Genome-Wide Analysis of Attention Deficit Hyperactivity Disorder in Norway

Background

Attention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci.

Materials and Methods

Participants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD.

Results

In total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28–1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21–1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14–1.66, p=8.31E-04).

Conclusion

This study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.     

Peridontitis as a Risk Factor for Attention Deficit Hyperactivity Disorder: Possible Neuro-inflammatory Mechanisms

Periodontitis is a condition caused mostly by the creation of a biofilm by the bacterium P. gingivalis, which releases toxins and damages the tooth structure. Recent research studies have reported association between dental health and neuropsychiatric illnesses. Neuroinflammation triggered by the first systemic inflammation caused by the bacterium present in the oral cavities is a plausible explanation for such a relationship. Substantial amount of evidence supports the role of neuroinflammation and dysfunction of the dopaminergic system in the pathology of ADHD (Attention deficit hyperactivity disorders). Recent epidemiological, microbiological and inflammatory findings strengthen that, periodontal bacteria, which cause systemic inflammation can contribute to neuroinflammation and finally ADHD. Although both diseases are characterized by inflammation, the specific pathways and crosslink’s between periodontitis and ADHD remain unknown. Here, the authors describe the inflammatory elements of periodontitis, how this dental illness causes systemic inflammation, and how this systemic inflammation contributes to deteriorating neuroinflammation in the evolution of ADHD. Therefore, the aim of this review is to present possible links and mechanisms that could confirm the evidence of this association.

     

Measurement of Stigmatization towards Adults with Attention Deficit Hyperactivity Disorder

Objectives

In general, assessment tools for stigma in mental disorders such as attention deficit hyperactivity disorder (ADHD) are lacking. Moreover, misbeliefs and misconceptions about ADHD are common, in particular with regard to the adult form of ADHD. The aim of the present study was to develop a questionnaire measuring stigma in adults with ADHD and to demonstrate its sensitivity.

Methods

A questionnaire initially containing 64 items associated with stigma in adults with ADHD was developed. A total number of 1261 respondents were included in the analyses. The psychometric properties were investigated on a sample of 1033 participants. The sensitivity of the questionnaire was explored on 228 participants consisting of teachers, physicians and control participants.

Results

Thirty-seven items were extracted due to exploratory factor analysis (EFA) and the internal consistency of items. Confirmatory factor analysis (CFA) revealed good psychometric properties of a 6-factor structure. Teachers and physicians differed significantly in their stigmatizing attitudes from control participants.

Conclusions

The present data shed light on various dimensions of stigma in adult ADHD. Reliability and Social Functioning, Malingering and Misuse of Medication, Ability to Take Responsibility, Norm-violating and Externalizing Behavior, Consequences of Diagnostic Disclosure and Etiology represent critical aspects associated with stigmatization.     

Response Inhibition Impairment in High Functioning Autism and Attention Deficit Hyperactivity Disorder: Evidence from Near-Infrared Spectroscopy Data

Background

Response inhibition, an important domain of executive function (EF), involves the ability to suppress irrelevant or interfering information and impulses. Previous studies have shown impairment of response inhibition in high functioning autism (HFA) and attention deficit hyperactivity disorder (ADHD), but more recent findings have been inconsistent. To date, almost no studies have been conducted using functional imaging techniques to directly compare inhibitory control between children with HFA and those with ADHD.

Method

Nineteen children with HFA, 16 age- and intelligence quotient (IQ)-matched children with ADHD, and 16 typically developing (TD) children were imaged using functional near-infrared spectroscopy (NIRS) while performing Go/No-go and Stroop tasks.

Results

Compared with the TD group, children in both the HFA and ADHD groups took more time to respond during the No-go blocks, with reaction time longest for HFA and shortest for TD. Children in the HFA and ADHD groups also made a greater number of reaction errors in the No-go blocks than those in the TD group. During the Stroop task, there were no significant differences between these three groups in reaction time and omission errors. Both the HFA and ADHD groups showed a higher level of inactivation in the right prefrontal cortex (PFC) during the No-go blocks, relative to the TD group. However, no significant differences were found between groups in the levels of oxyhemoglobin concentration in the PFC during the Stroop task.

