title: The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.
abstract: BACKGROUND
  Many genetic variants have been associated with susceptibility to complex traits by genome wide association studies (GWAS), but for most, causal genes and mechanisms of action have yet to be elucidated. Using bioinformatics, we identified index and proxy variants associated with autoimmune disease susceptibility, with the potential to affect splicing of candidate genes. PCR and sequence analysis of whole blood RNA samples from population controls was then carried out for the 8 most promising variants to determine the effect of genetic variation on splicing of target genes.
  
  
  RESULTS
  We identified 31 splice site SNPs with the potential to affect splicing, and prioritised 8 to determine the effect of genotype on candidate gene splicing. We identified that variants rs11078928 and rs2014886 were associated with altered splicing of the GSDMB and TSFM genes respectively. rs11078928, present in the asthma and autoimmune disease susceptibility locus on chromosome 17q12-21, was associated with the production of a novel Δ exon5-8 transcript of the GSDMB gene, and a separate decrease in the percentage of transcripts with inclusion of exon 6, whereas the multiple sclerosis susceptibility variant rs2014886, was associated with an alternative TFSM transcript encompassing a short cryptic exon within intron 2.
  
  
  CONCLUSIONS
  Our findings demonstrate the utility of a bioinformatic approach in identification and prioritisation of genetic variants effecting splicing of their host genes, and suggest that rs11078928 and rs2014886 may affect the splicing of the GSDMB and TSFM genes respectively.
authors.affiliation: RNA mediated mechanisms of disease group, University of Exeter Medical School, EX2 5DW Exeter, UK. L.W.Harries@exeter.ac.uk.
authors.forename: Faer S
authors.initials: FS
authors.lastname: Morrison
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Locke
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Wood
authors.forename: Marcus
authors.initials: M
authors.lastname: Tuke
authors.forename: Dorota
authors.initials: D
authors.lastname: Pasko
authors.forename: Anna
authors.initials: A
authors.lastname: Murray
authors.forename: Tim
authors.initials: T
authors.lastname: Frayling
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
mesh_terms: D017398:Alternative Splicing; D001327:Autoimmune Diseases / Q000235:genetics; D019295:Computational Biology; D005091:Exons; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007438:Introns; D024101:Mitochondrial Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009690:Nucleic Acid Conformation; D010445:Peptide Elongation Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D000094524:Gasdermins
chemical_list: D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D010445:Peptide Elongation Factors; D020033:Protein Isoforms; C527978:GSDMB protein, human; D000094524:Gasdermins
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