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

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

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Numerous genetic association studies have implicated the K/AA0319 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 K/AA0319, and (2) the strongest association has been found for the region spanning exon 1 of K/AA0319. Here, we test the hypothesis that variant(s) responsible for reduced K/AA0319 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 K/AA0319 and determined that three of these are strongly associated with multiple reading-related traits. Using luciferase-expressing constructs containing the K/AA0319 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 K/AA0319 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.

Original languageEnglish (US)
JournalPLoS Genetics
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Fingerprint

Dyslexia
Haplotypes
haplotypes
Gene Expression
gene expression
gene
allele
strategic approach
luciferase
Luciferases
Alleles
cell lines
chromosome
Genes
polymorphism
alleles
Cell Line
genetic traits
genes
Transcription Initiation Site

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Dennis, M., Paracchini, S., Scerri, T. S., Prokunina-Olsson, L., Knight, J. C., Wade-Martins, R., ... Monaco, A. P. (2009). A common variant associated with dyslexia reduces expression of the KIAA0319 gene. PLoS Genetics, 5(3). https://doi.org/10.1371/journal.pgen.1000436

A common variant associated with dyslexia reduces expression of the KIAA0319 gene. / Dennis, Megan; Paracchini, Silvia; Scerri, Thomas S.; Prokunina-Olsson, Ludmila; Knight, Julian C.; Wade-Martins, Richard; Coggill, Penny; Beck, Stephan; Green, Eric D.; Monaco, Anthony P.

In: PLoS Genetics, Vol. 5, No. 3, 01.03.2009.

Research output: Contribution to journalArticle

Dennis, M, Paracchini, S, Scerri, TS, Prokunina-Olsson, L, Knight, JC, Wade-Martins, R, Coggill, P, Beck, S, Green, ED & Monaco, AP 2009, 'A common variant associated with dyslexia reduces expression of the KIAA0319 gene', PLoS Genetics, vol. 5, no. 3. https://doi.org/10.1371/journal.pgen.1000436
Dennis M, Paracchini S, Scerri TS, Prokunina-Olsson L, Knight JC, Wade-Martins R et al. A common variant associated with dyslexia reduces expression of the KIAA0319 gene. PLoS Genetics. 2009 Mar 1;5(3). https://doi.org/10.1371/journal.pgen.1000436
Dennis, Megan ; Paracchini, Silvia ; Scerri, Thomas S. ; Prokunina-Olsson, Ludmila ; Knight, Julian C. ; Wade-Martins, Richard ; Coggill, Penny ; Beck, Stephan ; Green, Eric D. ; Monaco, Anthony P. / A common variant associated with dyslexia reduces expression of the KIAA0319 gene. In: PLoS Genetics. 2009 ; Vol. 5, No. 3.
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