Conclusion

Functional brain imaging using NIRS showed reduced activation in the right PFC in children with HFA or ADHD during an inhibition task, indicating that inhibitory dysfunction is a shared feature of both HFA and ADHD.     

注意缺陷多动障碍低觉醒模型的新证据

注意缺陷多动障碍（Attention Deficit Hyperactivity Disorder,ADHD）是儿童期常见的一种发展性的异常,其病因及发生机理至今未明。低觉醒模型是ADHD成因的一种假设。本文从睡眠障碍导致的低觉醒探讨ADHD发生机理。通过对ADHD儿童的睡眠障碍进行分析以及将ADHD外在表现与睡眠剥夺后的表现进行对比分析,得出ADHD儿童存在的低觉醒是由于外显的或内隐的睡眠障碍引起的,一方面间接证明了低觉醒模型,另一方面为ADHD的成因研究开拓了新的思路。     

注意缺陷多动障碍低觉醒模型的新证据

注意缺陷多动障碍(Attention Deficit Hyperactivity Disorder,ADHD)是儿童期常见的一种发展性的异常,其病因及发生机理至今未明。低觉醒模型是ADHD成因的一种假设。本文从睡眠障碍导致的低觉醒探讨ADHD发生机理。通过对ADHD儿童的睡眠障碍进行分析以及将ADHD外在表现与睡眠剥夺后的表现进行对比分析,得出ADHD儿童存在的低觉醒是由于外显的或内隐的睡眠障碍引起的,一方面间接证明了低觉醒模型,另一方面为ADHD的成因研究开拓了新的思路。     

Altered Biochemical Parameters in Saliva of Pediatric Attention Deficit Hyperactivity Disorder

Oxidative stress is one of the common causes in etiopathogenesis of attention deficit hyperactivity disorder (ADHD). Hence, the salivary levels of protein thiols, ceruloplasmin, magnesium and pseudocholinesterase were estimated in children with ADHD. The symptoms of ADHD were identified using Conner’s rating and DSM IV criteria. Saliva was collected and assessed for the levels of protein thiols, ceruloplasmin, magnesium and pseudocholinesterase, spectrophotometrically. It was also checked for pH and the flow rate was noted down. There was a significant increase (P < 0.001) in the salivary protein thiols and pseudocholinesterase levels in ADHD children when compared to controls. Ceruloplasmin levels did not show any significant change. Magnesium levels were significantly decreased (P < 0.001) in cases when compared to controls. Further, a receiver operating characteristic curve for validity of the biochemical parameters in saliva of ADHD children indicated a sensitivity and specificity above 90% for protein thiols and magnesium values. Our study shows that protein thiols, magnesium, and pseudocholinesterase might have a role in the pathogenesis of ADHD and saliva can be effectively used as a non-invasive tool for evaluation of such children.     

Neurofeedback: An Alternative and Efficacious Treatment for Attention Deficit Hyperactivity Disorder

Current research has shown that neurofeedback, or EEG biofeedback as it is sometimes called, is a viable alternative treatment for Attention Deficit Hyperactivity Disorder (ADHD). The aim of this article is to illustrate current treatment modalities(s), compare them to neurofeedback, and present the benefits of utilizing this method of treatment to control and potentially alleviate the symptoms of ADHD. In addition, this article examines the prevalence rates and possible etiology of ADHD, the factors associated with ADHD and brain dysfunction, the current pharmacological treatments of ADHD, Ritalin, and the potential risks and side effects. Behavior modification and cognitive behavioral treatment for ADHD is discussed as well. Lastly, a brief history of the study of neurofeedback, treatment successes and clinical benefits, comparisons to medication, and limitations are presented.     

