title: Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner.
abstract: 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, (p = 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 (p = 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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. ruairidh.martin@newcastle.ac.uk.
authors.forename: Ruairidh I R
authors.initials: RI
authors.lastname: Martin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. a.owens@newcastle.ac.uk.|Division of Cardiothoracic Services, The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesbrough, UK. a.owens@newcastle.ac.uk.
authors.forename: W Andrew
authors.initials: WA
authors.lastname: Owens
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. Michael.Cunnington@hey.nhs.uk.|Hull and East Yorkshire NHS Trust, Hull, UK. Michael.Cunnington@hey.nhs.uk.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Cunnington
authors.affiliation: Department of Medicine, University of Cape Town, Cape Town, South Africa. bongani.mayosi@uct.ac.za.
authors.forename: Bongani M
authors.initials: BM
authors.lastname: Mayosi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. mauro.santibanez-koref@newcastle.ac.uk.
authors.forename: Mauro Santibáñez
authors.initials: MS
authors.lastname: Koref
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. bernard.keavney@manchester.ac.uk.|Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK. bernard.keavney@manchester.ac.uk.
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Keavney
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000235:genetics; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009080:Mucocutaneous Lymph Node Syndrome / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; D012333:RNA, Messenger; C071660:ZFHX3 protein, human