High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder

Abstract

Associations have been reported of the 7-repeat (7R) allele of the human dopamine receptor D4 (DRD4) gene with both the personality trait of novelty seeking and attention-deficit/ hyperactivity disorder (ADHD). The increased prevalence of the 7R allele in ADHD probands is consistent with the common variant-common disorder hypothesis, which proposes that the high frequency of many complex genetic disorders is related to common DNA variants. Recently, based on the unusual DNA sequence organization and strong linkage disequilibrium surrounding the DRD4 7R allele, we proposed that this allele originated as a rare mutational event, which nevertheless increased to high prevalence in human populations by positive selection. We have now determined, by DNA resequencing of 250 DRD4 alleles obtained from 132 ADHD probands, that most ADHD 7R alleles are of the conserved haplotype found in our previous 600 allele worldwide DNA sample. Interestingly, however, half of the 24 haplotypes uncovered in ADHD probands were novel (not one of the 56 haplotypes found in our prior population studies). Over 10 percent of the ADHD probands had these novel haplotypes, most of which were 7R allele derived. The probability that this high incidence of novel alleles occurred by chance in our ADHD sample is much less than 0.0001. These results suggest that allelic heterogeneity at the DRD4 locus may also contribute to the observed association with ADHD.

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

“…However, there is evidence to suggest that there may be an evolutionary advantage of the 7R allele and that it may even have a protective effect in ADHD. [42][43][44]60 The current finding supports this notion in that larger prefrontal gray matter volume is associated with variant alleles of the DRD4. Previously, we reported that the affected siblings in this sample display a tendency towards reduced prefrontal gray matter volume (significant for the right hemisphere).…”

D4 receptor deficiency in mice has limited effects on impulsivity and novelty seeking

“…These data suggest that the absence of D 4 Rs is not sufficient to cause psychopathologies associated with heightened impulsivity and novelty seeking. Keywords impulsivity; D 4 receptors; mice; delay discounting; Go/No-go; inhibition; novelty seeking; locomotion Psychopathologies including pathological gambling (Comings et al, 2001), substance abuse (Vandenbergh et al, 2000), opiate dependence (Kotler et al, 1997), and attention-deficit hyperactivity disorder (ADHD; Faraone et al, 2001;Grady et al, 2003) are associated with the presence of dopamine D 4 receptor (D 4 R) gene (DRD4) polymorphisms. Novelty-seeking is often associated with these psychopathologies and is also observed in individuals possessing DRD4 alleles containing 7 repeats of a 48-nucleotide sequence (DRD4.7) (Benjamin et al, 1996;Ebstein et al, 1996Ebstein et al, , 1997.…”

Exploring DRD4 and its interaction with SLC6A3 as possible risk factors for adult ADHD: A meta‐analysis in four European populations

“…Further deep-sequencing of this genomic region may allow identification of the functional DRD4 variants directly involved in the genetic background of ADHD. In that regard, it is interesting to note that an increased burden of rare variants has been observed in the 7R allele of DRD4 in children with ADHD [Grady et al, 2003]. …”