Investigation of Dyslexia and SLI Risk Variants in Reading- and Language-Impaired Subjects

Abstract

Dyslexia (or reading disability) and specific language impairment (or SLI) are common childhood disorders that show considerable co-morbidity and diagnostic overlaps and have been suggested to share some genetic aetiology. Recently, genetic risk variants have been identified for SLI and dyslexia enabling the direct evaluation of possible shared genetic influences between these disorders. In this study we investigate the role of variants in these genes (namely MRPL19/C20RF3,ROBO1,DCDC2, KIAA0319, DYX1C1, CNTNAP2, ATP2C2 and CMIP) in the aetiology of SLI and dyslexia. We perform case–control and quantitative association analyses using measures of oral and written language skills in samples of SLI and dyslexic families and cases. We replicate association between KIAA0319 and DCDC2 and dyslexia and provide evidence to support a role for KIAA0319 in oral language ability. In addition, we find association between reading-related measures and variants in CNTNAP2 and CMIP in the SLI families.Electronic supplementary materialThe online version of this article (doi:10.1007/s10519-010-9424-3) contains supplementary material, which is available to authorized users.

Shining a light on CNTNAP2: complex functions to complex disorders

“…27 Significant association was identified for quantitative measures of expressive and receptive language ability as well as scores of non-word repetition (which are thought to relate to phonological working memory and therefore language-related processing ability) with a cluster of SNPs within introns 13-14 ( Figure 1a). 20,24 Non-word repetition was similarly associated with one of these intron 13 variants (rs2710102) in a cohort of dyslexia probands. 25 Strong evidence for a connection between CNTNAP2 and ASD has also emerged.…”

“…CNTNAP2 variants are associated with complex disorders Genome-wide association studies have also linked CNTNAP2 to complex neurological disorders, including language impairment, autism, dyslexia, schizophrenia, and depression 18,20,[22][23][24][25][26] (Table 2), although causal variants have not yet been identified. Convincing evidence has linked common variants (ie, single nucleotide polymorphisms; SNPs) in the CNTNAP2 region with the most common form of language disorder in children: specific language impairment (SLI).…”

ATP2C2andDYX1C1are putative modulators of dyslexia‐related MMR

“…Furthermore, several studies failed to replicate the initial association of rs3743205‐ DYX1C1 found by Taipale et al. (2003) (Bellini et al., 2005; Brkanac et al., 2007; Marino et al., 2005, 2007; Newbury et al., 2011; Saviour et al., 2008; Wigg et al., 2004). …”

“…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.…”

“…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). …”