Review
Imaging genetics in ADHD: A focus on cognitive control

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Abstract

This paper evaluates neuroimaging of cognitive control as an endophenotype for investigating the role of dopamine genes in ADHD. First, this paper reviews both data-driven and theory-driven approaches from genetics and neuroimaging. Several viable candidate genes have been implicated in ADHD, including the dopamine DRD4 and DAT1 genes. Neuroimaging studies have resulted in a good understanding of the neurobiological basis of deficits in cognitive control in this disorder. Second, this paper discusses imaging genetics in ADHD. Papers to date have taken one of two approaches: whereas early papers investigated the effects of one or two candidate genes on many brain areas, later papers constrained regions of interest by gene expression patterns. These papers have largely focused on cognitive control and the dopamine circuits involved in this ability. The results show that neuroimaging of cognitive control is useful as an endophenotype in investigating dopamine gene effects in ADHD. Other avenues of investigation are suggested by a combination of data- and theory-driven approaches in both genetics and neuroimaging.

Introduction

This special issue of Neuroscience and Biobehavioral Reviews is dedicated to control of action and cognition. This type of control is of longstanding interest to investigators interested in attention deficit/hyperactivity disorder (ADHD), as it is often compromised in individuals with this disorder. In ADHD research, this ability is often referred to as cognitive control and is defined as the ability to suppress inappropriate behaviors in favor of appropriate ones, leading to the ability to flexibly adapt behavior in the face of changing circumstances. Its relevance to ADHD is reflected by the diagnostic criteria for the disorder, which include descriptions of ‘not being able to sit still in class’ and ‘blurting out answers to questions before they have been completed’ (suppressing inappropriate behavior), as well as ‘having difficulty organizing tasks and activities’ and ‘losing things necessary for tasks or activities (e.g., toys, school assignments, pencils, books, or tools)’ (adapting behavior as required by circumstances) (APA, 2000). Problems in cognitive control have even been suggested to be central to this disorder (Barkley, 1997), although this simple explanation cannot explain all the phenotypic variance in ADHD, as only 30–50% of children with ADHD have significantly impaired performance on tests of this ability (Casey and Durston, 2006, Nigg et al., 2005).

This paper aims to evaluate neuroimaging measures of cognitive control as an endophenotype for investigating the neurobiology of ADHD, and specifically for investigating the role of dopamine genes in this disorder. The brain circuitry underlying cognitive control is widely investigated and, as a result, is relatively well understood (see Chambers et al., this issue for a comprehensive discussion). Catecholamine systems are central to cognitive control: small variations in noradrenaline or dopamine levels in prefrontal cortex have profound effects on cognitive functioning in animal models (Arnsten and Li, 2005, Castner et al., 2005). Furthermore, these neurotransmitter systems have been implicated in ADHD in a wide variety of studies. To name but one example: DAT1 knock-out mice shown hyperactivity in novel surroundings that can be improved using stimulant medication that works on catecholamine systems. Interestingly, this effect appears to be mediated by serotonin systems, illustrating the subtle nature of monoamine interactions that are involved in fine-tuning behavior (Gainetdinov et al., 1999).

Endophenotypes are intermediate between a behavioral classification (such as ADHD) and the biological variables that are the cause of the disorder (whether genetic or environmental). Using such intermediate phenotypes can be advantageous in studying psychiatric disorders, such as ADHD, as they have the potential to overcome some of the limitations of approaches using diagnostic categories as end-points: the use of diagnostic categories may create heterogeneous groups, as subjects are included based on a behavioral phenotype that may reflect an array of biological causes. This is obviously problematic in investigations of the neurobiology of such disorders, including both genetic association and fMRI studies (see Castellanos and Tannock, 2002, Gottesman and Gould, 2003). A particular strength of the endophenotype approach is that it aims to identify neurobiological markers within more homogeneous subgroups and, as such, is less susceptible to the noise inherent to heterogeneity. A number of theorists have outlined criteria that endophenotypes should meet in order to be beneficial the study of causative agents in psychiatry. These are summarized in Table 1. Endophenotype approaches by their nature require a theoretical approach to a disorder, as a phenotype associated with it is linked to a biological pathway. This is not necessarily true of genetics or neuroimaging, where whole-genome or whole-brain analyses can be conducted in a data-driven manner. In this paper, we first review the genetic and neuroimaging literature on ADHD. We discuss data-driven and theory-driven approaches from both. Next, we review the literature using neuroimaging measures as endophenotypes in ADHD and assess the value of cognitive control as such a measure.

Section snippets

Methods

Genetic and MRI original research papers were retrieved through Pubmed and ISI Web of Science. Search terms were ‘Attention deficit and hyperactivity disorder’; ‘ADHD’ and ‘association study’, ‘genetic study’, ‘heritability’, ‘linkage study’, ‘genome wide study’, ‘genome wide scan’ or ‘genetic risk’ for genetic studies. ‘ADHD’, ‘MRI’ and ‘fMRI’ were used for neuroimaging studies. Brain tissue expression and receptor localization for candidate genes were assessed by searches using the human UCSC

Heritability and genes in ADHD

ADHD is a common disorder with a significant heritable component. The disorder tends to cluster in families and additive genetic effects explaining up to 80% of the variance in the phenotype (e.g., Albayrak et al., 2008, Thapar et al., 1999). Concordance rates are estimated to lie between 50 and 80% for monozygotic twins and at around 30% dizygotic twins (Bradley and Golden, 2001, Thapar et al., 1999). Interestingly, although ADHD clusters in families, ADHD subtypes do not (Smalley et al., 2001

Imaging of brain structure and function in ADHD

Magnetic resonance studies of ADHD have often started from a theoretical perspective, where cognitive functions (in functional studies) and brain regions (in anatomical studies) of interest were selected. With the advent of whole-brain voxel-based analysis techniques and resting state fMRI approaches, this is no longer the case, and data-driven approaches can be used to suggest new avenues of theoretical interest.

Imaging heritability and genes in ADHD

ADHD is a highly heritable disorder (Table 2, Table 3, Table 4) and its neurobiological basis is well understood, at least in terms of cognitive control (Table 5, Table 6). As such, this disorder appears to be a strong candidate for investigation using an endophenotype approach, such as outlined in the Introduction (see also Aron and Poldrack, 2005). To date, there is very limited data available on the heritability of brain structure and activity in ADHD. Anatomical (and to a lesser extent

Conclusion

The first part of this paper reviews the literature on genetics and neuroimaging in ADHD. While data-driven approaches have been successful in suggesting new avenues for research, theory-driven approaches have resulted in the most encouraging findings to date: whole-genome scans have shown few regions of overlap, while candidate gene approaches have suggested several viable candidate genes, including the DRD4 and DAT1 genes. Neuroimaging studies have focused on (aspects of) cognitive control

Beyond studying the biology of ADHD

Imaging genetics approaches in ADHD have focused on cognitive control and are beginning to show us how risk alleles impact the brain and may ultimately result in symptoms. But will improved neurobiological understanding of these cascades actually benefit individuals with this disorder? We believe that imaging genetics approaches have the potential to reshape the way we think about ADHD: if multiple endophenotypes can be defined that lead to symptoms of ADHD, we will ultimately be able to define

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