Integration of population-level genotype data with functional annotation reveals over-representation of long noncoding RNAs at ovarian cancer susceptibility loci

Brett M. Reid, Jennifer B. Permuth, Y. Ann Chen, Jamie K. Teer, Alvaro N A Monteiro, Zhihua Chen, Jonathan Tyrer, Andrew Berchuck, Jennifer A. Doherty, Ellen L Goode, Edwin S. Iverson, Kate Lawrenson, Celeste L. Pearce, Paul D. Pharoah, Catherine M. Phelan, Susan J. Ramus, Mary Anne Rossing, Joellen M. Schildkraut, Jin Q. Cheng, Simon A. Gayther

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)116-125
Number of pages10
JournalCancer Epidemiology Biomarkers and Prevention
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Long Noncoding RNA
Ovarian Neoplasms
Genotype
Population
Single Nucleotide Polymorphism
Genome-Wide Association Study
Epigenomics
Ovarian epithelial cancer
Epidemiologic Studies
Epidemiology
Transcription Factors
Alleles
Genome
Gene Expression

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

Integration of population-level genotype data with functional annotation reveals over-representation of long noncoding RNAs at ovarian cancer susceptibility loci. / Reid, Brett M.; Permuth, Jennifer B.; Ann Chen, Y.; Teer, Jamie K.; Monteiro, Alvaro N A; Chen, Zhihua; Tyrer, Jonathan; Berchuck, Andrew; Doherty, Jennifer A.; Goode, Ellen L; Iverson, Edwin S.; Lawrenson, Kate; Pearce, Celeste L.; Pharoah, Paul D.; Phelan, Catherine M.; Ramus, Susan J.; Rossing, Mary Anne; Schildkraut, Joellen M.; Cheng, Jin Q.; Gayther, Simon A.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 26, No. 1, 01.01.2017, p. 116-125.

Research output: Contribution to journalArticle

Reid, BM, Permuth, JB, Ann Chen, Y, Teer, JK, Monteiro, ANA, Chen, Z, Tyrer, J, Berchuck, A, Doherty, JA, Goode, EL, Iverson, ES, Lawrenson, K, Pearce, CL, Pharoah, PD, Phelan, CM, Ramus, SJ, Rossing, MA, Schildkraut, JM, Cheng, JQ & Gayther, SA 2017, 'Integration of population-level genotype data with functional annotation reveals over-representation of long noncoding RNAs at ovarian cancer susceptibility loci', Cancer Epidemiology Biomarkers and Prevention, vol. 26, no. 1, pp. 116-125. https://doi.org/10.1158/1055-9965.EPI-16-0341
Reid, Brett M. ; Permuth, Jennifer B. ; Ann Chen, Y. ; Teer, Jamie K. ; Monteiro, Alvaro N A ; Chen, Zhihua ; Tyrer, Jonathan ; Berchuck, Andrew ; Doherty, Jennifer A. ; Goode, Ellen L ; Iverson, Edwin S. ; Lawrenson, Kate ; Pearce, Celeste L. ; Pharoah, Paul D. ; Phelan, Catherine M. ; Ramus, Susan J. ; Rossing, Mary Anne ; Schildkraut, Joellen M. ; Cheng, Jin Q. ; Gayther, Simon A. / Integration of population-level genotype data with functional annotation reveals over-representation of long noncoding RNAs at ovarian cancer susceptibility loci. In: Cancer Epidemiology Biomarkers and Prevention. 2017 ; Vol. 26, No. 1. pp. 116-125.
@article{f0304da1cbe946ea949d3b9371e9852f,
title = "Integration of population-level genotype data with functional annotation reveals over-representation of long noncoding RNAs at ovarian cancer susceptibility loci",
abstract = "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.",
author = "Reid, {Brett M.} and Permuth, {Jennifer B.} and {Ann Chen}, Y. and Teer, {Jamie K.} and Monteiro, {Alvaro N A} and Zhihua Chen and Jonathan Tyrer and Andrew Berchuck and Doherty, {Jennifer A.} and Goode, {Ellen L} and Iverson, {Edwin S.} and Kate Lawrenson and Pearce, {Celeste L.} and Pharoah, {Paul D.} and Phelan, {Catherine M.} and Ramus, {Susan J.} and Rossing, {Mary Anne} and Schildkraut, {Joellen M.} and Cheng, {Jin Q.} and Gayther, {Simon A.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1158/1055-9965.EPI-16-0341",
language = "English (US)",
volume = "26",
pages = "116--125",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

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.

PY - 2017/1/1

Y1 - 2017/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85009088560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009088560&partnerID=8YFLogxK

U2 - 10.1158/1055-9965.EPI-16-0341

DO - 10.1158/1055-9965.EPI-16-0341

M3 - Article

C2 - 28035019

AN - SCOPUS:85009088560

VL - 26

SP - 116

EP - 125

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 1

ER -