等位基因有传递不平衡现象(均P>0.05);(2)单体型分析:5-HTT基因与共患LD的ADHD和ADHD-C相关联(X2=11.391和13.343,v=3,P=0.010和P=0.004);单体型L／12在共患LD的ADHD和ADHD-C核心家系中传递较少(X2=10.317和8.948,v=1,P=0.001和0.003),而单体型L／10在共患LD的ADHD核心家系中传递较多(X2=4.065,v=1,P=0.044)。结论5-HTT基因可能与共患LD的ADHD相关联,其中主要为共患LD的ADHD-C亚型。     

The interference of local over global information processing in children with attention deficit hyperactivity disorder of the inattentive type

A classic finding in perception of compound patterns is normal individuals cannot skip global analysis in local-oriented processing, but they can successfully resist local analysis in global-oriented processing-the so-called global interference [1]. Recently, studies examining the role of brain hemisphere activity in the Navon task have indicated that the processing of global and local information can be, respectively, attributed to the right and left hemispheres. Moreover, many neuroimaging researches have revealed that certain core symptoms of attention deficit hyperactivity disorder (ADHD) are related to dysfunction of right hemisphere. These findings imply that global interference will be substantially less evident, and possibly even replaced by local interference in ADHD. The present study compared the performance of children with and without attention deficit hyperactivity disorder of the inattentive type (ADHD-I) in the processing of global and local information to examine the local interference hypothesis in ADHD. An ADHD-I group (n=15) and a paired control group (n=19) completed tasks using two versions of the Navon task, one requiring divided attention, in which no information was given to participants regarding the level at which a target would appear, and the other requiring selective attention, in which participants were instructed to attend to either the local or the global level. The results showed that children with ADHD-I exhibited local interference, regardless of which attention procedure was used. These results support the weak right hemisphere hypothesis in ADHD, and provide evidence against the deficit hypotheses for ADHD in the DSM-IV criteria [29], which postulates that inattention symptoms may manifest as a failure to provide close attention to details.     

多巴胺D4受体基因和5-羟色胺转运体基因与注意缺陷多动障碍及其相关症状的关联分析

目的 探讨多巴胺D4受体(DRD4)基因和5-羟色胺转运体(5-HTT)基因与注意缺陷多动障碍(ADHD)及其相关症状的关系.方法利用Achenbach父母用儿童行为调查表评定139例ADHD患儿(患者组)的临床症状;采用聚合酶链反应、聚丙烯酰胺凝胶电泳结合银染技术,检测患者组和115名正常儿童(对照组)的基因型和等位基因频率.结果 (1)患者组与对照组间DRD4和5-HTT基因的基因型及等位基因频率分布的差异无统计学意义(P>0.05).(2)5-HTT基因的S/S基因型个体的社会退缩[(4.4±3.0)分]、躯体主诉[(3.6±2.7)分]得分高于S/L+L/L基因型个体[(3.3±2.6)分和(2.6±2.6)分],差异有统计学意义(P<0.05).(3)在非携带DRD4基因3等位基因个体中,S/L+L/L基因型的注意问题[(10.4±3.1)分]和社交问题[(7.2±3.7)分]得分高于S/S基因型个体[分别为(8.7±3.1)分和(5.3±2.3)分],差异有统计学意义(P<0.05).结论 DRD4基因和5-HTT基因与ADHD可能无关联;但5-HTT基因与ADHD的某些内化性症状可能存在关联;对ADHD的某些症状(注意问题和社交问题),DRD4基因与5-HTT可能存在相互协同作用.     

突触体维系蛋白-25基因与注意缺陷多动障碍的关系

目的探讨突触体维系蛋白125（SNAP-25）基因3’端未翻译区T1065G和T1069C多态性位点与注意缺陷多动障碍（ADHD）的关系。方法采用聚合酶链反应．限制性片段长度多态性技术，检测138例ADHD患者（患者组）和119名对照者（对照组）基因型和等位基因频率。结果（1）患者组与对照组SNAP-25基因T1065G多态性基因型及等位基因频率的总体分布差异有统计学意义（P〈0．05），其中患者组1065T／1065T基因型（70．3％）和1065T等位基因频率（84．1％）高于对照组（分别为56．3％和74，4％；P〈0．05）；患者组1065G／1065G基因型频率（2．2％）略低于对照组（7．6％），但差异无统计学意义（P：0．07）。（2）SNAP-25基因T1069C多态性，两组均为1069T等位基因（100％，100％），均未发现1069C等位基因。结论SNAP-25基因T1065G多态性与ADHD可能存在关联，1065T／1065T基因型和1065T等位基因可能是ADHD发病的危险因素。     

