Associations between Gene Expression Variations and Ovarian Cancer Risk Alleles Identified from Genome Wide Association Studies

Hua Zhao,Shashikant Lele,Kunle Odunsi,Li Yan,Song Liu,Leonardo Medico,Jie Shen,Dan Wang,Qiang Hu,Steven Gregory,Yi Xing

doi:10.1371/journal.pone.0047962

Abstract

Functional genetic variations play important roles in shaping phenotypic differences among individuals through affecting gene expression, and thus, very likely to influence disease susceptibility, such as cancer susceptibility. One critical question in this era of post-genome wide association studies (GWAS) is how to assess the functional significance of the genetic variations identified from GWAS. In the current study, with lymphoblastoid cell lines (LCLs) from 74 non-related women with familial ovarian cancer and 47 unrelated controls matched on gender and race, we explored the associations between seven ovarian cancer risk variants identified from GWAS (rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21, and rs2363956 on 19p13) and whole genome mRNA expression profiles. We observed 95 significant trans-associations at a permutation level of 0.001. Compared to the other risk variants, rs10088218, rs1516982, and rs10098821 on 8q24.21 had the greatest number of significant associations (25, 16, and 38, respectively). Two possible cis-associations were observed between rs10098821 and c-Myc, and rs2072590 and HS.565379 (Permutated P = 0.0198 and 0.0399, respectively). Pathway enrichment analysis showed that several key biological pathways, such as cell cycle (P = 2.59×10−06), etc, were significantly overrepresented. Further characterization of significant associations between mRNAs and risk alleles might facilitate understanding the functions of GWAS discovered risk alleles in the genetic etiology of ovarian cancer.

Highlights

Genome wide association studies (GWAS) have successfully identified a number of genetic variations which confer risk to human cancer [1,2,3]
Lymphoblastoid cell lines were derived from the blood samples of 74 non-related women with familial ovarian cancer and 47 unrelated cancer-free controls recruited for the Gilda Radner Familial Ovarian Cancer Registry (GRFOCR)
We assessed the potential implications of these genome wide association studies (GWAS)-discovered variants in ovarian cancer, by performing association analysis to analyze the correlations between mRNA expression variations and variant genotypes

Summary

Introduction

Genome wide association studies (GWAS) have successfully identified a number of genetic variations which confer risk to human cancer [1,2,3]. Most of the risk variants identified from GWAS reside in intergenic, intronic, and other non-coding regions of the genome [4]. The observed associations have yet to be translated into a full understanding of the genes and genetic elements mediating disease susceptibility. Functional genetic variation, which leads to gene expression changes, may play a critical role in determining phenotypic differences among individuals, and is very likely to influence disease susceptibility. As such, studying the associations between genetic variation and gene expression could potentially help prioritize fine-mapping efforts and provide a shortcut to disease biology

Objectives

Methods

Results

Conclusion