Association of the calcyon gene (DRD1IP) with attention deficit/hyperactivity disorder

Abstract

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 ¼ 0.006; teacher's rating, P ¼ 0.003) and hyperactive/impulsive (parent's rating, P ¼ 0.004) dimensions of the disorder. Two of the nine marker alleles included in haplotype C1, rs4838721A located B10 kb 5 0 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.

Investigation of the G protein subunit Gαolf gene (GNAL) in attention deficit/hyperactivity disorder

“…This is further supported by a large combined analysis of 14 independent samples of 1980 probands (P = 0.00005), odds ratio 1.24 (Lowe et al, 2004) for DRD5 (a D1-like receptor). In the same vein, we have recently reported evidence of association between ADHD and the calcyon gene, a D1-interacting protein (Laurin et al, 2005). D1/D5 signalling mediates executive abilities including working memory , attention (Bayer et al, 2000;Granon et al, 2000), motor control (Dreher and Jackson, 1989;Meyer, 1993), and reward and reinforcement mechanisms (Beninger and Miller, 1998).…”

“…The methods of assessment, characteristics of the subjects, and inclusion/exclusion criteria have been described previously, including the instruments used to collect information for the diagnosis of ADHD and co-morbid conditions (Barr et al, 1999;Laurin et al, 2005;Quist et al, 2000). Briefly, probands and their siblings between 7 and 16 years old were included if they met DSM-IV criteria for one of the three ADHD subtypes.…”

Up-regulation of calcyon results in locomotor hyperactivity and reduced anxiety in mice

“…But, whether or how altered calcyon expression might influence behavior in not known. Polymorphisms in the calcyon gene are associated with attention deficit hyperactivity disorder (ADHD) [8]. Additionally, a genome wide linkage scan for loci influencing in ADHD reported that the strength of association of a marker at 10q26, the cytogenetic position of the calcyon locus, significantly exceeded that of the DA transporter (DAT1), and the D4R (DRD4) [9].…”

Association of the dopamine receptor D1 gene, DRD1, with inattention symptoms in families selected for reading problems

“…Before participating in the study, parents were queried as to whether their child had ever been diagnosed with ADHD, and any children identified as such were excluded from continuing in the present study, and were referred, instead, to a separate genetic study of ADHD. 33,[52][53][54] Following this prescreen for ADHD, children eligible for the present study underwent the full study assessment. Children were subsequently excluded from the study if they scored below 80 on both the verbal and performance domains of the Wechsler Intelligence Scale for Children-III (WISC-III).…”