Mendelian randomization: genetic anchors for causal inference in epidemiological studies

Abstract

Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.

Figure 1.

Schematic representation of MR. (A) Mendelian randomization can be used to test the hypothesis that trait A causes trait B, provided that conditions (1), (2) and (3) are met adequately, governing that Z_A is a valid instrument, in that (1) it is associated with the intermediate phenotype of interest; (2) has no association with the outcome except through the intermediate phenotype, and (3) is not related to measured or unmeasured confounding factors. (B). In bi-directional MR, the causal direction between traits (A and B) (if any) can be elucidated, if valid instruments are present for each trait.

Figure 2.

Effect of lower LDL-C on risk of CHD [taken from Ference et al. (2012) (52)]. Boxes represent the proportional risk reduction (1-OR) of CHD for each exposure allele plotted against the absolute magnitude of lower LDL-C associated with that allele (measured in mg/dl). SNPs are plotted in order of increasing absolute magnitude of associations with lower LDL-C. The line (forced to pass through the origin) represents the increase in proportional risk reduction of CHD per unit lower long-term exposure to LDL-C.