title: Integration of Population-Level Genotype Data with Functional Annotation Reveals Over-Representation of Long Noncoding RNAs at Ovarian Cancer Susceptibility Loci.
abstract: 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.
  
  
  
  Using imputed GWAS data from about 18,000 invasive EOC cases and 34,000 controls of European ancestry, the GENCODE (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.
  
  
  
  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.
  
  
  
  lncRNAs are significantly enriched at EOC risk regions, suggesting a mechanistic role for lncRNAs in driving predisposition to EOC.
  
  
  
  lncRNAs represent key candidates for integrative epidemiologic and functional studies. Further research on their biologic role in ovarian cancer is indicated. Cancer Epidemiol Biomarkers Prev; 26(1); 116-25. ©2016 AACR.
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Reid
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Permuth
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Chen
authors.affiliation: University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tyrer
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.affiliation: The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doherty
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
authors.affiliation: Duke University, Durham, North Carolina.
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Iverson
authors.affiliation: Cedars-Sinai Hospital, Los Angeles, California.
authors.forename: Kate
authors.initials: K
authors.lastname: Lawrenson
authors.affiliation: School of Public Health, University of Michigan, Ann Arbor, Michigan.
authors.forename: Celeste L
authors.initials: CL
authors.lastname: Pearce
authors.affiliation: University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Phelan
authors.affiliation: Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Ramus
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Rossing
authors.affiliation: University of Virginia, Charlottesville, Virginia.
authors.forename: Joellen M
authors.initials: JM
authors.lastname: Schildkraut
authors.affiliation: Moffitt Cancer Center & Research Institute, Tampa, Florida.
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
authors.affiliation: Cedars-Sinai Hospital, Los Angeles, California.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Gayther
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sellers
mesh_terms: D000328:Adult; D000368:Aged; D000077216:Carcinoma, Ovarian Epithelial; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D062085:RNA, Long Noncoding / Q000235:genetics*; D018570:Risk Assessment
chemical_list: D062085:RNA, Long Noncoding