A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk
File(s)Ovarian TWAS paper.pdf (953.33 KB)
Accepted version
Author(s)
Type
Journal Article
Abstract
Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in non-coding regions, and causal genes underlying these associations remain largely unknown. Here we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian-tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P<2.2×10-6, we identified 35 genes including FZD4 at 11q14.2 (Z=5.08, P=3.83×10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly-associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and 3 genes remained (P<1.47 x 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.
Date Issued
2018-09
Date Acceptance
2018-07-24
Citation
Cancer Research, 2018, 78 (18), pp.5419-5430
ISSN
1538-7445
Publisher
American Association for Cancer Research
Start Page
5419
End Page
5430
Journal / Book Title
Cancer Research
Volume
78
Issue
18
Copyright Statement
©2018, American Association for Cancer Research.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30054336
PII: 0008-5472.CAN-18-0951
Subjects
Science & Technology
Life Sciences & Biomedicine
Oncology
CORTICOTROPIN-RELEASING HORMONE
IN-VITRO FERTILIZATION
BREAST-CANCER
LOCI
EXPRESSION
MULTIPLE
HOXB2
IDENTIFICATION
VARIANTS
GWAS
1112 Oncology and Carcinogenesis
Oncology & Carcinogenesis
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2018-07-27