Family-genetic study of executive functioning in attention-deficit/hyperactivity disorder: Evidence for an endophenotype? (original) (raw)
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Familial Clustering of Executive Functioning in Affected Sibling Pair Families With ADHD
Journal of the American Academy of Child & Adolescent Psychiatry, 2005
Objective: To investigate familial clustering of executive functioning (i.e., response inhibition, fine visuomotor functioning, and attentional control) in attention-deficit/hyperactivity disorder (ADHD)-affected sibling pairs. Method: Fifty-two affected sibling pairs aged 6 to 18 years and diagnosed with ADHD according to DSM-IV performed the Stroop test, go/no-go task, two different fine visuomotor tracking tasks, and a sustained-, divided-, and focused attention task. Results: Significant correlations (r = 0.4) were found between siblings for response inhibition and attentional control and for fine visuomotor skills that made high demands on executive functioning. Conclusions: Response inhibition, higher order controlled fine visuomotor functioning, and attentional control seem to cluster in ADHD-affected siblings. This suggests that these aspects of executive dysfunctioning may reflect an endophenotype of ADHD. Measurement of these executive functions may facilitate the identification of genes involved in ADHD by forming more homogeneous subgroups. J. Am. Acad. Child Adolesc.
Archives of general psychiatry, 2010
Context Attention deficit hyperactivity disorder (ADHD) is associated with widespread cognitive impairments, but it is not known whether the apparent multiple impairments share etiological roots, or whether separate etiological pathways exist. A better understanding of the etiological pathways is important for the development of targeted interventions and for identification of suitable intermediate phenotypes for molecular genetic investigations. Objective To determine, using a multivariate familial factor analysis approach, whether one or more familial factors underlie the slow and variable reaction times (RTs), impaired response inhibition, sustained attention, and choice impulsivity that are associated with ADHD. Design An ADHD and control sibling-pair design. Setting Belgium, Germany, Ireland, Israel, Spain, Switzerland and the United Kingdom. Participants The sample consisted of 1265 participants, aged 6 to 18 years: 464 probands with ADHD and 456 of their siblings (524 with ADHD combined subtype), and 345 control participants. Main Outcome Measures Performance on a four-choice RT task, a go/no-go inhibition task and a choice-delay task. Results The final model consisted of two familial factors. The larger factor, reflecting 85% of the familial variance of ADHD, captured 98-100% of the familial influences on mean RT and RT variability. The second smaller factor, reflecting 12.5% of the familial variance of ADHD, captured 62-82% of the familial influences on commission and omission errors on the go/no-go task. Choice impulsivity was excluded in the final model, due to poor fit. Conclusions The findings suggest the existence of two familial pathways to cognitive impairments in ADHD and indicate promising cognitive targets for future molecular genetic investigations. The familial distinction between the two cognitive impairments is consistent with recent theoretical models -a developmental model and an arousal-attention model -on two separable underlying processes in ADHD. Future research that tests the familial model within a developmental framework may inform developmentally-sensitive interventions.
Psychological Medicine, 2012
Background. Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions from preparation to response control in ADHD. Method. Preparation and response control were assessed using behavioural and electrophysiological parameters of two versions of a cued continuous performance test with varying attentional load in boys with ADHD combined type (n=97), their non-affected siblings (n=27) and control children without a family history of ADHD (n=43). Results. Children with ADHD and non-affected siblings showed more variable performance and made more omission errors than controls. The preparatory Cue-P3 and contingent negative variation (CNV) following cues were reduced in both ADHD children and their non-affected siblings compared with controls. The NoGo-P3 was diminished in ADHD compared with controls whilst non-affected siblings were located intermediate but did not differ from both other groups. No clear familiality effects were found for the Go-P3. Better task performance was further associated with higher CNV and P3 amplitudes. Conclusions. Impairments in performance and electrophysiological parameters reflecting preparatory processes and to some extend also for inhibitory response control, especially under high attentional load, appeared to be familially driven in ADHD and may thus constitute functionally relevant endophenotypes for the disorder.
Executive Functioning in Subtypes of Attention Deficit Hyperactivity
Noropsikiyatri Arsivi-archives of Neuropsychiatry, 2015
Introduction: This study aims to evaluate executive functions (EF), such as inhibition, planning, working memory, and set shifting, in children with attention deficit hyperactivity disorder (ADHD) by comparing three ADHD subtype groups (ADHD-Inattentive, ADHD-Combined, and ADHD-Comorbid) and a normal control group. Methods: Participants included 147 children. In total, 111 children were assigned to the ADHD groups of the study. Each child was matched according to the WISC-R Full-Scale IQ-score, sex, and age and was grouped as follows: ADHD-Inattentive group (ADHD-I; n=37), ADHD-Combined (ADHD-C; n=37), ADHD-Comorbid group (ADHD-Comorbid with oppositional defiant disorder and/or conduct disorder; n=37), and control group (n=36). The tests used to assess the children were Conners' Parent and Teacher Rating Scales; Wechsler Intelligence Scale-Revised; Tower of London test; Wisconsin Card Sorting Test; Stroop Color-Word Test, and verbal fluency test. The data were analyzed by one-way ANOVA between subjects for all dependent variables. Results: Children in the ADHD-I group had significantly better performances in verbal working memory and verbal category shifting than children in the ADHD-C group. There was no significant difference between the ADHD-I and ADHD-C groups in terms of inhibition, set shifting, verbal fluency, cognitive flexibility, and planning. The ADHD-Comorbid group displayed more severe impairments in EF measures than the ADHD-C group; however, the severity was not statistically significant. EF performances of children in the control group were similar to children in the ADHD-I group but better than children in the ADHD-C and ADHD-Comorbid groups. Conclusion: The outcome of the study indicated that subjects in the ADHD-Comorbid and ADHD-C groups had more severe EF deficits than subjects in the ADHD-I and control groups.
