Reading disability is by far the most frequently diagnosed form of childhood learning disability, affecting between 5 and 10% of school-age children. Although several genome-wide linkage studies have been reported for reading disability, more powerful association studies have been limited to fine mapping of linkage regions and to small numbers of candidate genes. The proposed genetic research will use an innovative strategy to detect some of the associations between reading disability and quantitative trait loci (QTLs) of small effect size: using single-nucleotide polymorphism (SA/P) microarrays and pooled DNA (SNP-MaP). Pooled DNA makes it possible to study very large samples in order to provide statistical power to detect QTLs of small effect size. The Affymetrix GeneChip? Human Mapping 500K Array Set will genotype more than 500,000 SNPs. SNP-MaP using the 500K microarray set is a powerful tool for screening the genome systematically, efficiently, and inexpensively. SNPs nominated by this screening tool will be individually genotyped to confirm their association with reading disability. DNA and reading data already obtained for 5000 pairs of 7-year-old twins will be used in two independent studies to screen the 500K GeneChip using pooled DNA: low versus high MZ twins and low versus high DZ twins. Each of these 4 groups will have an N of about 500 and will be divided into 5 subpools of about 100 in order to estimate sampling variance. The 20 subpools will be genotyped twice on 500K GeneChips. This design will provide 99% power to detect a QTL that accounts for 1% of the variance (p = .001). From the results of these two studies, the 150 most significant SNPs will be selected for individual genotyping. 8200 children (one member of 1800 MZ pairs; both members of 3200 DZ pairs) will be individually genotyped in order to confirm the results of the two DNA pooling studies using variance components analysis but also testing the QTL hypothesis that the SNP associations operate across the population. The composite SNP-set will be useful as a genetic risk index in behavioral genomic research on reading. Finding replicated QTL associations responsible for the high heritability of reading will facilitate research on causal pathways between genes, brain and reading disability. Identifying genes associated with reading disability will eventually lead to better diagnoses, individually tailored treatments, and interventions that can prevent the development of reading disability.
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