A preliminary report of the dopamine receptor D4 and the dopamine transporter 1 gene polymorphism and its association with attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is one of the most prevalent childhood-onset psychiatric syndromes affecting 5%–10% of school-age children worldwide. Distortions in the catecholaminergic system seem to be responsible for this condition. Within this system there are several candidate genes, the dopamine receptor D₄ (DRD4) and the dopamine transporter 1 (DAT1), with common polymorphism which might be associated with ADHD. We performed a family based association study with 36 trios and 19 parent proband pairs. All diagnoses were confirmed by the “Hypescheme” diagnostic computer program. In this study we did not observe an association of ADHD with DRD4 and DAT1 polymorphism neither by the haplotype relative risk (HRR) method nor by the transmission disequilibrium test (TdT) method. The odds ratio for the DRD4 7-allele was 1.01 and 0.94 for both statistical tests, respectively, and the respective odds ratio for the DAT1 6-allele were 0.91 and 0.88.     

利培酮治疗注意缺陷障碍对照观察

目的:观察小剂量利培酮治疗注意缺陷障碍(ADHD)的疗效和安全性,方法:前瞻性研究,以利他林作为对照,采用康纳多动症评定量表及不良反应症状量表(TESS)评定,观察4周,结果:利培酮有效率为77%,利他林为78%,未见锥体外系副反应,结论:利培酮与利他林的疗效相似,小剂量使用时安全有效.     

The dopamine transporter gene and the impulsivity phenotype in attention deficit hyperactivity disorder: a case-control association study in a Korean sample

The dopamine transporter gene (DAT1) has been extensively studied as one of the candidate genes in attention-deficit/hyperactivity disorder (ADHD). Several studies have reported on the association between the DAT1 10-repeat allele and cognitive variables in ADHD. However, few studies have been designed to ascertain the association between DAT1 genotypes other than the 10-repeat allele and cognitive endophenotypes in ADHD. The aim of this study was to examine the relationship between the DAT1 genotypes and the candidate endophenotypes, inattention and impulsivity symptoms, as measured by the continuous performance test (CPT), in a Korean sample of 85 children diagnosed with DSM-IV ADHD. Compared to the normal control group, the frequencies of the 9/10 genotype were significantly higher in the ADHD probands (χ² = 13.45, p = 0.02, OR = 4.12, 95% CI: 2.21–12.34) and parents of probands (χ² = 11.60, p = 0.03). The 9-repeat allele frequencies were significantly higher in the ADHD probands (χ² = 11.55, p = 0.03, OR = 4.43, 95% CI: 1.55–11.78) and parents of probands (χ² = 12.70, p = 0.03) than the normal control group. Compared to the ADHD probands without the 9-repeat allele (n = 74), the mean T-score, with regard to the commission errors of the CPT, was significantly higher (p < 0.05) in the ADHD probands with the 9-repeat allele (n = 11). Compared to the ADHD probands with other DAT1 genotypes, the mean T-score, with respect to the commission errors of the CPT, was significantly higher in the ADHD probands with the 9/10 genotype (p < 0.05). The results of this study suggest the possibility of an association between the DAT1 9-repeat allele and the impulsivity phenotype of ADHD.     

Dissecting the attention deficit hyperactivity disorder (ADHD) phenotype: sustained attention, response variability and spatial attentional asymmetries in relation to dopamine transporter (DAT1) genotype

ADHD is a childhood-onset behavioural disorder with a heterogeneous profile of neuropsychological impairment. Neuropsychological heterogeneity may, in part, reflect underlying genetic differences. Here we examined sustained attention, response variability and spatial attentional asymmetries in a sample of children and adolescents with ADHD (n=22) in relation to dopamine transporter genotype (DAT1) and also controls (n=20). Participants performed the sustained attention to response task (SART) (testing sustained attention and response variability) and the greyscales task (a perceptual measure of attentional bias). The latter has previously been shown to yield a robust leftward attentional asymmetry in healthy subjects. The 10-repeat allele of the DAT1 gene has been associated with ADHD in a number of studies and appears to have biological significance. The ADHD group was sub-divided into those individuals with two copies of the "high-risk" 10-repeat allele (high-risk DAT1) versus those with one or no copies of this allele (low-risk DAT1). The high-risk DAT1 ADHD group displayed greater response variability on the SART than either the low-risk DAT1 group or healthy controls, whereas the latter two groups did not differ. Further, the high-risk DAT1 group showed an attenuated spatial asymmetry, relative to the low-risk DAT1 ADHD group, who showed the typical leftward attentional asymmetry. Our results suggest that the 10-repeat DAT1 allele may mediate neuropsychological impairment in ADHD. The application of molecular genetics may help to define neuropsychological impaired subgroups of ADHD.     

