Abstract
A key assumption of Mendelian randomisation (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, GWAS studies 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.
Original language | English |
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Article number | dyaa288 |
Pages (from-to) | 1350-1361 |
Number of pages | 12 |
Journal | International Journal of Epidemiology |
Volume | 50 |
Issue number | 4 |
Early online date | 11 Feb 2021 |
DOIs | |
Publication status | Published - 30 Aug 2021 |
Bibliographical note
Publisher Copyright:© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the International Epidemiological Association.
Keywords
- population stratification
- Mendelian randomization
- negative control outcomes
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MRC IEU UK Biobank GWAS pipeline version 2
Mitchell, R. E. (Creator), Elsworth, B. L. (Creator), Mitchell, R. (Creator), Raistrick, C. A. (Creator), Paternoster, L. (Creator), Hemani, G. (Creator) & Gaunt, T. R. (Creator), University of Bristol, 19 Feb 2019
DOI: 10.5523/bris.pnoat8cxo0u52p6ynfaekeigi, http://data.bris.ac.uk/data/dataset/pnoat8cxo0u52p6ynfaekeigi
Dataset