Identifying and ranking causal biochemical biomarkers for breast cancer: a Mendelian randomisation study

Abstract Background Only a few of the 34 biochemical biomarkers measured in the UK Biobank (UKB) have been associated with breast cancer, with many associations suffering from possible confounding and reverse causation. This study aimed to screen and rank all UKB biochemical biomarkers for possible causal relationships with breast cancer. Methods We conducted two-sample Mendelian randomisation (MR) analyses on ~420,000 women by leveraging summary-level genetic exposure associations from the UKB study (n = 194,174) and summary-level genetic outcome associations from the Breast Cancer Association Consortium (n = 228,951). Our exposures included all 34 biochemical biomarkers in the UKB, and our outcomes were overall, oestrogen-positive, and oestrogen-negative breast cancer. We performed inverse-variance weighted MR, weighted median MR, MR-Egger, and MR-PRESSO for 30 biomarkers for which we found multiple instrumental variables. We additionally performed multivariable MR to adjust for known risk factors, bidirectional MR to investigate reverse causation, and MR Bayesian model averaging to rank the significant biomarkers by their genetic evidence. Results Increased genetic liability to overall breast cancer was robustly associated with the following biomarkers by decreasing importance: testosterone (odds ratio (OR): 1.12, 95% confidence interval (CI): 1.04–1.21), high-density lipoprotein (HDL) cholesterol (OR: 1.08, 95% CI: 1.04–1.13), insulin-like growth factor 1 (OR: 1.08, 95% CI: 1.02–1.13), and alkaline phosphatase (ALP) (OR: 0.93, 95% CI: 0.89–0.98). Conclusions Our findings support a likely causal role of genetically predicted levels of testosterone, HDL cholesterol, and IGF-1, as well as a novel potential role of ALP in breast cancer aetiology. Further studies are needed to understand full disease pathways that may inform breast cancer prevention.