注意力缺陷伴多动障碍的家系调查、执行功能及基因水平研究进展

注意力缺陷伴多动障碍（ADHD）的确切病因还不十分清楚,已有证据表明是一种遗传异质性疾病,由遗传和环境因素共同作用造成,本文综述了ADHD的遗传家系研究及执行功能和基因研究的进展。     

Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia

OBJECTIVE: To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. SUBJECTS AND METHODS: 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. RESULTS: Both groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms (p=0.018, not significant after a Bonferroni correction). The 5-HT2A -1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p=0.028, OR=1.39 (95% CI=1.11-1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect (chi(2) (3)=11.51, p=0.009), whereby the combination of -1438A and 5-HTTLPR S alleles was associated with schizophrenia. CONCLUSIONS: Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia.     

No association between catechol-O-methyltransferase (COMT) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children

Objective: This study ascertained the association between attention deficit/hyperactivity disorder (ADHD) in Japanese children and a polymorphism of catechol-O-methyltransferase (COMT), a dopamine-control gene. The secondary aim of the study was the evaluation of a putative association between methylphenidate (MPH) effect/adverse effects and the COMT genotype. Methods: To ascertain the distribution of the Val158Met variant of COMT, 50 children meeting ADHD inclusion criteria were compared with 32 healthy children. Clinical improvement and the occurrence of adverse effects were measured before and 3 months after MPH administration in children with ADHD, and analyzed for genotype association. Wechsler Intelligence Scale for Children-Third Edition (WISC-III), age, MPH dose were included as co-variables. Results: The occurrence of the COMT Val/Val genotype was significantly higher in children with ADHD (χ²(1) = 7.13, p < 0.01). However, there was no significant difference in the Val/Val genotype according to disorder, and WISC and ADHD rating scale scores, after correcting for the interaction between disorder and COMT genotype. Furthermore, no significant difference in MPH effect/adverse effects was observed in association with the COMT genotype in the ADHD group. Conclusions: These results showed a lack of association between the COMT Val/Val genotype and ADHD in Japan.     

儿童品行问题与注意缺陷多动行为问题相互关系的双生子研究

目的 研究遗传因素、共享环境因素和非共享环境因素在儿童注意缺陷多动行为问题和品行问题相互关系中的作用.方法 采用困难和长处量表中的父母评定的注意缺陷多动(HYPER)和品行问题(CONO)分量表分作为定量表型,对西南双生子库中的140对双生子,采用表型的单因素和二因素结构方程模型,基于模型的似然值和拟合度寻找最优模型,分析遗传因素和环境因素的影响.结果 (1)同卵双生子注意缺陷多动行为问题与品行问题的相关性(r=0.55)明显高于异卵双生子(r=0.12);(2)注意缺陷多动行为问题与品行问题的表型相关性为0.44(P=0.00);(3)儿童注意缺陷多动行为问题与品行问题的相关性主要由遗传因素导致,遗传因素在品行问题与注意缺陷多动行为问题表型相关性中的贡献占70%,非共享环境因素占30%.结论 遗传因素对注意缺陷多动行为问题和品行问题的发生具有重要作用,遗传因素包括单纯影响注意缺陷多动行为问题的遗传因素、单纯影响品行障碍的遗传因素和对二者同时发生作用的遗传因素.大部分作用于注意缺陷多动行为问题的环境因素不会导致品行问题的发生.     

Identification of attention-deficit-hyperactivity disorder and conduct disorder in Mexican children by the scale for evaluation of deficit of attention and hyperactivity

The objective was weighing the usefulness of a Spanish-language Scale for the evaluation of deficit of attention and hyperactivity (EDAH) to identify children with attention deficit-hyperactivity disorder (AD-HD) and conduct disorder (CD) in a sample of school-aged children. We studied 132 children from a government-run public elementary school previously selected by teachers as having learning and attention disorders. We screened children of the sample with parents’ and teachers’ EDAH and Diagnostic and Statistical Manual of Mental Disorders-IV edition Text Revision (DSM-IV-TR) questionnaires, and performed an interdisciplinary clinical examination for the final diagnosis. We found 81 children with AD-HD and 51 children without AD-HD. AD-HD was classified as follows: AD-HD-combined (-C), n = 32; AD-HD-inattentive (-I), n = 17 and AD-HD-hyperactive (-H), n = 32. Cronbach's alpha calculation for the EDAH parents’ questionnaire was 0.76, and for teachers, 0.80. Sensitivity of the teachers’ EDAH questionnaire was 0.94, and specificity, 0.91. Sensitivity of the parents’ EDAH questionnaire was 0.91, while specificity was 0.87. The data of EDAH parents’ and teachers’ questionnaires have a concordance of 93.1% and 80%, respectively. The correlation of scores among parents’ and teachers’ EDAH scales was significant. The correlation between results from parents’ and teachers’ DSM-IV-TR and EDAH questionnaires was also significant. Our results partially support the use of EDAH questionnaires for AD-HD and CD screening in Spanish-speaking populations.     