脑源性神经营养因子基因多态性与注意缺陷多动障碍的关联性研究

目的：探讨脑源性神经营养因子（Brain-derivedneurotrophicfactor,BDNF）G196A、C270T及Val66Met3个单核苷酸多态性（SNP）位点与注意缺陷多动障碍（ADHD）的关系。方法：选取无亲缘关系的ADHD患者共114例,健康对照共96例。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测G196A、C270T和Val66Met3个多态性位点的多态性,采用HaploView4.0及SPSS13.0软件进行连锁不平衡分析并比较两组基因型分布和等位基因频率。结果：BDNF三个多态性位点基因型及等位基因频率分布均符合Hardy-Weinberg定律。ADHD组G196A和C270T多态性位点分布与正常对照组比较差异无统计学意义,而BDNF基因Val66Met位点的基因型及等位基因频率分布在ADHD组与对照组存在显著性差异（p〈0.05）,ADHD组Val66Met位点的等位基因G（Val）频率显著高于正常对照组。结论：BDNF基因Val66Met多态性可能与ADHD发病有关,携带有Val66Met多态性位点G等位基因的个体可能更容易产生ADHD。     

The relationship between central fatigue and Attention Deficit/Hyperactivity Disorder of the inattentive type

Neurochemical Research - Chronic fatigue and central fatigue with malaise significantly impair quality of life. Inattention caused by central fatigue is closely related to attention...     

脑源性神经营养因子基因多态性与注意缺陷多动障碍的关联性研究

目的:探讨脑源性神经营养因子(Brain-derivedneurotrophicfactor,BDNF)G196A、C270T及Val66Met3个单核苷酸多态性(SNP)位点与注意缺陷多动障碍(ADHD)的关系。方法:选取无亲缘关系的ADHD患者共114例,健康对照共96例。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测G196A、C270T和Val66Met3个多态性位点的多态性,采用HaploView4.0及SPSS13.0软件进行连锁不平衡分析并比较两组基因型分布和等位基因频率。结果:BDNF三个多态性位点基因型及等位基因频率分布均符合Hardy-Weinberg定律。ADHD组G196A和C270T多态性位点分布与正常对照组比较差异无统计学意义,而BDNF基因Val66Met位点的基因型及等位基因频率分布在ADHD组与对照组存在显著性差异(p<0.05),ADHD组Val66Met位点的等位基因G(Val)频率显著高于正常对照组。结论:BDNF基因Val66Met多态性可能与ADHD发病有关,携带有Val66Met多态性位点G等位基因的个体可能更容易产生ADHD。     

Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder

It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen’s flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand ¹¹C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.     

Role of SNAP25 Explored in Eastern Indian Attention Deficit Hyperactivity Disorder Probands

Synaptosomal-associated protein 25 (SNAP25) is an essential component for synaptic vesicle mediated release of neurotransmitters. Deficiencies or abnormal structure or function of SNAP25 protein, possibly arising through genetic variations in the relevant DNA code, has been suggested to play role in the pathology of several neurobehavioural disorders including Attention deficit Hyperactivity Disorder (ADHD) and a number of polymorphisms in the SNAP25 gene has been studied for association with the disorder. In the present investigation, for the first time association between ADHD and six SNAP25 polymorphisms, rs1889189, rs362569, rs362988, rs3746544, rs1051312, and rs8636 was explored in eastern Indian population. Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders-IV. Genomic DNA isolated from peripheral blood leukocytes of ADHD probands (n = 150), their parents (n = 272) and ethnically matched controls (n = 100) was used for amplifying target sites. Data obtained were subjected to population- as well as family-based analyses. While case–control analysis revealed lack of any significant difference for alleles, family-based studies revealed a mild over transmission rs3746544 ‘T’ and rs8636 ‘C’ alleles (P = 0.05 and 0.03 respectively). Haplotypes formed between rs362569 “T”, 362988 “G”, rs3746544 “T”, rs1051312 “T” and rs8636 “C” in different combinations showed statistically significant transmission to ADHD probands. Excepting rs3746544 and rs8636, all the tested sites showed very low linkage disequilibrium between them. Data obtained in this preliminary study indicates that rs3746544 ‘T’ allele may have some role in the disease etiology in the studied Indian population.     

