Review
Measured Gene-by-Environment Interaction in Relation to Attention-Deficit/Hyperactivity Disorder

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Objective

To summarize and evaluate the state of knowledge regarding the role of measured gene-by-environment interactions in relation to attention-deficit/hyperactivity disorder.

Method

A selective review of methodologic issues was followed by a systematic search for relevant articles on measured gene-by-environment interactions; the search yielded 16 studies, which are discussed in qualitative fashion.

Results

Relatively consistent evidence points to the interaction of genotype with psychosocial factors in the development of attention-deficit/hyperactivity disorder. The next step is to identify the mechanisms on the environment side and the gene combinations on the genetic side accounting for this effect. In contrast, evidence for gene-by-environment interactions involving pre- and perinatal risk factors is generally negative or unreplicated. The aggregate effect size for psychosocial interaction with genotype is more than double that for the interaction of pre- and perinatal risks with genotype. Only a small fraction of candidate environments and gene markers has been studied, and multivariate methods to integrate multiple gene or environment markers have yet to be implemented.

Conclusions

Gene-by-environment interaction appears likely to prove fruitful in understanding the etiology of attention-deficit/hyperactivity disorder. Findings to date already suggest new avenues of investigation particularly involving psychosocial mechanisms and their interplay with genotype. Further pursuit of theoretically promising leads is recommended.

Section snippets

General Methodologic Issues in G×E

Methodologic issues in G×E research have been frequently reviewed and are readily available to interested readers.1, 2, 3, 6, 7 Therefore, we only briefly note particularly salient methodologic issues that directly affect our ability to interpret the existing ADHD literature.

An overarching issue is the substantial danger of false-positive findings. One rather neglected issue involves measurement or statistical artifacts. Under some conditions (depending on allele frequency and on measurement

Etiologic Structure

ADHD differs from depression and externalizing behaviors in regard to its etiologic structure. Depression, conduct disorder, and oppositional defiant disorder tend to show a pattern of moderate heritability, with small-to-moderate shared (or common) environment effects.14, 15 ADHD, in contrast, has higher heritability with small nonshared environment effects and null shared environment effects,15, 16 although it remains possible that shared environment effects are masked by rater contrast

Approach to the Current Literature and Selection of Studies

The methodologic approach to this review was as follows. Literature searches were conducted in MEDLINE using “gene by environment,” “G×E,” “ADHD,” and “externalizing.” Reference sections of recent publications were also scanned. Researchers in the field were contacted to inquire about missed or in-press papers, including announcements to all researchers participating in the International ADHD Molecular Genetics Network.38 Studies identified were then examined to determine if they constituted an

Discussion

The resulting studies identified are summarized in Table 3.39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 It summarizes 16 studies that examined ADHD as an outcome. Although several gene markers were examined, only three were examined in multiple studies.

  • The DRD4 exon III variable number tandem repeat (a 48-basepair repeat often referred to by the number of repeats, such as the “7 repeat” or “4-repeat” variant) generally yielded negative findings, but did show unreplicated

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    This article is discussed in an editorial by Drs. James J. Hudziak and Stephen V. Faraone on page 729 of the August 2010 issue.

    This work was supported by NIMHR01 59105.

    This article is one of several articles published in the August and September issues of the Journal of the American Academy of Child and Adolescent Psychiatry that explores the intersection of genetics with mental health disorders in children and adolescents. The editors invite the reader to investigate the additional articles on this burgeoning area of developmental psychopathology.

    Disclosure: Drs. Nigg and Burt and Ms. Nikolas report no biomedical financial interests or potential conflicts of interest.

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