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

ABSTRACT 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, Sep 28, 2015
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    • "Fourteen markers previously showed evidence of replicated association with reading-, language-, and/or IQ-related traits within the DYX2 locus (Powers et al. 2013; Eicher et al. 2014); of these, 7 were directly genotyped in the PING study (Table 1). Additionally, rs9461045, a putative functional SNP associated with expression of KIAA0319, was directly genotyped in PING, totaling 8 DYX2 markers for analysis (Dennis et al. 2009). Three DYX3 markers had previously been associated with neuroimaging phenotypes and were directly genotyped in the PING study (Table 1) (Scerri et al. 2012; Melville et al. 2012). "
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    ABSTRACT: Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes.
    Brain Imaging and Behavior 05/2015; DOI:10.1007/s11682-015-9392-6 · 4.60 Impact Factor
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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.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2014; 165(8). DOI:10.1002/ajmg.b.32267 · 3.42 Impact Factor
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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.
    Behavioral and Brain Functions 07/2014; 10(1):23. DOI:10.1186/1744-9081-10-23 · 1.97 Impact Factor
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