Strong Evidence That KIAA0319 on Chromosome 6p Is a Susceptibility Gene for Developmental Dyslexia

Abstract

Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (approximately 2-3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P<.01-.003). After redundant SNPs were excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at P</=.05 were next genotyped in a semi-independent sample of 143 trios of probands with DD and their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P</=.04-.002), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an amino acid (P=.002; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global P=.00001 in the case-control sample; P=.02 in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P=.00003 in the case-control sample; P=.006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown.

Further evidence that the KIAA0319 gene confers susceptibility to developmental dyslexia

“…No association with DD was observed for any of the DCDC2 variants analyzed in the Cardiff sample (Table 1), in agreement with our previous study in KIAA0319, DCDC2 and DD D Harold et al which 30 SNPs across DCDC2 were examined using a DNA pooling strategy. 18 The intronic deletion showed no evidence of association in the Cardiff sample, having a frequency of 9% both in cases and controls, which is identical to that seen in the Oxford severe dyslexic probands (data not shown). Nor was any association with DD observed with the deletion/STR polymorphism either globally (P = 0.4236) or with the specific risk 'allele' comprised of the deletion and rare STR alleles as described in Meng et al 20 (P = 0.7468; see Supplementary Table 3).…”

“…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.…”

“…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.…”

“…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. In a complementary study, Cope et al 18 employed a case/control sample in which a severe definition of dyslexia was used to ascertain probands (hereafter referred to as the Cardiff sample). 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.…”

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

“…Thus, it is plausible to consider candidate single‐nucleotide polymorphisms (SNPs) reported to be associated with SLI also as relevant candidate SNPs for dyslexia and dyslexia‐related processes. Genes with already reported associations to both, SLI and dyslexia, include FOXP2 (Lai, Fisher, Hurst, Vargha‐Khadem, & Monaco, 2001; Wilcke et al., 2012), KIAA0319 (Cope et al., 2005; Newbury et al., 2011), CNTNAP2 (Newbury et al., 2011; Peter et al., 2011; Vernes et al., 2008), and CMIP (Newbury et al., 2009; Scerri et al., 2011). …”