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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Behavioral Genetics and Epidemiology Study Section (BGES)
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Miller, Brett
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Peter, Beate; Wijsman, Ellen M; Nato Jr, Alejandro Q et al. (2016) Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech. PLoS One 11:e0153864
Rubenstein, Kevin B; Raskind, Wendy H; Berninger, Virginia W et al. (2014) Genome scan for cognitive trait loci of dyslexia: Rapid naming and rapid switching of letters, numbers, and colors. Am J Med Genet B Neuropsychiatr Genet 165B:345-56
Saad, Mohamad; Wijsman, Ellen M (2014) Combining family- and population-based imputation data for association analysis of rare and common variants in large pedigrees. Genet Epidemiol 38:579-90
Saad, Mohamad; Wijsman, Ellen M (2014) Power of family-based association designs to detect rare variants in large pedigrees using imputed genotypes. Genet Epidemiol 38:1-9
Peter, Beate; Matsushita, Mark; Oda, Kaori et al. (2014) De novo microdeletion of BCL11A is associated with severe speech sound disorder. Am J Med Genet A 164A:2091-6
Button, Le; Peter, Beate; Stoel-Gammon, Carol et al. (2013) Associations among measures of sequential processing in motor and linguistics tasks in adults with and without a family history of childhood apraxia of speech: a replication study. Clin Linguist Phon 27:192-212
Peter, Beate; Button, Le; Stoel-Gammon, Carol et al. (2013) Deficits in sequential processing manifest in motor and linguistic tasks in a multigenerational family with childhood apraxia of speech. Clin Linguist Phon 27:163-91
Raskind, Wendy H; Peter, Beate; Richards, Todd et al. (2012) The genetics of reading disabilities: from phenotypes to candidate genes. Front Psychol 3:601
Peter, Beate; Matsushita, Mark; Raskind, Wendy H (2012) Motor sequencing deficit as an endophenotype of speech sound disorder: a genome-wide linkage analysis in a multigenerational family. Psychiatr Genet 22:226-34
Wijsman, Ellen M (2012) The role of large pedigrees in an era of high-throughput sequencing. Hum Genet 131:1555-63

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