Premium
Integrative functional genomics identifies regulatory genetic variant modulating RAB31 expression and altering susceptibility to breast cancer
Author(s) -
Zhang Yi,
Yang Beifang,
Cheng Xiang,
Liu Li,
Zhu Ying,
Gong Yajie,
Yang Yang,
Tian Jianbo,
Peng Xiating,
Zou Danyi,
Yang Lan,
Mei Shufang,
Wang Xiaoyang,
Lou Jiao,
Ke Juntao,
Li Jiaoyuan,
Gong Jing,
Chang Jiang,
Yuan Peng,
Zhong Rong
Publication year - 2018
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22902
Subject(s) - biology , genome wide association study , single nucleotide polymorphism , genetics , genetic association , expression quantitative trait loci , functional genomics , snp , genomics , computational biology , haplotype , genome , allele , gene , genotype
Despite the successes of genome‐wide association study (GWAS) in identifying breast cancer (BC) risk‐associated variants, only a small fraction of the heritability can be explained. The greatest challenge in the post‐GWAS is to identify causal variants and underlying mechanisms responsible for BC susceptibility. In this study, we integrated functional genomic data from ENCODE ChIP‐seq, ANNOVAR, and the TRANSFAC matrix to identify potentially regulatory variants with modulating FOXA1‐binding affinity across the whole genome, and then conducted a two‐stage case‐control study including 2164 cases and 2382 controls to investigate the associations between candidate SNPs and BC susceptibility. We identified a BC susceptibility SNP, rs6506689 G>T, with an odds ratio (OR) of 1.23 (95% confidence interval = 1.07‐1.40, P = 0.003) under a dominant model in the combined study. Biological assays indicated that the germline G>T variation at rs6506689 creates a FOXA1‐binding site and up‐regulates the expression of RAB31, thus playing an important role in the development of BC. Our results highlight the importance of regulatory genetic variants in the development of BC by influencing TF‐DNA interaction and provide critical insights to pinpoint causal genetic variants.