A Common Variant Associated with Dyslexia Reduces Expression of the KIAA0319 Gene

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
PLoS Genetics (Impact Factor: 7.53). 04/2009; 5(3):e1000436. DOI: 10.1371/journal.pgen.1000436
Source: PubMed


Numerous genetic association studies have implicated the KIAA0319 gene on human chromosome 6p22 in dyslexia susceptibility. The causative variant(s) remains unknown but may modulate gene expression, given that (1) a dyslexia-associated haplotype has been implicated in the reduced expression of KIAA0319, and (2) the strongest association has been found for the region spanning exon 1 of KIAA0319. Here, we test the hypothesis that variant(s) responsible for reduced KIAA0319 expression resides on the risk haplotype close to the gene's transcription start site. We identified seven single-nucleotide polymorphisms on the risk haplotype immediately upstream of KIAA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the KIAA0319 upstream region, we characterized the minimal promoter and additional putative transcriptional regulator regions. This revealed that the minor allele of rs9461045, which shows the strongest association with dyslexia in our sample (max p-value = 0.0001), confers reduced luciferase expression in both neuronal and non-neuronal cell lines. Additionally, we found that the presence of this rs9461045 dyslexia-associated allele creates a nuclear protein-binding site, likely for the transcriptional silencer OCT-1. Knocking down OCT-1 expression in the neuronal cell line SHSY5Y using an siRNA restores KIAA0319 expression from the risk haplotype to nearly that seen from the non-risk haplotype. Our study thus pinpoints a common variant as altering the function of a dyslexia candidate gene and provides an illustrative example of the strategic approach needed to dissect the molecular basis of complex genetic traits.

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Available from: Silvia Paracchini
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    • "In particular, a threemarker risk haplotype rs4504469-rs2038137-rs2143340 spanning TTRAP, THEM2 and KIAA0319 was found to associate with DD [Francks et al., 2004]. The follow-up studies found that presence of this haplotype could reduce KIAA0319 expression [Paracchini et al., 2006] and rs9461045, located within proposed promoter region of KIAA0319, was identified as the causative variant for reduced gene expression [Dennis et al., 2009]. Meanwhile, another study focusing on a 575-kb region of chromosome 6p22.2 "
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    ABSTRACT: Developmental dyslexia (DD) is characterized by difficulties in reading and spelling independent of intelligence, educational backgrounds and neurological injuries. Increasing evidences supported DD as a complex genetic disorder and identified four DD candidate genes namely DYX1C1, DCDC2, KIAA0319 and ROBO1. As such, DCDC2 and KIAA0319 are located in DYX2, one of the most studied DD susceptibility loci. However, association of these two genes with DD was inconclusive across different populations. Given the linguistic and genetic differences between Chinese and other populations, it is worthwhile to investigate association of DCDC2 and KIAA0319 with Chinese dyslexic children. Here, we selected 60 tag SNPs covering DCDC2 and KIAA0319 followed by high density genotyping in a large unrelated Chinese cohort with 502 dyslexic cases and 522 healthy controls. Several SNPs (Pmin = 0.0192) of DCDC2 and KIAA0319 as well as a four-maker haplotype (Padjusted = 0.0289, Odds Ratio (OR) = 1.3400) of KIAA0319 showed nominal association with DD. However, none of these results survived Bonferroni correction for multiple comparisons. Thus, the association of DCDC2 and KIAA0319 with DD in Chinese population should be further validated and their contribution to DD etiology and pathology should be interpreted with caution. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2014 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "Therefore, there is insufficient statistical power to detect the effect in this sample where only minority DD children have problems in phonological awareness. It is interesting to note that phonological awareness is the core deficit in Caucasian populations reading alphabetic scripts, but orthographic skill (OC-choice) was strongly associated with KIAA0319 in European samples [6,8,10,16]. In addition, the effect sizes associated with these markers are relatively small in these studies. "
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    ABSTRACT: Background: Previous studies have shown that KIAA0319 is a candidate gene for dyslexia in western populations. In view of the different languages used in Caucasian and Chinese populations, the aim of the present study was to investigate whether there is also an association of KIAA0319 in Chinese children with dyslexia and/or to the language-related cognitive skills. Method and results: A total of twenty six single nucleotide polymorphisms (SNPs) were genotyped from three hundred and ninety three individuals from 131 Chinese families. Four of the SNPs have been reported in the literature and twenty two being tag SNPs at KIAA0319. Analysis for allelic and haplotypic associations was performed with the UNPHASED program and multiple testing was corrected using permutation. Results indicate that KIAA0319 is not associated with Chinese children with dyslexia but a haplotype consisting of rs2760157 and rs807507 SNPs were significantly associated with an onset detection test, a measure of phonological awareness (pnominal = 6.85 10-5 and pcorrected = 0.0029). Conclusion: In conclusion, our findings suggest that KIAA0319 is associated with a reading-related cognitive skill.
    Full-text · Article · Jul 2014 · Behavioral and Brain Functions
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    • "Within KIAA0319, the most strongly associated variant with RD is a 3-marker risk haplotype that spans approximately the 5′ half of the gene and some of its upstream sequence and neighboring gene TDP2 (Cope et al. 2005; Francks et al. 2004; Paracchini et al. 2006). Both the risk haplotype itself and a putative functional SNP (rs9461045) in linkage disequilibrium with it have been shown to correlate with lower expression of the KIAA0319 gene (Dennis et al. 2009; Elbert et al. 2011). Interestingly, there is evidence that READ1 and the KIAA0319 risk haplotype interact in a non-additive fashion, suggesting that transcriptional co-regulation and interaction may play a key role in the relationship between the DYX2 locus and written/verbal language (Ludwig et al. 2008; Powers et al. 2013). "
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    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 material The online version of this article (doi:10.1007/s00439-014-1427-3) contains supplementary material, which is available to authorized users.
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