Recent advances in molecular genetics have greatly expanded the potential for studies of the genetic etiology and pathophysiology of neurological/behavior disorders. This application focuses on the common neurobehavioral disorder, Attention Deficit Hyperactivity Disorder (ADHD). Research on the molecular genetic bases of ADHD provides successful examples of the candidate gene approach, with association confirmed (by multiple replications and metaanalyses) between ADHD and alleles of the D4 dopamine receptor (DRD4) gene and the dopamine transporter (DAT1) gene. Single studies for other genes (e.g., the DRD2, DRD3, DRD5, MAO, and SNAP25 loci) also suggest a role in ADHD. We propose a rigorous replication of the association findings with the large well-characterized sample of children in the Multimodality Treatment of ADHD (MTA) study. Also, to go beyond the association studies to investigate the actual genotype - phenotype relationships, we propose to evaluate the functional significance by using genotype as an independent variable in studies of neuropsychological function, response to treatment, and long-term outcome.
Our specific aims are: 1. Collect DNA from MTA subjects, control classmates, and all available parents (n = 579 and 288 respectively for the original samples). 2. Replicate and extend the association studies with candidate genes starting with DRD4-7R and DAT-1OR. We will extend the published findings (based on the qualitative diagnoses of ADHD) to quantitative measures of severity and cognitive impairment. 3. Relate genotype to outcome and treatment response through use of the SNAP rating scale from parents and teachers at follow-up assessment. The important question is the relationship of the DRD4 genotypes and response to pharmacological and psychosocial treatments and to long-term outcome. 4. To investigate multiple genes in the dopamine pathway in addition to DRD4 and DAT including DRD1, DRD2, DRD3, DRD5 and TH. """"""""Genomic haplotypes"""""""", meaning haplo-specific genotypes at more than one locus, will be defined and tested for possible interactive roles among the genes.
