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.

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia

“…17,18 Briefly, the Oxford sample included 264 unrelated nuclear families identified from the dyslexia clinic at the Royal Berkshire Hospital in Reading, UK. The majority of families were recruited on the basis of having at least one proband whose single-word reading ability was > 2 s.d.…”

“…By performing a systematic, highdensity linkage disequilibrium screen of candidate genes within the DYX2 region, we found that variation in the KIAA0319 gene was most strongly implicated in dyslexia susceptibility. Subsequent functional analysis showed that the risk haplotype identified by Francks et al 17 is associated with a reduction of expression of KIAA0319, but does not affect either THEM2 or TTRAP. 19 Two recent studies have indicated that another gene within the DYX2 QTL, DCDC2, may also play a role in developmental dyslexia.…”

“…In independent samples from the UK and the US, we previously found evidence that variation in the KIAA0319 gene confers risk of dyslexia. [17][18][19] A 77 kb region was found to be associated with dyslexia in two independent samples of nuclear families from the UK (hereafter referred to as the Oxford sample) and the US. 17 The region extended from the first four exons of KIAA0319 to the first exon of THEM2, covering the entire TTRAP gene.…”

“…[17][18][19] A 77 kb region was found to be associated with dyslexia in two independent samples of nuclear families from the UK (hereafter referred to as the Oxford sample) and the US. 17 The region extended from the first four exons of KIAA0319 to the first exon of THEM2, covering the entire TTRAP gene. A specific three-SNP haplotype across this region was significantly associated with a range of reading-related measures in both the Oxford UK and US samples, particularly when the samples were selected for severity of phenotype.…”

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

“…Similarly, the identified effect sizes of SNP rs2143340‐ KIAA0319 were reported with opposing risk alleles (Francks et al., 2004; Luciano et al., 2007; Newbury et al., 2011). Contradicting effect size directions of risk alleles were also observed in studies investigating intermediate phenotypes of other diseases: Shulman et al.…”