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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH066275-04
Application #
7038308
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Desmond, Nancy L
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2006
Total Cost
$179,582
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ambrosini, Paul J; Bennett, David S; Elia, Josephine (2013) Attention deficit hyperactivity disorder characteristics: II. Clinical correlates of irritable mood. J Affect Disord 145:70-6
Albayrak, Özgür; Pütter, Carolin; Volckmar, Anna-Lena et al. (2013) Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 162B:295-305
Yang, Li; Neale, Benjamin M; Liu, Lu et al. (2013) Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. Am J Med Genet B Neuropsychiatr Genet 162B:419-430
Accardo, Jennifer A; Marcus, Carole L; Leonard, Mary B et al. (2012) Associations between psychiatric comorbidities and sleep disturbances in children with attention-deficit/hyperactivity disorder. J Dev Behav Pediatr 33:97-105
Takeda, Toshinobu; Ambrosini, Paul J; deBerardinis, Rachel et al. (2012) What can ADHD without comorbidity teach us about comorbidity? Res Dev Disabil 33:419-25
Elia, Josephine; Glessner, Joseph T; Wang, Kai et al. (2011) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44:78-84
Hinney, Anke; Scherag, André; Jarick, Ivonne et al. (2011) Genome-wide association study in German patients with attention deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 156B:888-97
Neale, Benjamin M; Medland, Sarah E; Ripke, Stephan et al. (2010) Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 49:884-97
Takeda, Toshinobu; Stotesbery, Kory; Power, Thomas et al. (2010) Parental ADHD status and its association with proband ADHD subtype and severity. J Pediatr 157:995-1000.e1
Elia, J; Gai, X; Xie, H M et al. (2010) Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Mol Psychiatry 15:637-46

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