Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner

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dc.contributor.authorMartin, Ruairidh I R
dc.contributor.authorOwens, W A
dc.contributor.authorCunnington, Michael S
dc.contributor.authorMayosi, Bongani M
dc.contributor.authorKoref, Mauro S
dc.contributor.authorKeavney, Bernard D
dc.date.accessioned2015-02-16T12:47:17Z
dc.date.available2015-02-16T12:47:17Z
dc.date.issued2014-12-24
dc.date.updated2015-01-21T19:05:06Z
dc.description.abstractBackground: The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression. Results: We genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (pā€‰=ā€‰4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (pā€‰=ā€‰7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies. Conclusions: ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements.en_ZA
dc.identifier.apacitationMartin, R. I. R., Owens, W. A., Cunnington, M. S., Mayosi, B. M., Koref, M. S., & Keavney, B. D. (2014). Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner. <i>BMC Genetics</i>, http://hdl.handle.net/11427/12481en_ZA
dc.identifier.chicagocitationMartin, Ruairidh I R, W A Owens, Michael S Cunnington, Bongani M Mayosi, Mauro S Koref, and Bernard D Keavney "Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner." <i>BMC Genetics</i> (2014) http://hdl.handle.net/11427/12481en_ZA
dc.identifier.citationMartin, Ruairidh I. R.; Owens, W. A.; Cunnington, Michael S.; Mayosi, Bongani M.; Koref, Mauro S. and Keavney, Bernard D. (2014) Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner. BMC Genetics. 15(1):136-143.en_ZA
dc.identifier.ris TY - Journal Article AU - Martin, Ruairidh I R AU - Owens, W A AU - Cunnington, Michael S AU - Mayosi, Bongani M AU - Koref, Mauro S AU - Keavney, Bernard D AB - Background: The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression. Results: We genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (pā€‰=ā€‰4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (pā€‰=ā€‰7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies. Conclusions: ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements. DA - 2014-12-24 DB - OpenUCT DO - 10.1186/s12863-014-0136-1 DP - University of Cape Town J1 - BMC Genetics LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner TI - Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner UR - http://hdl.handle.net/11427/12481 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/12481
dc.identifier.urihttp://dx.doi.org/10.1186/s12863-014-0136-1
dc.identifier.vancouvercitationMartin RIR, Owens WA, Cunnington MS, Mayosi BM, Koref MS, Keavney BD. Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner. BMC Genetics. 2014; http://hdl.handle.net/11427/12481.en_ZA
dc.language.rfc3066en
dc.publisherBioMed Centralen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsCreative Commons Attribution 4.0 International (CC BY 4.0)*
dc.rights.holderMartin et al.; licensee BioMed Central.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_ZA
dc.sourceBMC Geneticsen_ZA
dc.source.urihttp://www.biomedcentral.com/bmcgenet/
dc.subject.lcshAtrial fibrillationen_ZA
dc.subject.otherExpression QTL mappingen_ZA
dc.subject.otherTrans-ethnic mappingen_ZA
dc.subject.otherGenome-wide association studyen_ZA
dc.titleChromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manneren_ZA
dc.typeJournal Articleen_ZA
uct.type.filetype
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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