Variants at IRX4 as prostate cancer expression quantitative trait loci

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 riskassociated 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 r10%). 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 ¼ 4.91 Â 10 À5 ). 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.

Association of Prostate Cancer Risk Variants with Gene Expression in Normal and Tumor Tissue

“…rs10993994 was associated with NCOA4 in normal tissue with p=5.7x10 −5 , but was null in tumor (p=0.64), consistent with a previous finding (19). We also confirmed other previous findings (20, 21): rs12653946 with IRX4 (in tumor and normal), rs8102476 with PPP1R14A (in tumor and normal), rs6465657 with LMTK2 (in tumor only), and rs5945619 with NUDT10 (in tumor only). However, we did not confirm an association of rs4430796 with HNF1B in normal tissue (p=0.66) (19) or associations with FAM83F (p=0.29), YIF1B (p=0.37) , FAM98C (p=0.17) , FOXP4 (p=0.19) , or TFEB (p=0.78) in tumor tissue (21).…”

“…In addition to confirming the MSMB and NCOA4 results, NUDT11 was associated with rs5945619 and SLC22A3 was borderline significantly associated with rs9364554 in both tumor and normal tissue; and HNF1B was associated with rs4430796 in normal tissue only (19). Harries et al observed an association between rs6465657 and expression of nearby LMTK2 (20), while Xu et al found a proxy for rs12653946 to be strongly associated with the expression of nearby IRX4 (21). …”

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

“…Over-expression of IRX4 significantly increased invasion relative to controls in all conditions examined and IRX4 had high relative expression in a subset of basal-like breast cancers (Figures 5,6). IRX4 is a homeobox transcription factor involved in cardiogenesis, marking a ventricular-specific progenitor cell (Nelson et al, 2016) and is also associated with prostate cancer risk (Xu et al, 2014). SNX29 belongs to the sorting nexin protein family that function in endosomal sorting and signalling (Marat and Haucke, 2016).…”

Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

“…Multiple studies have shown that PrCa-and other disease-associated variants are enriched near variants that correlate with gene expression levels [9][10][11][12][13] . In fact, recent approaches have integrated expression quantitative trait loci (eQTLs) with GWAS to implicate several plausible genes for PrCa risk (e.g., IRX4, MSMB, NCOA4, NUDT11 and SLC22A3) 5; [14][15][16][17][18][19][20][21] . While overlapping eQTLs and GWAS is powerful, the high prevalence of eQTLs 22 coupled with linkage disequilibrium (LD) renders it difficult to distinguish the true susceptibility gene from spurious co-localization at the same locus 23 .…”