Cognitive functioning in affected sibling pairs with ADHD: familial clustering and dopamine genes
Journal of Child Psychology and Psychiatry, 2008
Background: This paper examines familiality and candidate gene associations of cognitive measures as potential endophenotypes in attention-deficit/hyperactivity disorder (ADHD). Methods: The sample consists of 540 participants, aged 6 to 18, who were diagnosed with ADHD from 251 families recruited for a larger genetic study of ADHD. All members of the family underwent psychiatric interviews and children were administered a large battery of cognitive tasks. Subjects were genotyped for several dopaminergic candidate genes (DAT1, DRD4, and DRD5). Results: Performance on measures of intelligence, working memory, and set-shifting had the highest sibling correlations and exhibited significant familial clustering. The 7-repeat allele of the dopamine receptor D4 (DRD4) gene was associated with poor performance on measures of intelligence, color naming, interference control, and working memory. There were no significant associations with DAT1 and DRD5. Conclusions: Sibling correlations, familial clustering and candidate gene associations provide strong support for verbal working memory as a candidate endophenotype for ADHD. More complex models of, and larger sample sizes for, genetic association with cognitive functions are encouraged for future study.
American Journal of Psychiatry, 2005
Method: ADHD-concordant pairs (21 probands and their affected siblings), ADHD-discordant pairs (18 probands and their nonaffected siblings), and a group of unrelated, demographically balanced, healthy individuals (N=24) were compared on measures of response inhibition, ADHD behavior, impairment, and environmental risk. Results: Concordant-pair probands, their affected siblings, and discordant-pair probands exhibited inhibitory control impairment relative to healthy comparison subjects. The performance of nonaffected siblings was intermediate between that of ADHD children and the healthy comparison subjects. Group differences persisted after age was controlled, and performance was not correlated with the number of ADHD symptoms. In ADHD-concordant sibling pairs, there was a significant relationship between proband and sibling inhibition deficit. In ADHD-discordant sibling pairs, inhibition deficit was evident in half of the no naf fected s iblin gs o f probands with an inhibition deficit. Groups did not differ in exposure to environmental risks. Conclusions: Impaired inhibitory control aggregates in the family members of individuals with ADHD and may serve as an indicator of genetic vulnerability to the disorder.
Executive function as an ADHD endophenotype
In an ever-changing world, a vital skill for survival is the preparation of possible actions, the monitoring of a selected action and the termination of an inappropriate action. Therefore, preparation, selection, monitoring and inhibition are all core aspects of executive function; they are also some of the key deficits in attention deficit hyperactivity disorder (ADHD).
Familiality and molecular genetics of attention networks in ADHD
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2009
Indices from a more elementary neuropsychological level might be useful in the search for genes for complex psychiatric disorders, such as ADHD. In this study we investigated systematically whether attentional performance as measured with the Attention Network Test (ANT) is suited for the identification of endophenotypes of ADHD. Attentional performance in affected sib pairs with ADHD (n ¼ 181) was compared to unaffected control siblings (n ¼ 121). Intrafamilial correlation patterns were calculated. In addition, linkage and association analyses were conducted between quantitative scores of attentional functions and dopamine receptor D4 (DRD4) and dopamine transporter (DAT1 or SLC6A3) gene variants. Only the executive attention network was significantly impaired in subjects with ADHD compared to controls (P < 0.05) and showed evidence for familiality in both affected and unaffected families. Linkage analyses revealed the highest LOD score for a severity score based on DSM-IV inattentive symptoms in the DAT1 chromosomal region (LOD score 2.6 at 15 cM). However, a SNP (rs6350) at the DAT1 locus showed a tendency for association with both alerting performance (P ¼ 0.02) and executive attention (P ¼ 0.01) although it did not survive alpha adjustment for multiple testing. No evidence was found for association of any of the investigated phenotypes with the VNTR in the DRD4. Thus, our data suggest that the quantitative behavioral ratings of inattentive symptoms might be more useful when searching for new genes associated with ADHD, however, among the ANT measures the executive attention network seems to be best suited for further endophenotype analyses.
Attention-Deficit/Hyperactivity Disorder Endophenotypes
Biological Psychiatry, 2005
Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.