Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Quantitative Trait Loci
- Protein Binding
- Ovarian Neoplasms
- Nuchal Cord
- Neoplasms, Glandular and Epithelial
- Neoplasm Proteins
- Humans
- Homeodomain Proteins
- Genetic Predisposition to Disease
- Genetic Association Studies
Citation
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Quantitative Trait Loci
- Protein Binding
- Ovarian Neoplasms
- Nuchal Cord
- Neoplasms, Glandular and Epithelial
- Neoplasm Proteins
- Humans
- Homeodomain Proteins
- Genetic Predisposition to Disease
- Genetic Association Studies