多巴胺D1受体基因多态性与注意缺陷多动障碍的相关性研究

目的:探讨多巴胺D1受体(Dopamine D1 receptor, DRD1)基因启动子区G-48A、外显子区T1403C两个SNP位点与注意缺陷多动障碍(attention deficit hyperactivity disorder,ADHD)的关联性.方法:选取87名ADHD患者和103名正常对照,提取基因组DNA,采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测G-48A和T1403C两个多态性位点的基因型,SPSS13.0软件分析各位点的等位基因及基因型频率.结果:DRD1的G-48A基因型及等位基因频率分布在ADHD和对照组之间有统计学差异(p<0.05),ADHD组中等位基因A频率显著高于正常组(p<0.05).T1403C位点基因型及等位基因频率在ADHD组与健康对照组无统计学差异.结论:DRD1基因G-48A多态性可能与ADHD的发病有关,携带有等位基因A的个体可能更容易患ADHD.T1403C多态性与ADHD的发病无明显相关性.     

Association Between Adult Attention Deficit/Hyperactivity Disorder and Obesity in the US Population

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects ～2.9–4.7% of US adults. Studies have revealed high rates of ADHD (26–61%) in patients seeking weight loss treatment suggesting an association between ADHD and obesity. The objective of the present study was to test the association between ADHD and overweight and obesity in the US population. Cross‐sectional data from the Collaborative Psychiatric Epidemiology Surveys were used. Participants were 6,735 US residents (63.9% white; 51.6% female) aged 18–44 years. A retrospective assessment of childhood ADHD and a self‐report assessment of adult ADHD were administered. Diagnosis was defined by three categories: never met diagnostic criteria, met full childhood criteria with no current symptoms, and met full childhood criteria with current symptoms. The prevalence of overweight and obesity was 33.9 and 29.4%, respectively, among adults with ADHD, and 28.8 and 21.6%, respectively, among persons with no history of ADHD. Adult ADHD was associated with greater likelihood of overweight, (odds ratio (OR) = 1.58; 95% confidence interval (CI) = 1.05, 2.38) and obesity (OR = 1.81; 95% CI = 1.14, 2.64). Results were similar when adjusting for demographic characteristics and depression. Mediation analyses suggest that binge eating disorder (BED), but not depression, partially mediates the associations between ADHD and both overweight and obesity. Results suggest that adult ADHD is associated with overweight and obesity.     

Attentional Control and Subjective Executive Function in Treatment-Naive Adults with Attention Deficit Hyperactivity Disorder

We investigated performance-derived measures of executive control, and their relationship with self- and informant reported executive functions in everyday life, in treatment-naive adults with newly diagnosed Attention Deficit Hyperactivity Disorder (ADHD; n = 36) and in healthy controls (n = 35). Sustained attentional control and response inhibition were examined with the Test of Variables of Attention (T.O.V.A.). Delayed responses, increased reaction time variability, and higher omission error rate to Go signals in ADHD patients relative to controls indicated fluctuating levels of attention in the patients. Furthermore, an increment in NoGo commission errors when Go stimuli increased relative to NoGo stimuli suggests reduced inhibition of task-irrelevant stimuli in conditions demanding frequent responding. The ADHD group reported significantly more cognitive and behavioral executive problems than the control group on the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). There were overall not strong associations between task performance and ratings of everyday executive function. However, for the ADHD group, T.O.V.A. omission errors predicted self-reported difficulties on the Organization of Materials scale, and commission errors predicted informant reported difficulties on the same scale. Although ADHD patients endorsed more symptoms of depression and anxiety on the Achenbach System of Empirically Based Assessment (ASEBA) than controls, ASEBA scores were not significantly associated with T.O.V.A. performance scores. Altogether, the results indicate multifaceted alteration of attentional control in adult ADHD, and accompanying subjective difficulties with several aspects of executive function in everyday living. The relationships between the two sets of data were modest, indicating that the measures represent non-redundant features of adult ADHD.     

