Mendelian Randomization as an Approach to Assess Causality Using Observational Data

Abstract

Mendelian randomization refers to an analytic approach to assess the causality of an observed association between a modifiable exposure or risk factor and a clinically relevant outcome. It presents a valuable tool, especially when randomized controlled trials to examine causality are not feasible and observational studies provide biased associations because of confounding or reverse causality. These issues are addressed by using genetic variants as instrumental variables for the tested exposure: the alleles of this exposure-associated genetic variant are randomly allocated and not subject to reverse causation. This, together with the wide availability of published genetic associations to screen for suitable genetic instrumental variables make Mendelian randomization a time- and cost-efficient approach and contribute to its increasing popularity for assessing and screening for potentially causal associations. An observed association between the genetic instrumental variable and the outcome supports the hypothesis that the exposure in question is causally related to the outcome. This review provides an overview of the Mendelian randomization method, addresses assumptions and implications, and includes illustrative examples. We also discuss special issues in nephrology, such as inverse risk factor associations in advanced disease, and outline opportunities to design Mendelian randomization studies around kidney function and disease.

Keywords: causality; mendelian randomization; statistical method.

Figure 1.

Use of MR and instrumental variable approaches in the literature increases over time. PubMed Search strategy (June of 2016): for MR analysis, “mendelian random*[tiab]” or “Mendelian Randomization Analysis” (medical subject headings [MeSH]); for instrumental variable analysis or MR analysis, “instrumental variable*[tiab],” “mendelian random*[tiab],” or “Mendelian Randomization Analysis” (MeSH). Note that the MeSH term “Mendelian Randomization Analysis” was introduced by MEDLINE in 2010.

Figure 2.

Conceptual illustration of the MR method and its three underlying core assumptions as directed acyclic graphs. (A) Conceptual model. (B) Assumption 1. (C) Assumption 2. (D) Assumption 3.

Figure 3.

Risk reduction of CHD associated with LDL cholesterol–lowering genetic variants compared with LDL cholesterol–lowering medications. A steeper risk relationship with the genetic variants than with medications for the same amount of lower cholesterol reflects the effects of lifelong exposure to genotypes. Effect estimates reflecting the risk reduction in CHD for the individual clinical trials were taken from Webfigure 3i of a meta-analysis of randomized trials of statins. Effect estimates for the genetic variants, the genetic and clinical summary effects, and 95% confidence intervals were taken from Table 1 and Figure 5 of the work by Ference et al.