Agreement in DNA methylation levels from the Illumina 450K array across batches, tissues, and time

Epigenome-wide association studies (EWAS) have focused primarily on DNA methylation as a chemically stable and functional epigenetic modification. However, the stability and accuracy of the measurement of methylation in different tissues and extraction types is still being actively studied, and the...

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Bibliographic Details
Published in:	Epigenetics Vol. 13; no. 1; pp. 19 - 32
Main Authors:	Forest, Marie, O'Donnell, Kieran J., Voisin, Greg, Gaudreau, Helene, MacIsaac, Julia L., McEwen, Lisa M., Silveira, Patricia P., Steiner, Meir, Kobor, Michael S., Meaney, Michael J., Greenwood, Celia M.T.
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 01-01-2018 Taylor & Francis Group
Subjects:	Brain-Derived Neurotrophic Factor - genetics Canada Catechol O-Methyltransferase - genetics DNA Methylation Dried Blood Spot Testing - methods Dried Blood Spot Testing - standards Epigenesis, Genetic Female Humans Intraclass correlations Male methylation Mouth Mucosa Netherlands Oligonucleotide Array Sequence Analysis - methods Oligonucleotide Array Sequence Analysis - standards Oligonucleotide Array Sequence Analysis - statistics & numerical data Receptors, Dopamine D2 - genetics Receptors, Dopamine D4 - genetics Receptors, Oxytocin - genetics redundancy analysis replication Reproducibility of Results Research Papers Serotonin Plasma Membrane Transport Proteins - genetics Time Factors tissue stability Canada Netherlands replication redundancy analysis tissue stability Intraclass correlations methylation
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Summary:	Epigenome-wide association studies (EWAS) have focused primarily on DNA methylation as a chemically stable and functional epigenetic modification. However, the stability and accuracy of the measurement of methylation in different tissues and extraction types is still being actively studied, and the longitudinal stability of DNA methylation in commonly studied peripheral tissues is of great interest. Here, we used data from two studies, three tissue types, and multiple time points to assess the stability of DNA methylation measured with the Illumina Infinium HumanMethylation450 BeadChip array. Redundancy analysis enabled visual assessment of agreement of replicate samples overall and showed good agreement after removing effects of tissue type, age, and sex. At the probe level, analysis of variance contrasts separating technical and biological replicates clearly showed better agreement between technical replicates versus longitudinal samples, and suggested increased stability for buccal cells versus blood or blood spots. Intraclass correlations (ICCs) demonstrated that inter-individual variability is of similar magnitude to within-sample variability at many probes; however, as inter-individual variability increased, so did ICC. Furthermore, we were able to demonstrate decreasing agreement in methylation levels with time, despite a maximal sampling interval of only 576 days. Finally, at 6 popular candidate genes, there was a large range of stability across probes. Our findings highlight important sources of technical and biological variation in DNA methylation across different tissues over time. These data will help to inform longitudinal sampling strategies of future EWAS.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supplemental data for this article can be accessed on the publisher's website. Co-first authors.
ISSN:	1559-2294 1559-2308
DOI:	10.1080/15592294.2017.1411443