Utilizing the vast number of marker loci being identified by the Human Genome Project, association studies are being applied to data on many complex disorders. Once an association is identified the issue for investigators is to determine what the association tells us about the disease process. When confirmed by numerous studies, the possibility of he association being a statistical artifact is remote. We are then left with two explanations: the associated allele plays a causative role in the disorder or the allele is in linkage disequilibrium with another locus(polymorphism) which does play a role. In order to truly understand the disorder we will have to distinguish between these, but how? This project is designed to capitalize on our ability to rapidly and accurately sequence DNA for a locus over a large number of individuals ascertained within a rigorous research design, and apply that information to determine the reason for he association. We have chosen to examine Attention Deficit Hyperactivity Disorder (ADHD) and the dopamine receptor gene DRD4. We first reported the association of ADHD with the D4.7 allele of this gene, which has now been confirmed by us and five other studies. ADHD affects about 3-5% of the school-aged population and is considered the most prevalent psychiatric disorder of childhood. Family, twin, and adoption studies have established a strong genetic basis for ADHD. Initial molecular genetic investigations of candidate genes focused on the neurotransmitter dopamine because most patients are responsive to methylphenidate. The DRD4 locus is a highly variable locus where the 7- repeat form of a 48 bp segment occurs in many allelic forms. Other polymorphisms have been identified in DRD4, some of which have known functional significance, but none of which have been evaluated in ADHD studies. Probands will be ascertained through clinical trials at the Child Development Center, UCI when they meet rigorous diagnostic criteria for ADHD. Probands, their parents, and siblings will be studied and their DNA sequenced for DRD4. Other dopamine pathway loci will be genotyped. Within those families who carry D4.7 we will determine the haplotype(s) present in affected individuals for all of the polymorphisms present in the DRD4 gene. For the non-D4.7 families we will test or tight linkage with the DRD4 region. If D4.7 is merely a marker in linkage disequilibrium with a causative polymorphism, then this latter subset of families should also show evidence for linkage.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Genome Study Section (GNM)
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Moldin, Steven Owen
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University of California Irvine
Schools of Medicine
United States
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Leung, Patrick W L; Lee, C C; Hung, S F et al. (2005) Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele. Am J Med Genet B Neuropsychiatr Genet 133B:54-6
Grady, D L; Harxhi, A; Smith, M et al. (2005) Sequence variants of the DRD4 gene in autism: further evidence that rare DRD4 7R haplotypes are ADHD specific. Am J Med Genet B Neuropsychiatr Genet 136B:33-5
Wang, E; Ding, Y-C; Flodman, P et al. (2004) The genetic architecture of selection at the human dopamine receptor D4 (DRD4) gene locus. Am J Hum Genet 74:931-44
Grady, D L; Chi, H-C; Ding, Y-C et al. (2003) High prevalence of rare dopamine receptor D4 alleles in children diagnosed with attention-deficit hyperactivity disorder. Mol Psychiatry 8:536-45
Ding, Yuan-Chun; Chi, Han-Chang; Grady, Deborah L et al. (2002) Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc Natl Acad Sci U S A 99:309-14