Genetic relationships and causality between overall and central adiposity and breast, prostate, lung and colorectal cancer

OBJECTIVE Diverse measures of obesity relate to cancer risk differently. Here we assess the relationship between overall and central adiposity and cancer. METHODS We constructed z-score weighted polygenic scores (PGS) for two obesity-related phenotypes; body mass index (BMI) and BMI adjusted waist-to-hip ratio (WHRadjBMI) and tested for their association with five cancers in the UK Biobank: overall breast (BrC), post-menopausal breast (PostBrC), prostate (PrC), colorectal (CrC) and lung (LungC) cancer. We utilised publicly available data to perform bi-directional Mendelian randomization (MR) between BMI/WHRadjBMI and BrC, PrC and CrC. RESULTS PGSBMI had significant multiple testing-corrected inverse association with PrC (OR[95%CI]=0.97[0.95-0.99], P =0.0012) but PGSWHRadjBMI was not associated with PrC. PGSBMI was associated with PostBrC (OR[95%CI]=0.97[0.96-0.99], P =0.00203) while PGSWHRadjBMI had nominal association with BrC. PGSBMI had nominal positive association with LungC. MR analyses showed significant multiple testing-corrected protective causal effect of BMI on PrC (OR[95%CI]=0.993[0.988-0.998], P =4.19×10−3). WHRadjBMI had a nominal causal effect on higher PrC risk (OR[95%CI]=1.022[1.0067-1.038], P =0.0053). We also report nominal causal protective effect of WHRadjBMI on breast cancer (OR[95%CI]=0.99[0.98-0.997], P =0.0068). Neither PGS nor MR analyses were significant for CrC. CONCLUSIONS Higher overall adiposity appears protective from PrC while higher central adiposity is a potential risk factor for PrC but protective from BrC. What is already known about this subject? What are the new findings in your manuscript? How might your results change the direction of research or the focus of clinical practice? ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research has been conducted using the UK Biobank Resource under Application Number 37685. This research was in part funded by the World Cancer Research Fund (WCRF UK) and World Cancer Research Fund International (2017/1641), the Diabetes UK (BDA number: 20/0006307), the European Union Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SCI-2019-874739), Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-00001), by the European Union through the Fonds Européen de Dévelopment Regional (FEDER), by the Counseil Régional des Hauts-de-France (Hauts-de-France Regional Council) and by the Métropole Européenne de Lille (MEL, European Metropolis of Lille ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We used the UK Biobank resource () I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors