The Research Projects in the Colorado Learning Disabilities Research Center are focused on the characterization of reading disabilities (RD) and ADHD using genetic analyses to define fundamental deficits based on etiology. This task is complicated by genetic heterogeneity (different genes affecting the same phenotype) and pleiotropism (a single gene affecting more than one phenotype). The studies in Project IV address these problems through identification and detailed phenotypic. characterization of quantitative trait loci (QTLs) underlying RD and ADHD and discovery of mutations in candidate genes. Identification of QTLs is critical to validating the independent genetic contributions to phenotypes examined by the projects in the CLDRC and to documenting deficits that are influenced by the same QTLs. In particular, the influences of separate loci on RD and ADHD will determine whether their frequent comorbidity is due to co-segregation of independent loci, or if they can have a common genetic, and therefore etiologic, basis. In addition to aiding the genetic dissection of cognitive abilities, we will also examine genetic influences at a clinical level, testing whether certain loci contribute to variation in response to intervention. While there have been many reports of linkage of chromosomal loci to RD and to ADHD, only a few of these have been replicated, and many of the regions of linkage are quite large. The size of our population and the depth of the phenotypic analysis will allow us to verify candidate loci, characterize their phenotypes, and narrow the critical region sufficiently to identify candidate genes. Discovery of mutations that affect the structure or regulation of the gene product will be strong evidence that a gene has a causal role, and knowledge of the function of such genes will lead to understanding of the neurological mechanisms underlying the processes of reading and attention. This detailed genetic and phenotypic information, along with the corresponding measures of response to intervention, will ultimately contribute to the development of more effective methods of treatment.
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