Analysis of variants in untranslated and promoter regions and breast cancer risk using whole genome sequencing data

Abstract

AbstractRecent exome-wide association studies have explored the role of coding variants in breast cancer risk, highlighting the role of rare variants in multiple genes includingBRCA1, BRCA2, CHEK2, ATMandPALB2, as well as new susceptibility genes e.g.,MAP3K1. These genes, however, explain a small proportion of the missing heritability of the disease. Much of the missing heritability likely lies in the non-coding genome. We evaluated the role of rare variants in the 5’ and 3’ untranslated regions (UTRs) of 18,676 genes, and 35,201 putative promoter regions, using whole-genome sequencing data from UK Biobank on 8,001 women with breast cancer and 92,534 women without breast cancer. Burden tests and SKAT-O tests were performed in UTR and promoter regions. For UTR regions of 35 putative breast cancer susceptibility genes, we additionally performed a meta-analysis with a large breast cancer case-control dataset. Associations for 8 regions at P<0.0001 were identified, including several with known roles in tumorigenesis. The strongest evidence of association was for variants in the 5’UTR ofCDK5R1(P=8.5×10−7). These results highlight the potential role of non-coding regulatory regions in breast cancer susceptibility.