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.

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