Association of DRD4 in children with ADHD and comorbid conduct problems

Holmes, Jane; Payton, Antony; Barrett, Jennifer; Harrington, Richard; McGuffin, Peter; Ollier, William; Worthington, Jane; Gill, Michael; Kirley, Aiveen; Hawi, Ziarih; Fitzgerald, Michael; Asherson, Philip; Curran, Sarah; Mill, Jonathan; Gould, Alison L.; Taylor, Eric; Kent, Lindsey; Craddock, Nicholas John; Thapar, Anita

doi:10.1002/ajmg.10149

Cited by 95 publications

(74 citation statements)

References 27 publications

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“…However, as all Ôcases' met diagnostic criteria for ADHD at baseline, they also all had high ADHD symptom counts in childhood (at baseline). Therefore, the range for the number of symptoms was restricted (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). By adolescence, the variation in symptom scores was much greater (range 0-18).…”

Section: Discussionmentioning

confidence: 99%

“…To improve the accuracy of retrospective phenotypic measurement, participants who had been taking stimulant medication for more than a year were excluded. More detail on the original crosssectional study and its findings can be found in Holmes et al [18], Langley et al [21] and Whittinger et al [37]. The baseline genetic data have since been expanded due to additional genotyping.…”

Section: Methodsmentioning

confidence: 99%

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Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder

Langley

Fowler

Grady

et al. 2008

Eur Child Adolesc Psychiatry

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Objective: The developmental trajectory of attention-deficit hyperactivity disorder (ADHD) is variable. Utilizing a longitudinally assessed sample, we investigated the contribution of susceptibility gene variants, previously implicated through pooled or meta-analyses, to the developmental course of Attention-Deficit Hyperactivity Disorder over time. Methods: 151 children (aged 6–12) who met diagnostic criteria for ADHD were assessed using research diagnostic interviews during childhood and 5 years later in adolescence. Severity was defined as total number of ADHD symptoms at baseline and reassessment. Association with variants at DRD4, DRD5, and the dopamine transporter gene, DAT was analyzed using linear regression. Results: As expected, affected individuals showed a decline in ADHD severity over time. The DRD4 48 bp VNTR 7-repeat and DRD5 CA(n) microsatellite marker 148 bp risk alleles were associated with persistent ADHD. Those possessing the DRD4 7 repeat risk allele showed less of a decline in severity at reassessment than those without the risk allele. Conclusions: Those carrying the DRD4 7 risk allele showed greater symptom severity at follow-up and less ADHD reduction over time. These findings support the hypothesis that some susceptibility genes for ADHD also influence its developmental course

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder

Langley

Fowler

Grady

et al. 2008

Eur Child Adolesc Psychiatry

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“…Faraone (2000) 16 has suggested that ADHD with conduct disorder may represent a sub-type with increased familial loading and this has been supported by recent twin evidence. 22 Holmes et al 23 combined all the UK and Irish studies looking at children with ADHD and conduct disorder symptoms. Despite previous findings of a lack of an association between DRD4 7 repeat allele and ADHD using the TDT, for 67 children who fulfilled diagnostic criteria for ADHD and displayed conduct disorder symptoms, evidence of an association between DRD4 and ADHD with 'conduct problems' was found (7 repeat allele-24 transmissions, 13 non-transmissions; P = 0.05).…”

Section: Discussionmentioning

confidence: 99%

Evidence to suggest biased phenotypes in children with Attention Deficit Hyperactivity Disorder from completely ascertained trios

et al. 2002

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The transmission disequilibrium test (TDT) is widely used as a robust statistical method to test for genetic association due to linkage based upon analysis of parent-proband trios. The TDT and other family-based tests (eg haplotype relative risk method) are commonly used in association studies including those of ADHD because of concerns that the case-control design has a strong tendency for false positives due to poor matching between cases and controls. Unfortunately, it is not always possible to obtain DNA from both parents in studies of this design, even where the onset of disorder is in childhood, and usually the missing parent is the father. Despite the fact that methods exist for analysis where one parent is missing, many family-based studies are based on the collection or analysis of complete trios only. However this selection process might potentially introduce bias, particularly for studies of behavioural phenotypes like ADHD because the phenotype of proband or parents might influence family stability and therefore complete parental ascertainment. We set out to examine whether children with ADHD and for whom DNA samples from fathers were missing ('duos') differed phenotypically from children for whom genotype information was available from both parents ('trios'). Children from duos showed a significantly higher frequency of DMS-IV ADHDcombined type, significantly more co-morbid conduct disorder and conduct disorder symptoms, and a trend for higher total ADHD symptom scores. Excluding duos from sample collection and analysis may result in systematic bias. If comorbid conduct disorder and ADHDcombined type index increased genetic liability, exclusion of duos could further reduce the power of the TDT (and similar tests) to detect susceptibility genes for ADHD, or replicate effects detected by case-control analysis. Molecular Psychiatry (2002) 7, 962-966.

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“…In a joint analysis of data from the UK and Eire, the subgroup of ADHD with CD was significantly associated with the DRD4 7 repeat allele, 46 whereas association was not detected in the full ADHD sample. That this is a genuine rather than chance finding is supported by similar observations in a follow-up study in an expanded Irish sample.…”

Section: Comorbiditymentioning

confidence: 93%

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies

et al. 2006

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It is well established that attention deficit hyperactivity disorder (ADHD) is a familial and highly heritable disorder. Consequently, much effort is being directed towards searching for specific susceptibility genes. There is a growing trend, across the field of complex disease genetics, towards undertaking secondary analyses based on refined phenotypic definitions and in testing whether specific susceptibility genes modify the phenotypic presentation of the disorder in question. It is crucial that good, empirically derived arguments are made before undertaking multiple analyses on different phenotype refinements. In this review article, we consider the evidence from genetic epidemiological studies as well as key clinical studies that provide guidance on examining the ADHD phenotype for the purpose of molecular genetic studies. Specifically, findings on categorical versus dimensional conceptualisations of ADHD, reporter effects, comorbidity, ADHD subtypes and persistence are reviewed. Current evidence suggests that for the purpose of identifying susceptibility genes for ADHD, parent and teachers should be used as informants and that focusing on the clinical diagnosis of ADHD is useful. There is also good empirical support in favour of examining antisocial behaviour in ADHD. Genetic studies of dimensional ADHD are useful for other complementary purposes.

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Association of DRD4 in children with ADHD and comorbid conduct problems

Cited by 95 publications

References 27 publications

Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder

Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder

Evidence to suggest biased phenotypes in children with Attention Deficit Hyperactivity Disorder from completely ascertained trios

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies

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