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

• Published in: Molecular psychiatry Vol. 8; no. 5; pp. 536 - 545
• Main Authors: GRADY, D. L, CHI, H-C, DING, Y-C, SMITH, M, WANG, E, SCHUCK, S, FLODMAN, P, SPENCE, M. A, SWANSON, J. M, MOYZIS, R. K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-05-2003
• Subjects: Alleles; Amino Acid Sequence; Attention Deficit Disorder with Hyperactivity - epidemiology; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit disorders. Hyperactivity; Attention deficit hyperactivity disorder; Base Sequence; Biological and medical sciences; Child; Child clinical studies; Deoxyribonucleic acid; DNA; Dopamine; Dopamine D4 receptors; Genes; Genetic disorders; Genetic Heterogeneity; Genetic Predisposition to Disease - epidemiology; Genetic testing; Genomes; Haplotypes; Humans; Hyperactivity; Hypotheses; Linkage disequilibrium; Medical sciences; Molecular Sequence Data; Nucleotide sequence; Personality traits; Phenotype; Polymorphism; Population studies; Positive selection; Prevalence; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D4; Statistical power; United States > US; California; Human; D4 Dopamine receptor; Allele; Prevalence; Attentional disorder; Hyperactivity; Genetic determinism; Child; Epidemiology
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/sj.mp.4001350

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.