Key Points
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Mendelian randomization uses genetic variants to test the causality of a relationship between an exposure and an outcome
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Mendelian randomization is not affected by the confounding inherent in observational studies but it does rely on several assumptions, which can be hard to test
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Mendelian randomization can provide a cost-effective substitute for clinical trials that would be expensive, or logistically or ethically challenging
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In rheumatoid arthritis (RA), Mendelian randomization has provided evidence for a protective effect of IL-1 receptor antagonism, and for relationships between vitamin D status, disease outcome and response to therapy
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Mendelian randomization can provide evidence that relationships suggested by observation are not causal; for example, it suggests IgG N-glycosylation is a biomarker of RA rather than an agent of disease
Abstract
Establishing causality of risk factors is important to determine the pathogenetic mechanisms underlying rheumatic diseases, and can facilitate the design of interventions to improve care for affected patients. The presence of unmeasured confounders, as well as reverse causation, is a challenge to the assignment of causality in observational studies. Alleles for genetic variants are randomly inherited at meiosis. Mendelian randomization analysis uses these genetic variants to test whether a particular risk factor is causal for a disease outcome. In this Review of the Mendelian randomization technique, we discuss published results and potential applications in rheumatology, as well as the general clinical utility and limitations of the approach.
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Change history
22 February 2017
In the originally published version of the above Review, in the left-hand panel of Figure 2b the residuals were represented by horizontal rather than vertical double-headed arrows between the individual data points and the regression line, and in the right-hand panel the labels for the axes were inverted; in the legend for Figure 2b and on page 487 of the article where Figure 2 is cited, the description of the two-stage least squares method was inaccurate; and owing to an editorial oversight, a sentence on page 488 mistakenly referred to the occurrence of “reverse causality” instead of “inverse causality”. These errors have been corrected in the online version of the article. Also, in the discussion of the Wald method on page 488, the sentence “However, estimating the effect size of an exposure on the outcome is not possible” has been deleted to avoid ambiguity.
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P.R. and T.R.M. researched data for the article and wrote the manuscript. P.R., H.K.C. and T.R.M. contributed substantially to discussions of the article content. R.D. undertook review and editing of the manuscript before submission.
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P.R. declares that he has received speaking and consulting fees from Menarini and speaking fees and research funding from AstraZeneca. T.R.M. declares that he has received consulting fees and research funding from Ardea Biosciences and AstraZeneca. H.K.C. declares that he has received consulting fees from AstraZeneca and Takeda. R.D. declares no competing interests.
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Robinson, P., Choi, H., Do, R. et al. Insight into rheumatological cause and effect through the use of Mendelian randomization. Nat Rev Rheumatol 12, 486–496 (2016). https://doi.org/10.1038/nrrheum.2016.102
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