Meta-Analysis and Mendelian randomization: A review.

Mendelian randomization (MR) uses genetic variants as instrumental variables to infer whether a risk factor causally affects a health outcome. Meta-analysis has been used historically in MR to combine results from separate epidemiological studies, with each study using a small but select group of genetic variants. In recent years it has been used to combine genome-wide association study (GWAS) summary data for large numbers of genetic variants. Heterogeneity amongst the causal estimates obtained from multiple genetic variants points to a possible violation of the necessary instrumental variable assumptions. In this article we provide a basic introduction to MR and the instrumental variable theory that it relies upon. We then describe how random effects models, meta-regression and robust regression are being used to test and adjust for heterogeneity in order to improve the rigour of the MR approach.