This proposal responds to FOA PAS-06-204, the goal of which is to use novel strategies, including intermediate phenotypes, to identify genes for complex conditions such as attention deficit-hyperactivity disorder (ADHD). Although the heritability of ADHD is well-established, progress in identifying susceptibility genes has been slow. """"""""Endophenotypes"""""""" that lie in the pathway from genes to behavior may increase the power of molecular genetic studies because of their reduced complexity relative to the disorder and their potential to partition heterogeneous neurobiological processes. Neurocognitive measures of functioning in prefrontal-striatal and related neural networks have been widely discussed as candidate endophenotypes for ADHD due to their impaired status in affected individuals and their relatives. Yet, they have not been investigated systematically in molecular genetics studies. The current proposal aims to evaluate the extent to which impairments in prefrontal cognition, attention and processing speed are useful endophenotypes for ADHD. Our central hypothesis is that these impairments index a latent trait, or traits, that partially overlap/s with the heritable pathophysiology of the disorder. Thus, we expect that they will be useful for finding ADHD genes. To test this hypothesis, we aim to capitalize on data already available from our affected sibling pair linkage study of ADHD. We propose to use biometrical modeling to reduce our neurocognitive battery to a small number of factors based on their familial architecture. We will incorporate these factors into a multivariate linkage analysis of ADHD, using a strategy that will allow us to identify loci that contribute jointly and separately to each phenotype. In exploratory analyses, we will investigate our most promising linkage peak at the phenotypic and genotypic levels. This work will advance the long-term goals of our research, which are to identify gene variants that increase the risk for ADHD and its correlated neurocognitive impairments and to clarify the neurobiology of the disorder. Our approach is innovative because multivariate genomewide linkage has not been used to explore ADHD endophenotypes. This proposal is significant because finding genes for ADHD and its correlated neurocognitive impairments will facilitate the identification of novel biological targets for intervention and prevention. Developing better models of and treatments for ADHD is an important public health goal due to the high prevalence of the condition and its association with academic and occupational failure, substance abuse, criminality, driving accidents and health care over-utilization. ? ? ?
| Doyle, Alysa E; Ferreira, Manuel A R; Sklar, Pamela B et al. (2008) Multivariate genomewide linkage scan of neurocognitive traits and ADHD symptoms: suggestive linkage to 3q13. Am J Med Genet B Neuropsychiatr Genet 147B:1399-411 |
