Pleiotropy-robust Mendelian randomization.
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Abstract
Abstract Background The potential of Mendelian Randomization studies is rapidly expanding due to (i) the growing power of GWAS meta-analyses to detect genetic variants associated with several exposures, and (ii) the increasing availability of these genetic variants in large-scale surveys. However, without a proper biological understanding of the pleiotropic working of genetic variants, a fundamental assumption of Mendelian Randomization (the exclusion restriction) can always be contested. Methods We build upon and synthesize recent advances in the econometric literature on instrumental variables (IV) estimation that test and relax the exclusion restriction. Our Pleiotropy-robust Mendelian Randomization (PRMR) method first estimates the degree of pleiotropy, and in turn corrects for it. If a sample exists for which the genetic variants do not affect the exposure, and pleiotropic effects are homogenous, PRMR obtains unbiased estimates of causal effects in case of pleiotropy. Results Simulations show that existing MR methods produce biased estimators for realistic forms of pleiotropy. Under the aforementioned assumptions, PRMR produces unbiased estimators. We illustrate the practical use of PRMR by estimating the causal effect of (i) cigarettes smoked per day on Body Mass Index (BMI); (ii) prostate cancer on self-reported health, and (iii) educational attainment on BMI in the UK Biobank data. Conclusions PRMR allows for instrumental variables that violate the exclusion restriction due to pleiotropy, and corrects for pleiotropy in the estimation of the causal effect. If the degree of pleiotropy is unknown, PRMR can still be used as a sensitivity analysis. Key messages If genetic variants have pleiotropic effects, causal estimates of Mendelian Randomization studies will be biased. Pleiotropy-robust Mendelian Randomization (PRMR) produces unbiased causal estimates in case (i) a subsample can be identified for which the genetic variants do not affect the exposure, and (ii) pleiotropic effects are homogenous. If such a subsample does not exist, PRMR can still routinely be reported as a sensitivity analysis in any MR analysis. If pleiotropic effects are not homogenous, PRMR can be used as an informal test to gauge the exclusion restriction.
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Any source of instrument invalidity can be expressed as algebraically equivalent to bias from pleiotropy.
“Although robust methods typically use the term ‘pleiotropy’, any source of instrument invalidity can be expressed as algebraically equivalent to bias from pleiotropy 87”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [87]
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- Authors
- van Kippersluis, H., & Rietveld, C. A.
- Affiliations
- Erasmus School of Economics, Erasmus University Rotterdam, The Netherlands
- Tinbergen Institute (NL)
- Corresponding author
- Rietveld, Cornelius A
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-02-22
- Volume
- 47
- Issue
- 4
- Pages
- 1279-1288
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- PMC
- PMC6124631
- OpenAlex
- W2952904845
- Cited by
- 125
- References
- 73
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 29 · 2023: 8 · 2022: 11 · 2021: 11 · 2020: 12 · 2019: 12 · 2018: 7 · 2017: 8
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- International Journal of Epidemiology (publishedVersion, other-oa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Netherlands Organization for Scientific Research (016-145-082, 016-165-004)
- National Institute on Aging (R01AG037398)
- 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
- pleiotropy, exclusion restriction, instrumental variables, causal effect estimation, sensitivity analysis, tobacco smoke exposure, body mass index, prostate cancer, educational attainment, self-reported health, UK Biobank
- MeSH terms
- Disease, Humans, Genetic Variation, Genetic Predisposition to Disease, Mendelian Randomization Analysis, Genetic Pleiotropy
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