Abstract
Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI—and their associated deficits—are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-014-1427-3) contains supplementary material, which is available to authorized users.
Highlights
Communication disorders and learning disabilities are common, and can have long-lasting, adverse effects on affected individuals’ academic performance, self-esteem, and socioeconomic outcomes
There was an association of a six-marker haplotype within DCDC2 that is linked to the risk element READ1 and Severe Reading disability (RD) that is explored fully in Powers et al (2013)
With Moderate RD, there was an association between rs1562422 near the gene FAM65B and the pseudogene CMAHP, which was replicated in the Colorado RD cohort (Tables 4, 6)
Summary
Communication disorders and learning disabilities are common, and can have long-lasting, adverse effects on affected individuals’ academic performance, self-esteem, and socioeconomic outcomes. Reading disability (RD or dyslexia) and language impairment (LI) affect 5–17 and 5–8 % of schoolchildren, respectively (Newbury et al 2010; Pennington and Bishop 2009). RD and LI are characterized by unexpected difficulties with reading and verbal language, respectively, despite adequate educational and socioeconomic opportunity and instruction, as well as otherwise normal development (Pennington and Bishop 2009; Newbury et al 2010). Children with LI are more likely to develop RD than their non-impaired peers (Pennington and Bishop 2009). RD and LI are complex disorders with substantial genetic and environmental components (Bishop and Hayiou-Thomas 2008; Viding et al 2004). Two DYX2 genes, DCDC2 and KIAA0319, have been identified as RD risk genes, with considerable genetic and functional molecular evidence supporting the involvement of each
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