Small-Magnitude Effect Sizes in Epigenetic End Points are Important in Children’s Environmental Health Studies: The Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group

Abstract

Background:Characterization of the epigenome is a primary interest for children’s environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes.Objectives:Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children’s Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis.Methods:We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research.Discussion:A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children’s health.Conclusion:The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.Citation:Breton CV, Marsit CJ, Faustman E, Nadeau K, Goodrich JM, Dolinoy DC, Herbstman J, Holland N, LaSalle JM, Schmidt R, Yousefi P, Perera F, Joubert BR, Wiemels J, Taylor M, Yang IV, Chen R, Hew KM, Freeland DM, Miller R, Murphy SK. 2017. Small-magnitude effect sizes in epigenetic end points are important in children’s environmental health studies: the Children’s Environmental Health and Disease Prevention Research Center’s Epigenetics Working Group. Environ Health Perspect 125:–526; http://dx.doi.org/10.1289/EHP595

Comparison of DNA methylation measured by Illumina 450K and EPIC BeadChips in blood of newborns and 14-year-old children

“…Since all samples from both datasets in our CHAMACOS study were isolated from whole blood, the results of this comparison are primarily informative to other studies analyzing DNA methylation in blood. This is one of the most frequently used sample type for epigenetic population studies of children and adults [8]. …”

“…We suggest that future studies incorporating data from one or both BeadChips conduct sensitivity analyses filtering sites with large differences, lower correlation, or lower variance, and/or validate hits with an alternative method, such as targeted pyrosequencing [8]. Since CpG sites with low variability or at the extreme ends of methylation distribution could still be biologically informative to certain studies, sensitivity analyses may be more appropriate rather than strict filtering based on variability or correlation between platforms.…”

Maternal serum PFOA concentration and DNA methylation in cord blood: A pilot study

“…We analyzed samples in four batches, and each row of each chip contained DNA from one high and one low PFOA group infant, with the columns counterbalanced. We followed recommended best practices to process, convert, and normalize raw DNA methylation data (Breton et al, 2017). After removing sex chromosomes, SNP-affected probes, cross-hybridizing probes, and probes having detection p-values > 0.05, the final data set included 358,933 autosomal probes.…”

An epigenetic pathway approach to investigating associations between prenatal exposure to maternal mood disorder and newborn neurobehavior

“…This is concerning given recent evidence that effect sizes are small and often fail correction for multiple comparisons (Breton et al, 2017; Mansell et al, 2016). Another disadvantage is that we typically select a candidate gene because it is involved in a known physiological or biochemical process (Zhu & Zhao, 2007).…”