The use of negative control outcomes in Mendelian randomization to detect potential population stratification
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Abstract
A key assumption of Mendelian randomization (MR) analysis is that there is no association between the genetic variants used as instruments and the outcome other than through the exposure of interest. One way in which this assumption can be violated is through population stratification, which can introduce confounding of the relationship between the genetic variants and the outcome and so induce an association between them. Negative control outcomes are increasingly used to detect unobserved confounding in observational epidemiological studies. Here we consider the use of negative control outcomes in MR studies to detect confounding of the genetic variants and the exposure or outcome. As a negative control outcome in an MR study, we propose the use of phenotypes which are determined before the exposure and outcome but which are likely to be subject to the same confounding as the exposure or outcome of interest. We illustrate our method with a two-sample MR analysis of a preselected set of exposures on self-reported tanning ability and hair colour. Our results show that, of the 33 exposures considered, genome-wide association studies (GWAS) of adiposity and education-related traits are likely to be subject to population stratification that is not controlled for through adjustment, and so any MR study including these traits may be subject to bias that cannot be identified through standard pleiotropy robust methods. Negative control outcomes should therefore be used regularly in MR studies to detect potential population stratification in the data used.
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Negative control outcomes or negative control populations can sometimes evaluate the reasonableness of the independence assumption.
“Negative control outcomes or negative control populations can sometimes evaluate the reasonableness of the assumption.66”
From Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomisation (STROBE-MR): explanation and elaboration. (2021) · cites this paper as [66]
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- Authors
- Sanderson, E., Richardson, T. G., Hemani, G., & Davey Smith, G.
- Affiliations
- University of Bristol (GB)
- MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
- Corresponding author
- Sanderson, Eleanor
- Venue
- International Journal of Epidemiology
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-02-11
- Volume
- 50
- Issue
- 4
- Pages
- 1350-1361
- ISSN
- 0300-5771 (ISSN-L)
- 1464-3685
- PMC
- PMC8407870
- OpenAlex
- W3123863341
- Cited by
- 115
- References
- 54
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 28 · 2023: 21 · 2022: 13 · 2021: 14 · 2020: 1
- FWCI
- 11.02
- 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)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- Explore Bristol Research (publishedVersion, cc-by)
- Funders
- Integrative Epidemiology Unit which is funded by the University of Bristol and the Medical Research Council (MC_UU_00011/1)
- UKRI Innovation Research Fellow (MR/S003886/1)
- 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
- negative control outcomes, population stratification, Mendelian randomization, pleiotropy, unmeasured confounding, assessment validity, tanning ability, hair color, adiposity, two-sample Mendelian randomization
- MeSH terms
- Humans, Phenotype, Bias, Polymorphism, Single Nucleotide, Adiposity, Genome-Wide Association Study, Mendelian Randomization Analysis
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