Skip to content

An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility

Research output: Contribution to journalArticle

Original languageEnglish
JournalInternational Journal of Epidemiology
DateAccepted/In press - 15 May 2019

Abstract

Background There is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation (DNAm). It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence it this regard has been challenging to uncover. Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNAm levels on disease susceptibility. Methods To illustrate our approach, we identified 412 CpG sites where DNAm was associated with smoking and where reverse caution is highly unlikely. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits using findings from large-scale genome-wide association studies. To strengthen evidence of mediatory mechanisms, we used multiple-trait colocalization to assess whether DNA methylation, nearby gene expression and complex trait variation were all influenced by the same causal genetic variant. Results We identified 22 associations which survived multiple testing (P<1.89x10-7). In-depth follow-up analyses of particular note suggested that the associations between DNA methylation at the ASPSCR1 and REST/POL2RB gene regions, both linked with reduced lung function, may be mediated by changes in gene expression. We validated associations between DNAm and traits using independent samples from different stages across the life course. Conclusions Our approach should prove valuable in prioritising CpG sites which may mediate the effect of causal risk factors on disease. In-depth evaluations of findings are necessary to robustly disentangle causality from alternative explanations such as horizontal pleiotropy.

    Research areas

  • DNA methylation, Mendelian randomization, Mediation, Smoking, ALSPAC, ARIES

Documents

Documents

  • Full-text PDF (accepted author manuscript)

    Accepted author manuscript, 466 KB, PDF-document

    Embargo ends: 1/01/99

    Request copy

  • Supplementary information XLS

    Accepted author manuscript, 150 KB, application/vnd.openxmlformats-officedocument.spreadsheetml.sheet

    Embargo ends: 1/01/99

    Request copy

View research connections

Related faculties, schools or groups