Mendelian Randomization as a Tool for Cardiovascular Research

Importance: Mendelian randomization (MR) is a statistical approach that has become increasingly popular in the field of cardiovascular disease research. It offers a way to infer potentially causal relationships between risk factors and outcomes using observational data, which is particularly important in cases where randomized clinical trials are not feasible or ethical. With the growing availability of large genetic data sets, MR has become a powerful and accessible tool for studying the risk factors for cardiovascular disease. Observations: MR uses genetic variation associated with modifiable exposures or risk factors to mitigate biases that affect traditional observational study designs. The approach uses genetic variants that are randomly assigned at conception as proxies for exposure to a risk factor, mimicking a randomized clinical trial. By comparing the outcomes of individuals with different genetic variants, researchers may draw causal inferences about the effects of specific risk factors on cardiovascular disease, provided assumptions are met that address (1) the association between each genetic variant and risk factor and (2) the association of the genetic variants with confounders and (3) that the association between each genetic variant and the outcome only occurs through the risk factor. Like other observational designs, MR has limitations, which include weak instruments that are not strongly associated with the exposure of interest, linkage disequilibrium where genetic instruments influence the outcome via correlated rather than direct effects, overestimated genetic associations, and selection and survival biases. In addition, many genetic databases and MR studies primarily include populations genetically similar to European reference populations; improved diversity of participants in these databases and studies is critically needed. Conclusions and Relevance: This review provides an overview of MR methodology, including assumptions, strengths, and limitations. Several important applications of MR in cardiovascular disease research are highlighted, including the identification of drug targets, evaluation of potential cardiovascular risk factors, as well as emerging methodology. Overall, while MR alone can never prove a causal relationship beyond reasonable doubt, MR offers a rigorous approach for investigating possible causal relationships in observational data and has the potential to transform our understanding of the etiology and treatment of cardiovascular disease.