A Principled Framework for Mendelian Randomization in Oral Health Research

In recent years, the popularity of Mendelian randomization (MR) as a technique to investigate causal relationships has grown exponentially. This approach leverages randomness inherent in the allocation of genetic variants to circumvent issues of unobserved confounding and reverse causation that compromise many causal claims based on observational data. In this manuscript, the key assumptions required for MR analyses to yield credible causal inferences are reviewed. It is emphasized that even technically rigorous MR analyses may yield implausible conclusions if these assumptions are violated. The goal is to provide readers from nonstatistical backgrounds with a clear understanding of the foundational assumptions underpinning MR, complemented by a detailed discussion of specific considerations in oral health research, particularly when periodontitis is used as the exposure or outcome. As with any study design, MR is appropriate and can provide compelling evidence for causality in certain contexts, while its application may be unwarranted in others. This methodological article aims to equip readers with the tools to critically assess MR findings, distinguish scenarios where its use is justified, and understand the key steps for correct execution and reporting. A checklist for assessing the credibility of MR investigations is also provided.