Mendelian randomization

Eleanor Sanderson*, M. Maria Glymour, Michael V. Holmes, Hyunseung Kang, Jean Morrison, Marcus R. Munafò, Tom Palmer, C. Mary Schooling, Chris Wallace, Qingyuan Zhao, George Davey Smith

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Mendelian randomization (MR) is a term that applies to the use of genetic variation to address causal questions about how modifiable exposures influence different outcomes. The principles of MR are based on Mendel’s laws of inheritance and instrumental variable estimation methods, which enable the inference of causal effects in the presence of unobserved confounding. In this Primer, we outline the principles of MR, the instrumental variable conditions underlying MR estimation and some of the methods used for estimation. We go on to discuss how the assumptions underlying an MR study can be assessed and describe methods of estimation that are robust to certain violations of these assumptions. We give examples of a range of studies in which MR has been applied, the limitations of current methods of analysis and the outlook for MR in the future. The differences between the assumptions required for MR analysis and other forms of epidemiological studies means that MR can be used as part of a triangulation across multiple sources of evidence for causal inference.
Original languageEnglish
Article number6
JournalNature Reviews Methods Primers
Volume2
Issue number1
Early online date10 Feb 2022
DOIs
Publication statusE-pub ahead of print - 10 Feb 2022

Bibliographical note

Funding Information:
E.S., M.R.M., T.P. and G.D.S. are members of the UK Medical Research Council (MRC) Integrative Epidemiology unit, which is funded by the MRC (MC_UU_00011/1, MC_UU_00011/3 and MC_UU_00011/7) and the University of Bristol. M.M.G. is supported by the National Institutes of Health/National Institute on Aging (NIH/NIA) grant R01AG057869. M.V.H. works in a unit that receives funding from the MRC and is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. H.K. is supported by the National Science Foundation grant DMS-1811414. C.W. is funded by the MRC (MC UU 00002/4, MC UU 00002/13) and the Wellcome Trust (WT107881).

Publisher Copyright:
© 2022, Springer Nature Limited.

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