An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings
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Abstract
Background: Mendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that are instrumental variables (IVs) for the exposure. This has been extended to multivariable MR (MVMR) to estimate the effect of two or more exposures on an outcome. Methods and results: We use simulations and theory to clarify the interpretation of estimated effects in a MVMR analysis under a range of underlying scenarios, where a secondary exposure acts variously as a confounder, a mediator, a pleiotropic pathway and a collider. We then describe how instrument strength and validity can be assessed for an MVMR analysis in the single-sample setting, and develop tests to assess these assumptions in the popular two-sample summary data setting. We illustrate our methods using data from UK Biobank to estimate the effect of education and cognitive ability on body mass index. Conclusion: MVMR analysis consistently estimates the direct causal effect of an exposure, or exposures, of interest and provides a powerful tool for determining causal effects in a wide range of scenarios with either individual- or summary-level data.
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MR provides credible information on causation that can inform public health policies for environmental exposures such as alcohol.
“In this case, a trial would be challenging and/or unethical to conduct, despite previous attempts, however MR provides credible information on causation that can inform public health policies. 59 60”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [60]
Mendelian randomization analyses for investigating drug targets often use variants in a single gene region, typically the gene that encodes the protein target under investigation.
“Mendelian randomization analyses for investigating drug targets often use variants in a single gene region, typically the gene that encodes the protein target under investigation 57, 58 .”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [58]
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- Authors
- Sanderson, E., Davey Smith, G., Windmeijer, F., & Bowden, J.
- Affiliations
- University of Bristol (GB)
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Corresponding author
- Sanderson, Eleanor
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-12-10
- Volume
- 48
- Issue
- 3
- Pages
- 713-727
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- PMC
- PMC6734942
- OpenAlex
- W2949275660
- Cited by
- 1,085
- References
- 53
- Citations by year
- 2026: 114 · 2025: 172 · 2024: 273 · 2023: 163 · 2022: 141 · 2021: 115 · 2020: 70 · 2019: 32 · 2018: 3
- FWCI
- 33.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- International Journal of Epidemiology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Funders
- UK Medical Research Council Integrative Epidemiology Unit
- University of Bristol (MC_UU_00011/2, MC_UU_00011/1)
- UK Biobank Resource (8786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Keywords
- multivariable Mendelian randomization, causal inference, unmeasured confounding, mediation, pleiotropy, collider bias, assessment validity, instrument strength, cognitive ability, body mass index
- MeSH terms
- Adult, Aged, Cognition, Educational Status, Female, Humans, Male, Middle Aged, Body Mass Index, Multivariate Analysis, Least-Squares Analysis, Models, Econometric, Mendelian Randomization Analysis
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