eQTL Colocalization Analyses Identify NTN4 as a Candidate Breast Cancer Risk Gene.
Breast cancer genome-wide association studies (GWASs) have identified 150 genomic risk regions containing more than 13,000 credible causal variants (CCVs). The CCVs are predominantly noncoding and enriched in regulatory elements. However, the genes underlying breast cancer risk associations are largely unknown. Here, we used genetic colocalization analysis to identify loci at which gene expression could potentially explain breast cancer risk phenotypes. Using data from the Breast Cancer Association Consortium (BCAC) and quantitative trait loci (QTL) from the Genotype-Tissue Expression (GTEx) project and The Cancer Genome Project (TCGA), we identify shared genetic relationships and reveal novel associations between cancer phenotypes and effector genes. Seventeen genes, including NTN4, were identified as potential mediators of breast cancer risk. For NTN4, we showed the rs61938093 CCV at this region was located within an enhancer element that physically interacts with the NTN4 promoter, and the risk allele reduced NTN4 promoter activity. Furthermore, knockdown of NTN4 in breast cells increased cell proliferation in vitro and tumor growth in vivo. These data provide evidence linking risk-associated variation to genes that may contribute to breast cancer predisposition.
['Beesley|Jonathan|J|', 'Sivakumaran|Haran|H|', 'Moradi Marjaneh|Mahdi|M|', 'Shi|Wei|W|', 'Hillman|Kristine M|KM|', 'Kaufmann|Susanne|S|', 'Hussein|Nehal|N|', 'Kar|Siddhartha|S|', 'Lima|Luize G|LG|', 'Ham|Sunyoung|S|', 'Möller|Andreas|A|', 'Chenevix-Trench|Georgia|G|', 'Edwards|Stacey L|SL|', 'French|Juliet D|JD|']
D000483:Alleles D000818:Animals D001943:Breast Neoplasms D045744:Cell Line, Tumor D004742:Enhancer Elements, Genetic D005260:Female D020869:Gene Expression Profiling D015972:Gene Expression Regulation, Neoplastic D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D023281:Genomics D064593:Heterografts D006801:Humans D061986:MCF-7 Cells D051379:Mice D008819:Mice, Nude D009363:Neoplasm Proteins D000075385:Netrins D010641:Phenotype D040641:Quantitative Trait Loci D012306:Risk
eQTL colocalization NTN4 breast cancer enhancer GWAS tumor suppressor