Our goal is to identify genes that confer susceptibility to dyslexia, a complex disorder affecting 5-7 percent of school-age children. Children with dyslexia have unexpected difficulty learning to read and spell. There is ample evidence that genetic factors contribute to dyslexia. Multiple loci have been implicated and candidate genes in some of these regions are now being evaluated. Although rare families may evidence Mendelian forms of dyslexia that result from defects in single genes, the common form of the disorder is genetically complex. Dyslexia is therefore both phenotypically and genetically heterogeneous. To address the issue of phenotypic heterogeneity, we will study individual measures of reading and writing ability and processes contributing to fluency, alone and with covariates chosen on the basis of linguistic and cognitive neuroscience. A ten-year collaborative effort in an NIH-funded Learning Disabilities Center (UWLDC; 1996-2005) resulted in a dataset of 283 multigenerational families with dyslexia. This exceptional resource includes extensive data on a wide range of quantitative phenotypes related to dyslexia. The data set is further enriched by genome scan data recently provided by the NHLBI-supported Mammalian Genotyping Service for 1131 individuals in 144 pedigrees. We will (i) complete recruitment, phenotypic evaluation, and DMA sampling of a small number of outstanding individuals; (ii) develop models of transmission of phenotypes, including measures of executive function, and select those most likely to yield good power for linkage mapping in our sample; (iii) carry out linkage analyses including genomewide scans, evaluation of candidate polymorphisms as covariates, joint analyses of more than one chromosome simultaneously, and sensitivity analyses to guard against false-positive results; and (iv) carry out fine scale mapping of regions identified in the linkage analyses, as well as initial steps towards identifying causative genes. Analyses completed during the tenure of the UWLDC found that genes on chr 2q and 13q affect the speed and therefore fluency of decoding and reading, and corroborated involvement of a gene on chr 15 in real word reading, thus validating our approach. This study will identify genetic causes of dyslexia, which will in turn lead to earlier identification of children at risk and more tailored interventions for this common disability that has life-long educational, economic, and social repercussions. ? ? ? ?
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