This is an application for a Mentored Clinical Scientist Development Award. The candidate is proposing a program of research that examines the genetics of executive functions in families with and without attention deficit hyperactivity disorder (ADFID). The goals of this research are 1) to integrate the candidate's knowledge of developmental neuropsychology, behavioral genetics and disruptive behavior disorders and 2) to help her develop new methodological and biostatistical skills in the domain of molecular genetics. ? ? Although family, twin and adoption studies indicate that ADHD is a familial condition with a robust genetic component, the complexity of the ADFID phenotype has impeded the identification 01 the specific genes involved in the pathogenesis of this condition. Because ADHD is associated with executive function deficits, and because both genetic and neuropsychological studies implicate dopamine pathways in the pathophysiology of this disorder, the current project will use measures of executive functions to create refined ADHD phenotypes (i.e. familial subtypes and/or endophenotypes) that will then be examined in association and linkage studies of candidate dopamine genes. This project represents the first programmatic work on ADHD that moves from clinically defined phenotypes to phenotypes that are more directly linked to brain function. ? ? Research Plan: Because of uncertainties in the taxonomy of executive functions, various operational definitions of executive functions will be empirically and conceptually derived. These definitions will be examined for familiality, course, stability and relationship to functional impairment and external correlates. Definitions will then be used to characterize potential neuropsychological heterogeneity in ADHD across DSM-IV subtypes, gender, development and comobidities. Based on the above findings, relative risk ratios and prediction of membership in multiplex families will identify the quantitative and categorical executive function phenotypes and neuropsychologically impaired ADHD subgroups that would enhance the power of subsequent linkage and association studies. Finally, these optimized phenotypes will be subjected to linkage analysis and family-based and genomic-control association analyses. Candidate genes to be examined are DRD4, DAT and DRD5 because of their neurobiologic relevance to ADHD and because meta-analyses of extant association studies suggest that they mediate susceptibility to this condition. ? ? Career Development Plan: Training will emphasize the methodological and biostatistical skills necessary for conducting molecular genetics studies of complex phenotypes. Courses will be taken in statistical genetics and the use of software for genetic analyses at the Harvard School of Public Health and Rockefeller University. Tutorials and supervision by expert consultants will focus on phenotype definition, genetic epidemiology and statistical genetics. This training will prepare the candidate to be an independent researcher who can conduct interdisciplinary work on neuropsychology, genetics and developmental psychopathology.
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| Doyle, Alysa E; Wilens, Timothy E; Kwon, Anne et al. (2005) Neuropsychological functioning in youth with bipolar disorder. Biol Psychiatry 58:540-8 |
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| Doyle, Alysa E; Biederman, Joseph; Seidman, Larry J et al. (2005) Neuropsychological functioning in relatives of girls with and without ADHD. Psychol Med 35:1121-32 |
| Faraone, Stephen V; Perlis, Roy H; Doyle, Alysa E et al. (2005) Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 57:1313-23 |
| Nigg, Joel T; Willcutt, Erik G; Doyle, Alysa E et al. (2005) Causal heterogeneity in attention-deficit/hyperactivity disorder: do we need neuropsychologically impaired subtypes? Biol Psychiatry 57:1224-30 |
| Willcutt, Erik G; Doyle, Alysa E; Nigg, Joel T et al. (2005) Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 57:1336-46 |
| Doyle, Alysa E; Faraone, Stephen V; Seidman, Larry J et al. (2005) Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD? J Child Psychol Psychiatry 46:774-803 |
