Leveraging Mendelian Randomisation for Causal Inference in Endodontics

Endodontic diseases have been linked to many potential risk factors and systemic conditions. However, observational associations may reflect sources of bias such as confounding and reverse causality. Mendelian randomisation (MR) can strengthen causal inference, although its assumptions require scrutiny.

To provide an overview of MR in endodontic research and synthesise evidence specifically on causal relationships of endodontic diseases.

PubMed/MEDLINE, Web of Science and Scopus were searched to May 2026. The narrative component established MR's conceptual and analytical framework, including core assumptions, MR designs, data sources, instrument selection, estimators, diagnostics, implementation and appraisal of MR evidence. Original MR studies involving endodontic diseases were identified and compared by phenotype, data source, direction, estimates, replication and assumption support.

The narrative part of the review mapped MR from formulation of a causal question and basic principles to credibility assessment, emphasising the distinction between statistical robustness and biological validity when interpreting causal claims. The systematic search identified 10 studies (2023-2025). Rheumatoid arthritis liability showed the most consistent positive association with endodontic outcomes, but effects were biologically non-specific and unreplicated. Other systemic exposures were mainly null, heterogeneous, borderline or unreplicated; evidence that endodontic disease causes systemic outcomes was limited to isolated findings, including a single lacunar-stroke analysis. Core assumption appraisal showed that instrument relevance was generally well supported from a solely statistical perspective, with most studies using genome-wide instrument selection, reporting strength metrics and drawing on large GWAS datasets. Independence was also addressed in many analyses through ancestry matching, linkage disequilibrium control and confounder screening. The principal limitation concerned exclusion restriction: shared biological pathways and broad pulp and periapical phenotypes often weakened biological specificity and plausibility, while absent colocalisation, relaxed or sparse instrument selection and limited replication left horizontal pleiotropy unresolved.

MR offers a valuable framework for generating and testing causal hypotheses in endodontics, but current evidence does not definitively establish broad causal effects between endodontic disease and systemic health. Progress depends on biologically justified instrument selection, larger and more diverse GWAS, clinically validated phenotypes, independent replication, colocalisation, advanced MR designs, triangulation with non-genetic evidence and transparent reporting.