Appraising the link between excess adiposity and obesity-related gynaecologic cancers: A Mendelian Randomisation Study (360G-Wellcome-316115_Z_24_Z)

Observational evidence links excess adiposity to cancer but the underlying mechanisms are not clearly understood. Sex and growth hormones, chronic inflammation, and insulin signaling are key mediators of the obesity-cancer relationship but these explain a small proportion of the variation in cancer risk, therefore other mechanisms remain to be discovered. This research will use large genomic datasets and the two-step two-sample Mendelian randomisation (MR) design to appraise the link between excess adiposity and obesity-related gynaecologic cancers. Objectives will include: 1) test the associations between genetically-proxied anthropometry measures e.g., body mass index, waist circumference, waist-hip ratio, and circulating proteins and metabolites as intermediate biomarkers (step 1). 2) Test the associations between genetically-proxied anthropometry-related intermediate biomarkers (in step 1) and site-specific obesity-related gynaecologic cancers (step 2). 3) Perform sensitivity analyses (e.g., weighted median, weighted mode, MR-Egger) to determine if the results are robust to horizontal pleiotropy. 4) Perform functional annotation of the putatively causal biomarkers of exposure to identify the implicated metabolic pathways. 5) Conduct colocalisation analyses to determine if the single nucleotide polymorphisms associated with the top protein biomarkers (pQTLs) overlap with those that drive protein expression in target tissues (eQTLs). Key words: Obesity, Biomarkers, Gynaecologic Cancer, Ovarian, Endometrial, Mendelian Randomisation