A structural mean modelling Mendelian randomization approach to investigate the lifecourse effect of adiposity: applied and methodological considerations.

The application of a lifecourse approach to genetic epidemiology is key to better understanding causal effects of adversities on health outcomes over time. For some time-varying phenotypes, it has been shown that genetic effects may have differential importance in the development of an exposure at different periods in the lifecourse. Mendelian randomization (MR) is a technique that uses genetic variation to address causal questions about how modifiable exposures influence health. MR studies often employ conventional instrumental variable (IV) methods designed to estimate lifelong effects. Recently, several extensions of MR have been used to investigate time-varying effects, including structural mean models (SMMs). SMMs exploit IVs through g-estimation and circumvent some of the parametric assumptions of other MR methods. In this study, we apply g-estimation of SMMs to MR. We aim to estimate the period effects of adiposity measured at two different life stages on cardiovascular disease (CVD), type 2 diabetes (T2D) and breast cancer in later life. We found persistent period effects of higher adulthood adiposity on increased risk of CVD and T2D. Higher childhood adiposity had a protective period effect on breast cancer. We compare this method to an inverse variance weighted multivariable MR approach: a technique also using multiple IVs to assess time-varying effects, however, relying on a different set of assumptions and subsequent interpretations. We discuss the potentials and limitations of each approach and emphasise the importance of underlying methodological assumptions in the application of MR to lifecourse research questions. ### Competing Interest Statement TGR is an employee of GlaxoSmithKline outside of this research. All other authors declare no conflict of interest. ### Funding Statement This work was in part supported by the Integrative Epidemiology Unit which receives funding from the UK Medical Research Council and the University of Bristol (MC\_UU\_00032/01 and MC\_UU\_00032/02). GDS conducts research at the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. GMP is supported by the GW4 Biomed Doctoral Training Programme, awarded to the Universities of Bath, Bristol, Cardiff and Exeter from the Medical Research Council (MRC)/UKRI (MR/N0137941/1). NMW is supported by a National Health and Medical Research Council (NHMRC; Australia) Emerging Leadership Fellowship (APP2008723). VD acknowledges funding from the German Research Foundation (DFG Project 459360854). ### 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: The UK Biobank study have obtained ethics approval from the Research Ethics Committee (REC; approval number: 11/NW/0382). The UK Biobank study have obtained informed consent from all participants enrolled in UK Biobank. Estimates were derived using data from the UK Biobank (app #76538). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This research has been conducted using the UK Biobank resource under application number 76538. All data are available within the article, the supplementary material or from the authors upon request.