Attention deficit/hyperactivity disorder (
ADHD) is a childhood-onset disorder characterized by marked inattention, hyperactivity and impulsivity. The dopaminergic system has been hypothesized to be involved in the development of
ADHD. Positive associations have been found for the
dopamine receptors D1 and D5 genes, suggesting that other genes involved in D1/D5 signalling may also contribute to
ADHD. In this study, we tested the
calcyon gene (DRD1IP), which encodes a brain-specific D1-interacting
protein involved in D1/D5
receptors calcium signalling, for association with
ADHD. The inheritance of nine polymorphisms in the
calcyon gene was examined in a sample of 215 nuclear families, with 260 affected children, using the transmission/disequilibrium test. The most common haplotype, designated C1, demonstrated significant evidence for excess transmission. Quantitative trait analyses of this haplotype showed significant relationships with both the inattentive (parent's rating, P=0.006; teacher's rating, P=0.003) and hyperactive/impulsive (parent's rating, P=0.004) dimensions of the disorder. Two of the nine marker alleles included in haplotype C1, rs4838721A located approximately 10 kb 5' of the gene and rs2275723C located 10 bp upstream of the exon 5 acceptor splice site, also showed significant evidence for association when analysed individually. As these two variants are not predicted to alter
calcyon function, we screened the gene exons by sequencing. No variation in the coding region was identified, suggesting that a causal variant allele resides elsewhere in a regulatory sequence of the gene. These findings support the proposed involvement of the
calcyon gene in
ADHD and implicate haplotype C1 as containing a risk allele.