Journal
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Volume 41, Issue 1, Pages 161-176Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ije/dyr233
Keywords
DNA methylation; Mendelian randomization; confounding; reverse causation; mediation
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Funding
- Medical Research Council
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust
- European Union
- Medical Research Council [G0600705] Funding Source: researchfish
- MRC [G0600705] Funding Source: UKRI
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The burgeoning interest in the field of epigenetics has precipitated the need to develop approaches to strengthen causal inference when considering the role of epigenetic mediators of environmental exposures on disease risk. Epigenetic markers, like any other molecular biomarker, are vulnerable to confounding and reverse causation. Here, we present a strategy, based on the well-established framework of Mendelian randomization, to interrogate the causal relationships between exposure, DNA methylation and outcome. The two-step approach first uses a genetic proxy for the exposure of interest to assess the causal relationship between exposure and methylation. A second step then utilizes a genetic proxy for DNA methylation to interrogate the causal relationship between DNA methylation and outcome. The rationale, origins, methodology, advantages and limitations of this novel strategy are presented.
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