1. High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder
- Author
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Grady, DL, Chi, H-C, Ding, Y-C, Smith, M, Wang, E, Schuck, S, Flodman, P, Spence, MA, Swanson, JM, and Moyzis, RK
- Subjects
Biomedical and Clinical Sciences ,Biological Psychology ,Clinical and Health Psychology ,Clinical Sciences ,Psychology ,Behavioral and Social Science ,Human Genome ,Brain Disorders ,Pediatric ,Mental Health ,Genetics ,Attention Deficit Hyperactivity Disorder (ADHD) ,Mental Illness ,2.1 Biological and endogenous factors ,Mental health ,Amino Acid Sequence ,Attention Deficit Disorder with Hyperactivity ,Base Sequence ,Child ,Genetic Heterogeneity ,Genetic Predisposition to Disease ,Haplotypes ,Humans ,Molecular Sequence Data ,Phenotype ,Prevalence ,Receptors ,Dopamine D2 ,Receptors ,Dopamine D4 ,DRD4 ,ADHD ,cSNPs ,allelic heterogeneity ,common variant-common disorder (CVCD) hypothesis ,Allelic heterogeneity ,Common variant-common disorder (CVCD) hypothesis ,dopamine 2 receptor ,dopamine 4 receptor ,allele ,amino acid sequence ,article ,attention deficit disorder ,child ,childhood disease ,DNA sequence ,female ,gene linkage disequilibrium ,genetic association ,genetic disorder ,genetic heterogeneity ,genetic predisposition ,genetics ,haplotype ,human ,major clinical study ,male ,molecular genetics ,nucleotide sequence ,phenotype ,prevalence ,priority journal ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - 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.
- Published
- 2003