TY - JOUR
T1 - Integration of population-level genotype data with functional annotation reveals over-representation of long noncoding RNAs at ovarian cancer susceptibility loci
AU - Reid, Brett M.
AU - Permuth, Jennifer B.
AU - Ann Chen, Y.
AU - Teer, Jamie K.
AU - Monteiro, Alvaro N.A.
AU - Chen, Zhihua
AU - Tyrer, Jonathan
AU - Berchuck, Andrew
AU - Doherty, Jennifer A.
AU - Goode, Ellen L.
AU - Iverson, Edwin S.
AU - Lawrenson, Kate
AU - Pearce, Celeste L.
AU - Pharoah, Paul D.
AU - Phelan, Catherine M.
AU - Ramus, Susan J.
AU - Rossing, Mary Anne
AU - Schildkraut, Joellen M.
AU - Cheng, Jin Q.
AU - Gayther, Simon A.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/1
Y1 - 2017/1
N2 - Background: Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P <5 × 10-8). Most risk SNPs lie within non-protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets. Methods: Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, theGENCODE(v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10-5 > P > 5 × 10-8) overlapping lncRNAs. Results: Of 5,294 EOC-Associated SNPs (P <1.0-10-5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-Associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P =5.0 × 10-4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-Associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression. Conclusions: lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC. Impact: lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated.
AB - Background: Genome-wide association studies (GWAS) have identified multiple loci associated with epithelial ovarian cancer (EOC) susceptibility, but further progress requires integration of epidemiology and biology to illuminate true risk loci below genome-wide significance levels (P <5 × 10-8). Most risk SNPs lie within non-protein-encoding regions, and we hypothesize that long noncoding RNA (lncRNA) genes are enriched at EOC risk regions and represent biologically relevant functional targets. Methods: Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, theGENCODE(v19) lncRNA database was used to annotate SNPs from 13,442 lncRNAs for permutation-based enrichment analysis. Tumor expression quantitative trait locus (eQTL) analysis was performed for sub-genome-wide regions (1 × 10-5 > P > 5 × 10-8) overlapping lncRNAs. Results: Of 5,294 EOC-Associated SNPs (P <1.0-10-5), 1,464 (28%) mapped within 53 unique lncRNAs and an additional 3,484 (66%) SNPs were correlated (r2 > 0.2) with SNPs within 115 lncRNAs. EOC-Associated SNPs comprised 130 independent regions, of which 72 (55%) overlapped with lncRNAs, representing a significant enrichment (P =5.0 × 10-4) that was more pronounced among a subset of 5,401 lncRNAs with active epigenetic regulation in normal ovarian tissue. EOC-Associated lncRNAs and their putative promoters and transcription factors were enriched for biologically relevant pathways and eQTL analysis identified five novel putative risk regions with allele-specific effects on lncRNA gene expression. Conclusions: lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC. Impact: lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated.
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U2 - 10.1158/1055-9965.EPI-16-0341
DO - 10.1158/1055-9965.EPI-16-0341
M3 - Article
C2 - 28035019
AN - SCOPUS:85009088560
SN - 1055-9965
VL - 26
SP - 116
EP - 125
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 1
ER -