A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States

Abstract

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 approximately 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.

Figure 1

Linkage across 6p24.3-21.1 with reading-related measures in sample 1 (223 U.K. siblings, 195 total sibling pairs), before and after adjustment for IQ. IQ adjustment increased the strength of linkage and refined the QTL position.

Figure 2

Representation of the 225-kb region surrounding the QTL in sample 1. The LD map shows a three-dimensional color-coded plot for pairwise intermarker LD statistics (48 biallelic markers). The colors represent D′ values: green indicates high LD, and blue indicates low LD. The height of the peaks represents the −log₁₀ significance of pairwise LD; high peaks indicate significant LD. Three major LD regions are distinguishable: A, B, and C. The red ribbon represents the significance of SNP associations (−ln[P value]) with the IQ-adjusted orthographic coding (OC-irreg) phenotype (see also table A1 [online only]). The SNPs that showed the strongest associations (and the corresponding P values) are indicated by arrows. The genes within the region and the locations of the SNPs are shown at the bottom.