Genome-wide association studies in ADHD

Abstract

Attention-deficit/hyperactivity disorder, ADHD, is a common and highly heritable neuropsychiatric disorder that is seen in children and adults. Although heritability is estimated at around 76%, it has been hard to find genes underlying the disorder. ADHD is a multifactorial disorder, in which many genes, all with a small effect, are thought to cause the disorder in the presence of unfavorable environmental conditions. Whole genome linkage analyses have not yet lead to the identification of genes for ADHD, and results of candidate gene-based association studies have been able to explain only a tiny part of the genetic contribution to disease, either. A novel way of performing hypothesis-free analysis of the genome suitable for the identification of disease risk genes of considerably smaller effect is the genome-wide association study (GWAS). So far, five GWAS have been performed on the diagnosis of ADHD and related phenotypes. Four of these are based on a sample set of 958 parent–child trio’s collected as part of the International Multicentre ADHD Genetics (IMAGE) study and genotyped with funds from the Genetic Association Information Network (GAIN). The other is a pooled GWAS including adult patients with ADHD and controls. None of the papers reports any associations that are formally genome-wide significant after correction for multiple testing. There is also very limited overlap between studies, apart from an association with CDH13, which is reported in three of the studies. Little evidence supports an important role for the ‘classic’ ADHD genes, with possible exceptions for SLC9A9, NOS1 and CNR1. There is extensive overlap with findings from other psychiatric disorders. Though not genome-wide significant, findings from the individual studies converge to paint an interesting picture: whereas little evidence—as yet—points to a direct involvement of neurotransmitters (at least the classic dopaminergic, noradrenergic and serotonergic pathways) or regulators of neurotransmission, some suggestions are found for involvement of ‘new’ neurotransmission and cell–cell communication systems. A potential involvement of potassium channel subunits and regulators warrants further investigation. More basic processes also seem involved in ADHD, like cell division, adhesion (especially via cadherin and integrin systems), neuronal migration, and neuronal plasticity, as well as related transcription, cell polarity and extracellular matrix regulation, and cytoskeletal remodeling processes. In conclusion, the GWAS performed so far in ADHD, though far from conclusive, provide a first glimpse at genes for the disorder. Many more (much larger studies) will be needed. For this, collaboration between researchers as well as standardized protocols for phenotyping and DNA-collection will become increasingly important.

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

“…60,63,64 Although several genes affected by CNVs identified in this study contain SNPs that yield significant signals in GWA studies, there is presently no obvious relationship between the heritability of ADHD and the number or strength of the observed effects. Unlike rare CNVs, common variants for ADHD may be of very small effect and thus require very large samples to be reliably detected.…”

ADHD: a critical update for educational professionals

“…Combined, they explain less than 10% of variance (Franke, Neale, & Faraone, 2009). This means they occur only slightly more often in diagnosed individuals than in controls, and they do not explain nor predict ADHD behaviours.…”

Phenotypic and measurement influences on heritability estimates in childhood ADHD

“…Linkage studies elicited several loci likely containing rare genetic variants of major effect only present in single large families, but also common variants of smaller effect present across several families [92]. In addition, genome-wide association studies indicated a very limited number of common variants of small effect to date [33,62].…”