A genome-wide search strategy for identifying quantitative trait loci involved in reading and spelling disability (developmental dyslexia)

Family and twin studies of developmental dyslexia have consistently shown t hat there is a significant heritable component for this disorder. However, any genetic basis for the trait is likely to be complex, involving reduced penetrance, phenocopy, heterogeneity and oligogenic inheritance. This compl exity results in reduced power for traditional parametric linkage analysis, where specification of the correct genetic model is important. One strateg y is to focus on large multigenerational pedigrees with severe phenotypes a nd/or apparent simple Mendelian inheritance, as has been successfully demon strated for speech and language impairment. This approach is limited by the scarcity of such families. An alternative which has recently become feasib le due to the development of high-throughput genotyping techniques is the a nalysis of large numbers of sib-pairs using allele-sharing methodology. Thi s paper outlines our strategy for conducting a systematic genome-wide searc h for genes involved in dyslexia in a large number of affected sib-pair fam ilites from the UK. We use a series of psychometric tests to obtain differe nt quantitative measures of reading deficit, which should correlate with di fferent components of the dyslexia phenotype, such as phonological awarenes s and orthographic coding ability. This enables us to use QTL (quantitative trait locus) mapping as a powerful tool for localising genes which may con tribute to reading and spelling disability.