Association and linkage of DRD4 and DRD5 with attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children

The search for genetic factors predisposing to Attention Deficit Hyperactivity Disorder (ADHD) has focused on genes that regulate dopaminergic pathways such as dopamine receptors and enzymes that regulate levels of dopamine in the synapse. There have been several reports of association between ADHD and polymorphic variants within or near DRD4, DRD5, DAT1, DBH and COMT. In this study we set out to investigate specific alleles of DRD4 and DRD5, previously reported to be associated with ADHD, in a sample of Turkish children with DSM-IV ADHD children, as well as their relation to methylphenidate response and dimensional measures of symptom domains. One hundred and four independent trios and seven dyads were analysed using the transmission disequilibrium test (TDT). We found increased transmission of the DRD4 7-repeat allele (DRD4*7) (TDT chi2 = 2.79, P = 0.047). Given that we were testing specific a priori hypotheses regarding the associated alleles, we have used one-tailed P-values throughout. There was evidence of an interaction with methlyphenidate (MPH) response and analysis of the sample excluding non-responders revealed more significant evidence for the association (TDT chi2 = 4.48, P = 0.017). We also detected a trend for linkage and association in the DRD5 polymorphism (TDT chi2 = 2. 38, P = 0.06). Similar findings were obtained in relation to MPH response as analysis of MPH responders alone gave rise to a more significant association than that of the group as a whole (TDT chi2 = 4.9, P = 0.013). t-Test and logistic regression TDT analyses of DRD4*7 transmission with respect to dimensional rating scales of hyperactivity and impulsivity showed an inverse relation suggesting that in this sample DRD4*7 is associated with a lower level of ADHD symptomatology. While this may be due to stratification along a dimension of severity such that severe cases belong to a more extreme group with other specific genetic and environmental causes, similar to the model for low cognitive ability, it is more likely the result of a chance selection bias in this sample.     

The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder

The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.     

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。     

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.     

Bimanual coordination deficits in attention deficit/hyperactivity disorder (ADHD)

Although motor difficulties have been implicated in ADHD, studies investigating bimanual coordination have been few and their results inconsistent. This study examined the performance of 12 boys with ADHD combined type and their matched controls on a simple in-phase bimanual movement task (requiring symmetrical hand movements) and a complex out-of-phase bimanual movement task (requiring asymmetrical hand movements), at different designated speeds (1 and 2 Hz). Compared to controls, ADHD children were significantly more variable in both velocity and coordination, and less accurate in coordination, with the in-phase movements. For out-of-phase movements, the ADHD children were significantly more variable in velocity and coordination. These findings suggest a problem of bimanual coordination in the syndrome.     

Investigation of the G protein subunit Galphaolf gene (GNAL) in attention deficit/hyperactivity disorder

The dopamine system plays an important role in the regulation of attention and motor behavior, subsequently, several dopamine-related genes have been associated with Attention Deficit/Hyperactivity Disorder (ADHD). Among them are the dopamine receptors D1 and D5 that mediate adenylyl cyclase activation through coupling with G(s)-like proteins. We thus hypothesized that the G(s)-like subunit Galpha(olf), expressed in D1-rich areas of the brain, contributes to the genetic susceptibility of ADHD. To evaluate the involvement of the Galpha(olf) gene, GNAL, in ADHD, we examined the inheritance pattern of 12 GNAL polymorphisms in 258 nuclear families ascertained through a proband with ADHD (311 affected children) using the transmission/disequilibrium test (TDT). Categorical analysis of individual marker alleles demonstrated biased transmission of one polymorphism in GNAL intron 3 (rs2161961; P=0.011). We also observed significant relationships between rs2161961 and dimensional symptoms of inattention and hyperactivity/impulsivity (P=0.003 and P=0.008). In addition, because of recent evidence of imprinting at the GNAL locus, secondary analyses were split into maternal and paternal transmissions to assess a contribution of parental effects. We found evidence of strong maternal effect, with preferential transmission of maternal alleles for rs2161961A (P=0.005) and rs8098539A (P=0.035). These preliminary findings suggest a possible contribution of GNAL in the susceptibility to ADHD, with possible involvement of parent-of-origin effects.     