Gap Effect Abnormalities during a Visually Guided Pro-Saccade Task in Children with Attention Deficit Hyperactivity Disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that starts in early childhood and has a comprehensive impact on psychosocial activity and education as well as general health across the lifespan. Despite its prevalence, the current diagnostic criteria for ADHD are debated. Saccadic eye movements are easy to quantify and may be a quantitative biomarker for a wide variety of neurological and psychiatric disorders, including ADHD. The goal of this study was to examine whether children with ADHD exhibit abnormalities during a visually guided pro-saccadic eye-movement and to clarify the neurophysiological mechanisms associated with their behavioral impairments. Thirty-seven children with ADHD (aged 5–11 years) and 88 typically developing (TD) children (aged 5–11 years) were asked to perform a simple saccadic eye-movement task in which step and gap conditions were randomly interleaved. We evaluated the gap effect, which is the difference in the reaction time between the two conditions. Children with ADHD had a significantly longer reaction time than TD children (p < 0.01) and the gap effect was markedly attenuated (p < 0.01). These results suggest that the measurement of saccadic eye movements may provide a novel method for evaluating the behavioral symptoms and clinical features of ADHD, and that the gap effect is a potential biomarker for the diagnosis of ADHD in early childhood.     

注意缺损多动障碍的X染色体基因组扫描分析

摘 要：注意缺损多动障碍（ADHD）是儿童期多见行为障碍。男孩发病多于女孩。家系、双生儿和寄养子研究显示该障碍发生具有遗传基础。但是病因尚不清楚。分子遗传学和药理学研究表明ADHD涉及到多巴胺和去甲肾上腺素等神经递质系统,一系列报告发现ADHD与多巴胺D4受体（DRD4）、多巴胺转运体（DAT1）和儿茶酚-O-甲基转移酶（COMT）等基因相关联。我们以往研究表明ADHD与X染色体上DXS7位点和MAOA基因相关联,而DXS7是紧密连锁于MAO基因。依此假设,我们应用基因组扫描技术探讨ADHD在X染色体上易感位点。采用TDT方法分析X染色体上48个DNA标志的多态性与中国人群中84个ADHD核心家系间的连锁关系,ADHD诊断依据DSM-III-R标准。TDT分析结果观察到如下位点与ADHD相连锁,DXS1214(TDT:χ2=18.1,df=7, P<0.01), DXS8102(TDT: χ2=7.9, df=3, P<0.05),DXS1068(TDT: χ2=21.9, df=9, P<0.01), DXS8015(TDT:χ2=14.6, df=7, P<0.05),DXS1059(TDT: χ2=27.8, df=10, P<0.01) 和DXS8088(TDT:χ2=20.4, df=3, P<0.01).研究资料提示X染色体上Xp11.4-Xp21和Xq23区域可能存在ADHD的易感基因。     

Decreased Coherent Motion Discrimination in Autism Spectrum Disorder: The Role of Attentional Zoom-Out Deficit

Autism spectrum disorder (ASD) has been associated with decreased coherent dot motion (CDM) performance, a task that measures magnocellular sensitivity as well as fronto-parietal attentional integration processing. In order to clarify the role of spatial attention in CDM tasks, we measured the perception of coherently moving dots displayed in the central or peripheral visual field in ASD and typically developing children. A dorsal-stream deficit in children with ASD should predict a generally poorer performance in both conditions. In our study, however, we show that in children with ASD, CDM perception was selectively impaired in the central condition. In addition, in the ASD group, CDM efficiency was correlated to the ability to zoom out the attentional focus. Importantly, autism symptoms severity was related to both the CDM and attentional zooming-out impairment. These findings suggest that a dysfunction in the attentional network might help to explain decreased CDM discrimination as well as the “core” social cognition deficits of ASD.