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 strengths and limitations of each approach and emphasise the importance of underlying methodological assumptions in the application of MR to lifecourse research questions.