Interaction-based Mendelian randomization with measured and unmeasured gene-by-covariate interactions
Open accessAbstract
Studies leveraging gene-environment (GxE) interactions within Mendelian randomization (MR) analyses have prompted the emergence of two methodologies: MR-GxE and MR-GENIUS. Such methods are attractive in allowing for pleiotropic bias to be corrected when using individual instruments. Specifically, MR-GxE requires an interaction to be explicitly identified, while MR-GENIUS does not. We critically examine the assumptions of MR-GxE and MR-GENIUS, and propose sensitivity analyses to evaluate their performance. Finally, we explore the association between body mass index (BMI) and systolic blood pressure (SBP) using data from the UK Biobank. We find both approaches share similar assumptions, though differences between the approaches lend themselves to differing research settings. Where interactions are identified, MR-GxE relies on weaker assumptions and allows for further sensitivity analyses. MR-GENIUS circumvents the need to identify interactions, but relies on the MR-GxE assumptions holding globally. Through applied analyses we find evidence of a positive effect of BMI upon SBP.
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A large-effect genetic variant influencing alcohol consumption that has been of considerable value in MR studies of the effects of alcohol is only prevalent in East Asian populations.
“For example, a large-effect genetic variant influencing alcohol consumption that has been of considerable value in MR studies of the effects of alcohol75,130 is only prevalent in East Asian populations.”
From Mendelian randomization (2022) · cites this paper as [75]
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- Authors
- Spiller, W., Hartwig, F. P., Sanderson, E., Smith, G. D., & Bowden, J.
- Affiliations
- University of Bristol (GB)
- Universidade Federal de Pelotas (BR)
- University of Exeter (GB)
- Corresponding author
- Spiller, Wes
- Venue
- PLoS ONE
- Publisher
- openRxiv
- Published
- 2020-07-29
- Volume
- 17
- Issue
- 8
- Pages
- e0271933-e0271933
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC9365161
- OpenAlex
- W4291283607
- Cited by
- 15
- References
- 27
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 3
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- PLoS ONE (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Explore Bristol Research (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (108902, 108902/B/15/Z)
- Medical Research Council (MC_PC_17228, MC_UU_00011/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- Mendelian randomization, gene-environment interaction, pleiotropy, sensitivity analysis, body mass index, systolic blood pressure, causal inference
- MeSH terms
- Blood Pressure, Bias, Causality, Body Mass Index, Genome-Wide Association Study, Mendelian Randomization Analysis
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