eQTL Colocalization Analyses Identify NTN4 as a Candidate Breast Cancer Risk Gene

• Published in: American journal of human genetics Vol. 107; no. 4; pp. 778 - 787
• Main Authors: Beesley, Jonathan, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Shi, Wei, Hillman, Kristine M., Kaufmann, Susanne, Hussein, Nehal, Kar, Siddhartha, Lima, Luize G., Ham, Sunyoung, Möller, Andreas, Chenevix-Trench, Georgia, Edwards, Stacey L., French, Juliet D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2020; Elsevier
• Subjects: Alleles; Animals; breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Line, Tumor; colocalization; enhancer; Enhancer Elements, Genetic; eQTL; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics - methods; GWAS; Heterografts; Humans; MCF-7 Cells; Mice; Mice, Nude; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Netrins - genetics; Netrins - metabolism; NTN4; Phenotype; Quantitative Trait Loci; Risk; tumor suppressor; enhancer; GWAS; NTN4; breast cancer; tumor suppressor; eQTL; colocalization
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2020.08.006

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.