Variants at IRX4 as prostate cancer expression quantitative trait loci

Eur J Hum Genet. 2014 Apr;22(4):558-63. doi: 10.1038/ejhg.2013.195. Epub 2013 Sep 11.

Abstract

Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer risk-associated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript-genotype associations, of which 27 were significant (false discovery rate ≤10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P=4.91 × 10(-5)). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Mapping
  • Gene Expression Regulation, Neoplastic*
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Homeodomain Proteins / genetics*
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide*
  • Prostatic Neoplasms / genetics*
  • Quantitative Trait Loci*

Substances

  • Genetic Markers
  • Homeodomain Proteins
  • IRX4 protein, human