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From promises to practical strategies in epigenetic epidemiology

Nature Reviews Genetics volume 14, pages 585–594 (2013)Cite this article

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Abstract

The epigenome has been heralded as a key 'missing piece' of the aetiological puzzle for complex phenotypes across the biomedical sciences. The standard research approaches developed for genetic epidemiology, however, are not necessarily appropriate for epigenetic studies of common disease. Here, we discuss the optimal execution of population-based studies of epigenetic variation, which will contribute to the emerging field of 'epigenetic epidemiology' and emphasize the importance of establishing a causal role in pathology for disease-associated epigenetic changes. We propose that improved understanding of the molecular mechanisms underlying human health and disease are best achieved through carrying out studies of epigenetics in populations as a part of an integrated functional genomics strategy.

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Figure 1: Examples of study designs for analysing epigenetic variation in populations.
Figure 2: Longitudinal analysis of epigenetic changes in a population cohort of monozygotic twins.

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Acknowledgements

J.M. is supported by grants from the US National Institutes of Health (grants AG036039 and HD068437), the Brain and Behavior Research Foundation (formerly NARSAD), the UK Medical Research Council (MRC) and a Senior Award from the American Asthma Foundation (AAF). B.T.H. is supported by grants from BBMRI‑NL, a Research Infrastructure financed by the Dutch government (NWO 184.021.007), the US National Institutes of Health (grant AG042190-01), the European Union’s Seventh Framework Program IDEAL (FP7/2007‑2011) under grant agreement number 259679, The Netherlands CardioVascular Research Initiative from the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences, and the Netherlands Consortium for Healthy Ageing (grant 05060810) in the framework of the Netherlands Genomics Initiative and the Netherlands Organization for Scientific Research.

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Author notes

  1. Jonathan Mill and Bastiaan T. Heijmans: Both authors contributed equally to this work.

Authors and Affiliations

  1. Jonathan Mill is at the University of Exeter Medical School, Exeter University, St Luke's Campus, Magdalen Street, Exeter EX1 2LU, UK,

    Jonathan Mill & Bastiaan T. Heijmans

  2. and the Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.,

    Jonathan Mill & Bastiaan T. Heijmans

  3. Bastiaan T. Heijmans is at the Molecular Epidemiology Section, Leiden University Medical Center, Consortium for Healthy Ageing, Einthovenweg 20, 2333 ZC Leiden, The Netherlands.,

    Jonathan Mill & Bastiaan T. Heijmans

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PowerPoint slides

Glossary

Chromatin

The combination of DNA, RNA and protein that constitute the chromosomes in eukaryotic cells. Broadly, heterochromatin is associated with transcriptional repression and euchromatin is associated with transcriptional activity.

DNA methylation

The covalent binding of a methyl group at position 5 of the cytosine pyrimidine ring in CG dinucleotides often associated with the repression of transcription when present at promoters and enhancers.

Epigenetic

Describes mitotically heritable, but reversible, changes in gene expression mediated primarily by modifications to DNA and chromatin structure.

Epigenome

The entirety of epigenetic information in a cell, including DNA methylation, histone modifications, histone variants and non-coding RNAs.

Epigenome-wide association studies

(EWASs). Systematic assessments of a specific epigenetic mark, usually DNA methylation, across the genome in groups of individuals that are different for a given environmental exposure, trait or disease with the goal of identifying differences associated with that exposure or phenotype.

Histone

Histone proteins package DNA into structural units called nucleosomes. Covalent post-translational histone modifications include acetylation, methylation, phosphorylation, sumoylation and ubiquitylation; these can influence gene expression through changes in chromatin structure.

Mendelian randomization

An approach that uses a genetic proxy for DNA methylation (that is, methylation quantitative trait loci (meQTLs)) to identify a causal relationship between exposure and epigenetic variation, assuming that genetic associations are largely immune to residual confounding and reverse causation. Although such an approach requires that DNA methylation at relevant loci is influenced by both the environment and genetic variation, some examples of such a scenario have been reported.

Methylation quantitative trait loci

(meQTLs). Genetic variants that influence DNA methylation in cis via allele-specific DNA methylation or in trans:for example, by affecting the gene function of a DNA methylation modifier.

Methylome

The entirety of DNA methylation marks across the genome.

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Mill, J., Heijmans, B. From promises to practical strategies in epigenetic epidemiology. Nat Rev Genet 14, 585–594 (2013). https://doi.org/10.1038/nrg3405

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