Molecular genetic techniques and quantitative genetic analysis have evolved together to the point where localization of genes influencing complex disorders has become a reality. These genes do not have to show Mendelian inheritance patterns, and may only confer susceptibility for a disorder. Isolation of these genes will help define both the genetic and environmental pathways that contribute to these disorders. We have demonstrated the success of such techniques in the localization of a gene influencing reading disability to 6p21.3. We now propose to expand both the molecular and analytic aspects of the study to include allelic association, fine mapping, and mutation analysis in order to identify the gene (or genes) in this region and the mutations that affect reading. The CLDC design is unique in that the data allow the comparison of a number of phenotypes of known heritability, their association and linkage with specific marker loci, and, ultimately, determination of the influence of specific genes. In addition to phenotypes related to reading, we will also analyze measures of CNS morphology and attention deficit hyperactivity disorder (ADHD) for linkage to a panel of CNS-related genes. Determination of the function of the genes will reveal the mechanism relating the genotype to the phenotype, which in turn should lead to improved diagnosis and treatment of RD and ADHD, and will lead to improved understanding of CNS development.
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