A 77-Kilobase Region of Chromosome 6p22.2 Is Associated with Dyslexia in Families From the United Kingdom and From the United States

• Published in: American journal of human genetics Vol. 75; no. 6; pp. 1046 - 1058
• Main Authors: Francks, Clyde, Paracchini, Silvia, Smith, Shelley D., Richardson, Alex J., Scerri, Tom S., Cardon, Lon R., Marlow, Angela J., MacPhie, I. Laurence, Walter, Janet, Pennington, Bruce F., Fisher, Simon E., Olson, Richard K., DeFries, John C., Stein, John F., Monaco, Anthony P.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.12.2004; University of Chicago Press; The American Society of Human Genetics
• Subjects: Biological and medical sciences; Chromosome Mapping; Chromosomes, Human, Pair 6 - genetics; Colorado; Disorders of higher nervous function. Focal brain diseases. Central vestibular syndrome and deafness. Brain stem syndromes; Dyslexia - genetics; General aspects. Genetic counseling; Genotype; Haplotypes - genetics; Humans; Linkage Disequilibrium; Medical genetics; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Phenotype; Polymorphism, Genetic; Quantitative Trait Loci - genetics; Siblings; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins - genetics; United Kingdom; United Kingdom; United States; North America; Europe; America; British Isles; USA; Genetic mapping; Human; Nervous system diseases; Reading disorder; Family study; Chromosome; Chromosome C6; Language disorder; Communication disorder; Association; Family environment; Dyslexia; Genetics; Neurological disorder
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/426404

Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of ∼12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.