Mendelian randomization in a multi-ancestry world: reflections and practical advice

Abstract: Many Mendelian randomization (MR) papers have been conducted only in people of European ancestry, limiting transportability of results to the global population. Expanding MR to diverse ancestry groups is essential to ensure equitable biomedical insights, yet presents analytical and conceptual challenges. This review examines the practical challenges of MR analyses beyond the European only context, including use of data from multi-ancestry, mismatched ancestry, and admixed populations. We explain how apparent heterogeneity in MR estimates between populations can arise from differences in genetic variant frequencies and correlation patterns, as well as from differences in the distribution of phenotypic variables, complicating the detection of true differences in the causal pathway. We summarize published strategies for selecting genetic instruments and performing analyses when working with limited ancestry-specific data, discussing the assumptions needed in each case for incorporating external data from different ancestry populations. We conclude that differences in MR estimates by ancestry group should be interpreted cautiously, with consideration of how the identified differences may arise due to social and cultural factors. Corroborating evidence of a biological mechanism altering the causal pathway is needed to support a conclusion of differing causal pathways between ancestry groups.