This proposal seeks to provide supervised training to enable Josephine Elia, MD, to develop into an independent physician scientist. During the five-year training period, the candidate will collect and make publicly available a large sample (N=500) of ADHD parent-proband trios (and available affected siblings), study the techniques and theory of molecular genetic studies of psychiatric disorders, with a focus on attention deficit/hyperactivity disorder (ADHD). The specific research project will investigate dopaminergic (DA) and noradrenergic (NA) candidate susceptibility alleles and their interaction in ADHD children. Background: ADHD is familial and has a substantial heritability. There are a number of reports of associations between ADHD and specific alleles at two candidate loci in the DA system (DAT1 and DRD4). Results are modest, suggesting that multiple genes underlie susceptibility to ADHD. While drugs enhancing DA neurotransmission are generally effective for ADHD, the efficacy of drugs interacting with NA receptors suggest that this system also deserves further study. The interaction of these two systems may be important. Hypotheses: Alleles at DAT1, DRD4, DbetaH, COMT, alpha2A, alpha2B, and alpha2C will confer increased risk for ADHD, with an interaction of allelic effects at DA and NA loci having a greater effect on ADHD susceptibility than either system alone. Specific predictions are made about ADHD subtypes. Research Project: Five-hundred parent-child trios with an ADHD proband will be collected over a five year period. The clinical data, genotypes and DNA will become part of the NIMH Human Genetics Initiative. SNPs in each of the candidate genes will be selected and assays optimized. 500 trios will be genotyped for these SNPs and the transmission disequilibrium test will be used to investigate the transmission of DA and NA alleles at the seven candidate loci. We will test each of these genes for preferential transmission of a risk-increasing haplotype and detect possible gene-gene interactions. Environment: This training period will be conducted at The Children's Hospital of Philadelphia and the University of Pennsylvania under the supervision and mentorship of Wade Berrettini, M.D., Ph.D. Research Career Development: The candidate will take relevant courses at Penn and elsewhere, and attend meetings and seminars. Dr. Douglas Levinson will provide mentoring in statistical methods and data analyses and Dr. Judith Rapoport will provide mentoring in defining novel phenotypic definitions for ADHD.
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