Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?
Abstract
Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of-that is randomized with respect to-the inheritance of other traits, according to Mendel's law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers' compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.
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Causal effects estimated in a Mendelian randomization analysis represent long-term relationships, equivalent to a randomized trial where the intervention is made at conception.
“As genetic subgroups of a population defined by an IV represent subpopulations with long-term average differences in the exposure of interest,31 the causal effects estimated in a Mendelian randomization analysis represent long-term relationships, equivalent to a randomized trial where the intervention is made at conception.”
From Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. (2015) · cites this paper as [31]
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- Authors
- Ebrahim, S., & Davey Smith, G.
- Affiliations
- London School of Hygiene & Tropical Medicine (GB)
- Corresponding author
- Ebrahim, Shah
- ORCID
- Ebrahim, Shah
- Venue
- Human Genetics
- Published
- 2007-11-23
- Volume
- 123
- Issue
- 1
- Pages
- 15-33
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- OpenAlex
- W2116908385
- Cited by
- 410
- References
- 11
- Citations by year
- 2026: 13 · 2025: 42 · 2024: 53 · 2023: 39 · 2022: 32 · 2021: 32 · 2020: 16 · 2019: 13 · 2018: 13 · 2017: 13 · 2016: 16 · 2015: 14 · 2014: 12 · 2013: 25 · 2012: 16
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- 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, causal inference, environmental exposure, confounding, reverse causality, selection bias, linkage disequilibrium, population stratification, pleiotropy, canalization, genetic epidemiology
- MeSH terms
- Humans, Linkage Disequilibrium, Genome, Human, Molecular Epidemiology, Genetic Diseases, Inborn
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