Imaging genetics in ADHD

doi:10.1016/j.neuroimage.2010.02.071

NeuroImage

Volume 53, Issue 3, 15 November 2010, Pages 832-838

https://doi.org/10.1016/j.neuroimage.2010.02.071 Get rights and content

Abstract

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neuropsychiatric disorder, with 5% of school age children affected. Up to 80% of the phenotypic variance can be explained by genetic factors. The intermediate or endophenotype approach allows for mapping of the effect of individual risk genes on neurobiological parameters, such as brain structure, chemistry and, ultimately, function. There are two obvious advantages of applying such an approach to complex disorders: first, these measures are causally closer to genes and gene expression than behavior, meaning that gene effects should be magnified. Second, neuroimaging provides a means to uncover the neurobiological mechanisms by which gene variants impact the brain. To date, only fourteen studies have applied an imaging genetics approach to ADHD. Eight of these used MRI, four SPECT and two EEG. These imaging modalities have afforded us a window on the brain, permitting a glimpse of how genetic changes can affect brain structure, chemistry and function. The studies to date have often focused on two prime candidate genes in the dopamine system, the DRD4 and DAT1 genes. However, the effects of neither are yet fully understood. Imaging genetics in ADHD is in its infancy. While attempts to integrate the findings to date are hinting at how genes may impact various aspects of neural functioning, studies testing clear model-based hypotheses, using multimodal approaches may provide a means to link various windows on the brain.

Introduction

This special issue of Neuroimage focuses on imaging genetics in the brain, both in the healthy brain and in disorders. This is relevant as although many psychiatric disorders have well-established heritable bases, psychiatric genetic research has not been able to uncover the genetic causes underlying them. Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neuropsychiatric disorder, with 5% of school age children receiving the diagnosis, compared to prevalence rates of .5% for schizophrenia and .5–1.0% for epilepsy. However, its prevalence is not necessarily reflected in the amount of studies published on it: a Pubmed search in July 2009 gave nearly 16 000 hits for ADHD, but over 84 000 for schizophrenia, and 116 000 for epilepsy. ADHD is a heritable disorder, making it a prime candidate for imaging genetics studies. Up to 80% of the phenotypic variance can be explained by additive genetic factors (Faraone et al., 2005), similar to estimates for schizophrenia and some (familial) forms of epilepsy (Cardno and Gottesman, 2000, Kjeldsen et al., 2003). Of the approximately 16 000 publications to date that mention ADHD, only 14.5% mention imaging modalities (MRI, EEG, or PET/SPECT). That is similar to the total number of publications on ADHD that mention neuropsychology (13.5%).

Section snippets

The intermediate or endophenotype approach

The intermediate or endophenotype approach is the focus of this special issue and is explained in some detail by Bigos & Weinberger (2010). As such, it is not outlined in detail here. Briefly, the intermediate or endophenotype approach allows for mapping of the effect of individual risk genes on neurobiological parameters, such as brain structure, brain activity or neurochemistry. Criteria for an endophenotype in psychiatry include being continuously quantifiable, stable, closer to the

Modalities used to date in endophenotype approaches to ADHD

As Fig. 1 illustrates, most studies to date that have applied an endophenotype approach to ADHD have used neuropsychology as an outcome measure. The advantages are obvious: the methods are cheap and readily available. Furthermore, neuropsychological measures have been shown to meet a number of criteria for endophenotypes, including being (1) affected in ADHD; (2) under familial influences in ADHD and (3) relatively stable over time (for review, see Bellgrove et al., 2008, Nigg, 2005, Rommelse

Imaging genetics in ADHD

A systematic review of the published literature on imaging genetics in ADHD shows that to date, only fourteen imaging genetics studies have been published in ADHD (see Table 1). These papers were retrieved through a pubmed search using the search terms “ADHD” and “MRI” “fMRI” “SPECT” “PET” “EEG” or “ERP” and “gene” “DAT1” “DAT” or “DRD4”. The reference lists of retrieved papers (and reviews) were further checked for other publications in this area. Of the fourteen publications to date, eight

Concluding remarks

Imaging genetics in ADHD is in its infancy. To date, only fourteen studies have used neuroimaging methods to assess the effect of ADHD risk genes on the brain. However, this is of pivotal importance if we want to address how genetic risk can impact a biological system and ultimately result in ADHD. Genetic variations that affect gene expression in the brain can affect brain function. Imaging approaches permit us to visualize these changes in vivo. This is essentially the simple approach that we

Acknowledgments

The author gratefully acknowledges two anonymous reviewers for their helpful suggestions. The work by the author's group described here was supported by an NWO VIDI grant to SD.

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ReviewImaging genetics in ADHD

Abstract

Introduction

Section snippets

The intermediate or endophenotype approach

Modalities used to date in endophenotype approaches to ADHD

Imaging genetics in ADHD

Concluding remarks

Acknowledgments

Neuroimage

Eur. Neuropsychopharmacol.

J. Am. Acad. Child Adolesc. Psychiatry

Biol. Psychiatry

J. Am. Acad. Child Adolesc. Psychiatry

Neurosci. Biobehav. Rev.

Biol. Psychiatry

Neurosci. Biobehav. Rev.

J. Pediatrics

Epilepsy Res.

J. Am. Acad. Child. Adolesc. Psychiatry

J. Am. Acad. Child. Adolesc. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Neuroimage

Clin. Psychol. Rev.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design

Am. J. Med. Genet.

Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms

J. Pediatr.

The pinhole: gateway to ultra-high-resolution three-dimensional radionuclide imaging

Eur. J. Nucl. Med. Mol. Imaging

Genetics of cognitive deficits in ADHD: clues for novel treatment methods

Exp. Rev. Neurother.

Support for association between ADHD and two candidate genes: NET1 and DRD1

Am. J. Med. Genet. B Neuropsychiatr. Genet.

A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy

Arch. Gen. Psychiatry

Review
Imaging genetics in ADHD