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

D L Grady,E Wang,P Flodman,Y-C Ding,M Smith,S Schuck,H-C Chi,M A Spence,R K Moyzis,J M Swanson

doi:10.1038/sj.mp.4001350

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.

Highlights

The exon 3 VNTR region of the DRD4 gene was increased frequency in our predominantly European amplified from these DNAs, and the distribution of ancestry ADHD sample (Table 1)
Two-fold greater (43.2%) than that found in alleles) because of PCR and/or sequencing failures
The observed allele frequency identified previously in our analysis of 600 DRD4 for DRD4 is 2R 1⁄4 0.07, 3R 1⁄4 0.03, 4R 1⁄4 0.73, 5R 1⁄4 0.01, alleles obtained from a worldwide population sample

Summary

ORIGINAL RESEARCH ARTICLE

ADHD probands (l 1⁄4 1.9), calculated from a recent wide allele sample The probability that this high meta-analysis is consistent with the common var- prevalence of novel alleles occurred by chance in our iant–common disorder (CVCD) hypothesis Most of these called the common disease–common variant hypoth- novel haplotypes were 7R allele derived. Perhaps predisposing alleles Clinical are under positive selection, and only result in ADHD probands were recruited to participate in deleterious effects when combined with other envir- either clinical trials or the Multimodality Treatment onmental/genetic factors This would explain the Study of Children with ADHD (MTA) at the Molecular Psychiatry.

Results

Allele N Haplotype Allele N

What can account for the high frequency of novel

Schaffner SF et al Detecting recent positive selection in the human