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

Mendelian randomization (MR) is a technique that uses genetic variation to address causal questions about how modifiable exposures influence health. For some time-varying phenotypes, genetic effects may have differential importance at different periods in the lifecourse. MR studies often employ conventional instrumental variable (IV) methods designed to estimate lifelong effects. Recently, several extensions of MR have been proposed 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.

We apply g-estimation of SMMs to MR to estimate the period effects of adiposity measured at two life stages, childhood and adulthood, on cardiovascular disease (CVD), type 2 diabetes (T2D) and breast cancer. 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 but relying on a different set of assumptions. We highlight the strengths and limitations of each approach and conclude by emphasising the importance of underlying
methodological assumptions in the application of MR to lifecourse research.