Recent Developments in Mendelian Randomization Studies

Abstract

Purpose of ReviewMendelian randomization (MR) is a strategy for evaluating causality in observational epidemiological studies. MR exploits the fact that genotypes are not generally susceptible to reverse causation and confounding, due to their fixed nature and Mendel’s First and Second Laws of Inheritance. MR has the potential to provide information on causality in many situations where randomized controlled trials are not possible, but the results of MR studies must be interpreted carefully to avoid drawing erroneous conclusions.Recent FindingsIn this review, we outline the principles behind MR, as well as assumptions and limitations of the method. Extensions to the basic approach are discussed, including two-sample MR, bidirectional MR, two-step MR, multivariable MR, and factorial MR. We also consider some new applications and recent developments in the methodology, including its ability to inform drug development, automation of the method using tools such as MR-Base, and phenome-wide and hypothesis-free MR.SummaryIn conjunction with the growing availability of large-scale genomic databases, higher level of automation and increased robustness of the methods, MR promises to be a valuable strategy to examine causality in complex biological/omics networks, inform drug development and prioritize intervention targets for disease prevention in the future.

Mendelian Randomization Study of Obesity and Cerebrovascular Disease

“…Finally, when significant MR results between traits were found, we used (1) MR pleiotropy residual sum and outlier (MR-PRESSO) test 30 to explore presence of outliers that could bias the results and (2) bidirectional MR to test for any inverse associations using obesity traits as outcomes and cerebrovascular disease phenotypes as exposures. 31 In our bidirectional MR, we pruned at r 2 < 0.5 using SNPs associated with cerebrovascular disease at genome-wide significance. The higher r 2 threshold for bidirectional MR was required given the reduced number of significant SNPs associated with cerebrovascular disease.…”

Mendelian randomization: Progressing towards understanding causality

“…Even though the underlying MR principle is the same, a number of extensions have been developed on the methods that are reviewed in the literature (eg, see previous works10, 11, 12). The two studies presented in this issue reflect part of the spectrum of MR approaches that are utilized today: In the work by Kobylecki et al,2 the MR was performed in a single sample using two genetic variants, both singly and in combination, with individual‐level data on genetic variants, urate levels, PD, and a number of confounders.…”

High-density lipoprotein characteristics and coronary heart disease: a Mendelian randomization study

“…However, our study also has limitations. First, in order to use a MR approach, we had to make some assumptions 10 , among which stands out the absence of pleiotropy. In our case, most of the genetic variants used as instruments were associated with more than one lipid trait.…”