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.