Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease

Caroline L. Relton*, George Davey Smith

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

197 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)161-176
Number of pages16
JournalInternational Journal of Epidemiology
Volume41
Issue number1
DOIs
Publication statusPublished - Feb 2012

Keywords

  • DNA methylation
  • Mendelian randomization
  • confounding
  • reverse causation
  • mediation
  • C-REACTIVE PROTEIN
  • DNA METHYLATION ANALYSIS
  • CORONARY-HEART-DISEASE
  • ALLELE-SPECIFIC METHYLATION
  • COMMON HUMAN-DISEASES
  • GENE-EXPRESSION
  • CARDIOVASCULAR-DISEASE
  • BLOOD-PRESSURE
  • HUMAN GENOME
  • HUMAN BRAIN

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