Distinct genetic profiles of obesity have different effects on breast cancer risk: leveraging Mendelian randomisation to interrogate causal pathways and identify mediating proteins

BACKGROUND: Obesity is a well-established risk factor for many cancers, but its association with breast cancer remains inconsistent. Obesity is a highly complex and polygenic condition, driven by multiple biological pathways, some of which have been linked to beneficial health effects, defining a metabolically healthy obese phenotype. We hypothesise that this heterogeneity may partly underlie the variable association with breast cancer, where different biological pathways may play divergent roles in disease risk. METHODS: We applied an approach in two parts to explore the heterogeneous effects of high body mass index (BMI) on breast cancer risk. First, we applied Mendelian randomisation (MR)-based clustering on genetic data (FinnGen, GIANT, BCAC) to identify clusters of BMI-increasing SNPs with differential effects on breast cancer, and the cluster-specific MR results were replicated in the UK Biobank. Second, we integrated proteomic data to estimate the cluster-specific effects of BMI on protein levels and the effect of these proteins on breast cancer risk, using two-sample MR. Mediation analyses were then carried out using the product-of-coefficient method. RESULTS: We identified three clusters of SNPs associated with increased BMI while having differential effects on breast cancer risk: one risk-increasing (inverse variance weighted MR estimate: 1.27 [1.10, 1.44]), one medium protective (− 0.75 [− 0.82, − 0.68]), and one highly protective (− 1.92 [− 2.21, − 1.62]), comprising 24, 73, and 7 SNPs respectively, with similar magnitude of effects in the UK Biobank. In the two-sample MR, each cluster was associated with many proteins (70, 369 and 44 respectively, FDR q-value < 0.05), and the mediation analysis identified that three proteins significantly mediate cluster-specific effects on breast cancer risk. Among these proteins, MET is known to be involved in breast cancer, while little is known about the roles of CPM and CST6. CONCLUSIONS: These findings suggest that the effect of obesity on breast cancer is mediated through multiple distinct biological pathways. The identified proteins provide a first insight into the mechanisms underlying these pathways. With further investigation, these results could provide a basis for developing personalised treatment strategies.