Objective measurement of weekly physical activity and sensory modulation problems in children with attention deficit hyperactivity disorder

This study aimed to objectively compare the daily physical activity (PA), as indicated by moderate-to-vigorous physical activity (MVPA) during a week and metabolic equivalents (METs) per minute, between children with attention deficit hyperactivity disorder (ADHD) and typically developing children. Moreover, sensory modulation problems were examined using behavioral and physiological measures. Twenty boys with ADHD (mean age 8.64 ± 2.57 years), and 20 matched typically developing boys (mean age 9.10 ± 1.79 years) participated in our study. Each child wore a PA monitor for 14 h a day, seven days a week. All participants’ parents were asked to fill out daily activity logs for their children. The problems of sensory modulation were detected using sensory profile (SP) questionnaires and Sensory Challenge Protocol that measured electrodermal response (EDR) to repeated sensory stimulation. Compared with the controls, the children with ADHD had a generally higher level of PA (1.48 ± 0.10 vs. 1.60 ± 0.12 METs/min; p = 001), and tended to spend more time in MVPA on weekdays (35.71%) and the weekend (57.14%). However, when analyzing hourly recorded PA, the group differences were obvious only for certain hours. Our data suggested that children with ADHD were more hyperactive in structure-free than structured settings. The ADHD group showed their sensory modulation problems on the SP but not on the EDR. We found some correlations between sensory modulation problems and hyperactivity in children with ADHD.     

Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene

BACKGROUND: Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive-compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. METHODS: The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. RESULTS: Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. CONCLUSIONS: Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD.     

Genetic influences of dopamine transport gene on alcohol dependence: a pooled analysis of 13 studies with 2483 cases and 1753 controls

Previous genetic association studies have reported a possible role of the dopamine transporter (DAT, gene symbol: SLC6A3) gene in the etiology of alcohol dependence, but the results were conflicting with each other. We conducted a pooled analysis of published population-based case-control genetic studies investigating associations between polymorphisms in SLC6A3 and alcohol dependence. We also explored whether geographic area, ethnicity, gender, and diagnostic criteria moderated any association by using stratified analysis. Through combining 13 studies with 2483 cases and 1753 controls, the 40-base pair variable number tandem repeat (VNTR) in the 3′ un-translated region, the well studied polymorphism in SLC6A3, did not show any association with alcohol dependence in general or in stratified analyses according to geographic area, ethnicity, gender, and diagnostic criteria. Due to limited studies focused on polymorphisms in other regions of the SLC6A3 gene, we cannot rule out the role of the SLC6A3 gene in the involvement of the genetic risk of alcohol dependence. Further clarification of the genetic role of SLC6A3 in the susceptibility to alcohol dependence should be centered on other potential functional regions of the SLC6A3 gene.     

A transmission disequilibrium test of the Ser9/Gly dopamine D3 receptor gene polymorphism in adult attention-deficit hyperactivity disorder

Convincing data support the hypothesis that genetic factors are involved in the etiology of attention-deficit hyperactivity disorder (ADHD). Various lines of evidence have shown that the dopamine system plays a crucial role in the pathophysiology of ADHD. The dopamine D3 receptor gene (DRD3) represents a promising candidate to examine in ADHD. Animal studies have shown that DRD3 mRNA is highly expressed in the ventral striatum suggesting an involvement of this receptor in the control of motor behaviour. Manipulation of DRD3 in rodents has led to a mouse model with nonfunctional D3 receptors that displays hyperactive behaviour in various environmental conditions. Furthermore, administration of 7-OH-DPAT, a dopaminergic agonist that binds preferentially to D3 receptors exerts an inhibitory effect on locomotor activity while D3 antagonists induce hyperactivity. Among various polymorphisms described for DRD3, the BalI polymorphism is most interesting because it codes for an aminoacid substitution in the N-terminus of the receptor. The receptor products of the two alleles (Ser/Gly) exhibit differential affinity for dopamine. To determine if DRD3 Ser9/Gly is involved in the susceptibility to ADHD we genotyped 39 adults with ADHD and their respective parents (trios). Adult ADHD represents a promising phenotype for studying the genetic component of the disorder. In fact, a recent family study has shown that relatives of adult ADHD patients have a higher rate of ADHD compared to relatives of children with ADHD suggesting a stronger genetic component for the adult version. The results of genotyping in the 39 trios analyzed with the transmission disequilibrium test showed no excess of transmission for DRD3 MscI/BalI alleles (χ²=0.360; DF=1; P=0.54). This result, although from a relatively small sample, indicates that it is unlikely that DRD3 is playing a major role in the etiology of ADHD in our sample.