Articlegold2009

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

Megan Y. Dennis · Silvia Paracchini · Thomas S. Scerri · Ludmila Prokunina‐Olsson · Julian Charles Knight · Richard Wade‐Martins +4 more

104 citations0/0 files storedPLoS Genetics

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Reading and Literacy Development Genetic Associations and Epidemiology Genomic variations and chromosomal abnormalities

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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References

1985Developmental dyslexia: Four consecutive patients with cortical anomalies 1990Prevalence of reading disability in boys and girls. Results of the Connecticut Longitudinal Study 1998Neuroimaging studies of word reading 1998Dyslexia 1990Prevalence of Reading Disability in Boys and Girls 2005DCDC2 is associated with reading disability and modulates neuronal development in the brain 2002Developmental dyslexia: genetic dissection of a complex cognitive trait 2003A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain

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2013Knockdown of the Dyslexia-Associated Gene Kiaa0319 Impairs Temporal Responses to Speech Stimuli in Rat Primary Auditory Cortex 2011Genetics of Speech and Language Disorders 2013The Genetics of Reading Disabilities: From Phenotypes to Candidate Genes 2016Advances in Dyslexia Genetics—New Insights Into the Role of Brain Asymmetries 2013Genetic analysis of dyslexia candidate genes in the European cross-linguistic NeuroDys cohort

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