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。     

药物假日与注意缺陷/多动障碍(英文)

The concept of ' drug holidays' ( defined as the structured interruption of pharmacological treatment[1] ) in the management of attention deficit hyperactivity disorder ( ADHD) is well established,but poorly researched[1] . The question is whether there is indeed a justifiable basis for the practice. In the opinion piece by Professors Du and Wang[2] ,they argue that on the balance of available evidence it is not justified. Herein lies the issue—the evidence. In reality significant numbers     

Sustained attention in sensory modulation disorder and attention deficit/hyperactivity disorder

BackgroundThere are high comorbidity rates between sensory modulation disorder (SMD) and attention deficit hyperactivity disorder (ADHD). Knowledge regarding the objective neuropsychological differentiation between them is scarce.AimThis study examines the effects of SMD and ADHD on a sustained attention task with and without aversive auditory conditions.MethodSixty six young adult females were tested on the Conjunctive - Continuous Performance Task-Visual (CCPT-V) measuring sustained attention, under two conditions: 1) aversive condition (with the three most aversive sounds chosen by the participant), and 2) non-aversive condition (without sounds).ResultsBoth the SMD and ADHD factors exhibited performance deficits in the sustained attention task. All study participants performed worse on both sustained attention and speed of processing when aversive sounds were present.ConclusionWe conclude that impaired sustained attention cannot differentiate between SMD and ADHD. Hence, these results should be taken under consideration in the assessment process of ADHD vs. SMD.     

Neurobiology of attention deficit hyperactivity disorder

This article addresses the current understanding of the neurobiological bases of attention deficit hyperactivity disorder (ADHD), focusing on empiric research findings that connect genetic and environmental factors to structural and functional brain abnormalities, ultimately leading to a set of age-dependent behavioral manifestations. Section one presents evidence for genetic risk factors for ADHD and discusses the role of potential environmental factors in the etiology of the disorder. Section two focuses on brain imaging studies and how they have helped generate different hypotheses regarding the pathophysiology of ADHD. Finally, the article addresses the longitudinal course of symptoms in ADHD from infancy to adulthood in an attempt to place biological findings for this complex brain disorder in the context of maturation and development.     

Genetics of attention deficit hyperactivity disorder

Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention deficit hyperactivity disorder (ADHD). Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. In contrast to a handful of genome-wide scans conducted thus far, many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effects. These small effects emphasize the need for future candidate gene studies to implement strategies that will provide enough statistical power to detect such small effects.     

Handwriting performance in children with attention deficit hyperactivity disorder (ADHD)

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral condition of childhood. Consequences are multifaceted and include activity limitations in daily-living skills, academic challenges, diminished socialization skills, and motor difficulties. Poor handwriting performance is an example of an affected life skill that has been anecdotally observed by educators and clinicians for this population and can negatively impact academic performance and self-esteem. To guide health and educational service delivery needs, the authors reviewed the evidence in the literature on handwriting difficulties in children with ADHD. Existing evidence would suggest that children with ADHD have impaired handwriting performance, characterized by illegible written material and/or inappropriate speed of execution compared to children without ADHD. Studies with larger sample sizes using standardized measures of handwriting performance are needed to evaluate the prevalence of the problem and to better understand the nature of handwriting difficulties and their impact in this population.     

Neuropsychiatric bases of the methylphenidate-therapy of the attention deficit/hyperactivity disorder (ADHD)

High prevalence and high co-morbidity rates with frequently aggravating psychosocial problems make the attention-deficit/hyperactivity disorder (ADHD) of children, adolescents and adults an important target for research and healthcare. Recent findings suggest a dopaminergic fronto-striatal information processing deficit in ADHD-patients (executive functions). This review summarizes and presents, in the context of recent studies (MRI, f-MRI, PET, SPECT, Mapping Genes) the neurobiochemical bases of the methylphenidate-therapy, clinically successfully applied since almost one half century by the ADHD. The increased striatal dopamine transporter density by the ADHD-methylphenidate-responder is reported as a scientifically sound and useful clinical working model.