Multi-omics Mendelian randomization integrating GWAS, eQTL, and mQTL data identified genes associated with breast cancer.

Abstract

Breast cancer (BC) remains a major disease posing a threat to women's health, but the underlying biological interpretation remains largely unknown. Here, we aimed to identify genes associated with breast cancer and analyze their pathophysiological mechanisms based on multi-omics Mendelian randomization (MR). Summary-data-based MR (SMR) was performed to estimate the causal effects of blood and breast mammary tissue expression quantitative trait loci (eQTLs) on BC. External validation analysis was used to validate the identified genes. Integration analyses BC GWAS summaries with eQTLs and DNA methylation QTLs (mQTLs) from the blood were conducted using SMR to prioritize putative blood genes and their regulatory elements associated with BC risk. Finally, two prior genes (ATG10 and RCCD1) from blood tissue reached significant levels in both BCAC (ATG10: ORBRCR = 0.91, PBRCR = 1.29 × 10-11; RCCD1: ORBRCR = 0.90, PBRCR = 3.72 × 10-15) and FinnGen cohorts (ATG10: ORFinnGen = 0.89, PFinnGen = 8.55 × 10-5; RCCD1: ORFinnGen = 0.89, PFinnGen = 2.38 × 10-8). Additionally, those two genes from breast tissues also replicated in both BCAC (ATG10: ORBRCR = 0.95, PBRCR = 1.02 × 10-9; RCCD1: ORBRCR = 0.87, PBRCR = 4.70 × 10-10) and FinnGen cohorts (ATG10: ORFinnGen = 0.93, PFinnGen = 2.38 × 10-4; RCCD1: ORFinnGen = 0.85, PFinnGen = 3.81 × 10-6). Sensitive analysis and external validation analysis validated those two identified genes. Multi-omics MR analysis showed that the SNP signals associated with ATG10 and RCCD1 were significant across the data from BC Genome-wide association study (GWAS), eQTL, and mQTL studies. In conclusion, we identified two priority genes that are potentially associated with BC. These findings improve our limited understanding of the mechanism of BC and shed light on the development of therapeutic agents for treating BC.