Non-linear Mendelian randomization with Two-stage prediction estimation and Control function estimation

Most of the existing Mendelian randomization (MR) methods are limited by the assumption of linear causality between exposure and outcome, and the development of new non-linear MR methods is highly desirable. We introduce two-stage prediction estimation and control function estimation from econometrics to MR and extend them to non-linear causality. We give conditions for parameter identification and theoretically prove the consistency and asymptotic normality of the estimates. We compare the two methods theoretically under both linear and non-linear causality. We also extend the control function estimation to a more flexible semi-parametric framework without detailed parametric specifications of causality. Extensive simulations numerically corroborate our theoretical results. Application to UK Biobank data reveals non-linear causal relationships between sleep duration and systolic/diastolic blood pressure.