In:
Nature Communications, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2015-09-22)
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2015
detail.hit.zdb_id:
2553671-0
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