A common variant associated with dyslexia reduces expression of the KIAA0319 gene.

Megan Y Dennis,Thomas S Scerri,Silvia Paracchini,Stephan Beck,Eric D Green,Anthony P Monaco,Penny Coggill,Julian C Knight,Richard Wade-Martins,Ludmila Prokunina-Olsson

doi:10.1371/journal.pgen.1000436

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.

Highlights

Dyslexia, or reading disability (RD), is a condition that affects an individual’s ability to read and spell in the absence of any obvious sensory or neurological impairment and despite adequate intelligence and educational opportunity [1]
Genetic studies have implicated a number of genes as candidates for playing a role in dyslexia
Previous studies have shown that OCT-1 binding to a specific DNA sequence upstream of a gene can reduce the expression of that gene

Summary

Introduction

Reading disability (RD), is a condition that affects an individual’s ability to read and spell in the absence of any obvious sensory or neurological impairment and despite adequate intelligence and educational opportunity [1]. Numerous candidate genes have emerged from genetic association studies and the characterization of chromosomal translocations in individuals with RD, including DYX1C1 on 15q21 [9,10,11], ROBO1 on 3p12 [12], DCDC2 [13,14] and KIAA0319 [15,16,17,18,19] on 6p22, and MRPL19 and C2ORF3 on 2p12 [20]. Several of these genes have been implicated in brain development [21]. Altered neuronal migration has been implicated in RD based on the only post-mortem anatomical study conducted to date [27]; the brains of dyslexic individuals were found to have subtle structural anomalies consistent with defective neuronal migration

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Discussion

Conclusion