J Rheum Dis.  2020 Oct;27(4):241-246. 10.4078/jrd.2020.27.4.241.

Overview of Mendelian Randomization Analysis

• Lee YH

• KMID: 2506977
• DOI: http://doi.org/10.4078/jrd.2020.27.4.241

Abstract

he inference of causality from observational evidence may be problematic, as observational studies frequently include confounding factors or reverse causation for the identification of associations between exposure and outcome. Thus, in observational studies, the association between a risk factor and a disease of interest may not be causal. A randomized controlled trial (RCT) is considered the gold standard, because it has the best possibility to establish a relationship between a risk factor and an outcome. However, RCTs cannot always be performed, because they can be costly, impractical, or even unethical. One of the alternatives is to perform Mendelian randomization (MR) experiments that are similar to RCTs in terms of study design. The MR technique uses genetic variants related to modifiable traits/exposures as tools to detect causal associations with outcomes. MR can provide more credible estimates of the causal effect of a risk factor on an outcome than those obtained in observational studies by overcoming the limitations of observational studies. Therefore, MR can make a substantial contribution to our understanding of complex disease etiology. MR approaches are increasingly being used to evaluate the causality of associations with risk factors, because well-performed MR studies can be a powerful method for exploring causality in complex diseases. However, there are some limitations in MR analyses, and an awareness of these limitations is essential to interpret the results. The validity of results from MR studies depends on three assumptions that should be carefully checked and interpreted in the context of prior biological information.

Keyword

Mendelian randomization; Causality; Review

Figure

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  Figure 1 The analogy between randomized controlled trial and Mendelian randomization (A) and principle of Mendelian randomization (B).

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  Figure 2 Three core assumptions for Mendelian randomization. (A) Instrumental variable (IV) assumption 1: The genetic variant should be associated with the exposure. (B) IV assumption 2: The genetic variant should not associate with confounder. (C) IV assumption 3: The genetic variant should influence the outcome only through the exposure.

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  Figure 3 Forest plot of the causal effects of years of education-associated SNPs on RA. SNP: single nucleotide polymorphism, RA: rheumatoid arthritis, MR: Mendelian randomization, IVW: Inverse-variance weighted.

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  Figure 4 Scatter plots of genetic associations with years of education against the genetic associations with RA. The slopes of each line represent the causal association for each method. The blue line represents the IVW estimate, the green line represents the weighted median estimate, and the dark blue line represents the MR‐Egger estimate. SNP: single nucleotide polymorphism, RA: rheumatoid arthritis, MR: Mendelian randomization, IVW: Inverse-variance weighted.

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