A common variant associated with dyslexia reduces expression of the KIAA0319 gene.
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 KIAA0...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2009-03-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2653637?pdf=render |
| _version_ | 1828894334778343424 |
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| author | Megan Y 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 |
| author_facet | Megan Y 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 |
| author_sort | Megan Y Dennis |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T14:09:38Z |
| format | Article |
| id | doaj.art-d79197052bf24d4d834af42e43ca394f |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-13T14:09:38Z |
| publishDate | 2009-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-d79197052bf24d4d834af42e43ca394f2022-12-21T23:42:31ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-03-0153e100043610.1371/journal.pgen.1000436A common variant associated with dyslexia reduces expression of the KIAA0319 gene.Megan Y DennisSilvia ParacchiniThomas S ScerriLudmila Prokunina-OlssonJulian C KnightRichard Wade-MartinsPenny CoggillStephan BeckEric D GreenAnthony P MonacoNumerous 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.http://europepmc.org/articles/PMC2653637?pdf=render |
| spellingShingle | Megan Y 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 A common variant associated with dyslexia reduces expression of the KIAA0319 gene. PLoS Genetics |
| title | A common variant associated with dyslexia reduces expression of the KIAA0319 gene. |
| title_full | A common variant associated with dyslexia reduces expression of the KIAA0319 gene. |
| title_fullStr | A common variant associated with dyslexia reduces expression of the KIAA0319 gene. |
| title_full_unstemmed | A common variant associated with dyslexia reduces expression of the KIAA0319 gene. |
| title_short | A common variant associated with dyslexia reduces expression of the KIAA0319 gene. |
| title_sort | common variant associated with dyslexia reduces expression of the kiaa0319 gene |
| url | http://europepmc.org/articles/PMC2653637?pdf=render |
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