ArticlePloS one2016
Adjustment of Cell-Type Composition Minimizes Systematic Bias in Blood DNA Methylation Profiles Derived by DNA Collection Protocols.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Guidelines for pre-analytical conditions for assessing the methylation of circulating cell-free DNA.Clinical epigenetics · 2021Pooled it
- Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.Scientific reports · 2021Trial
- Epigenome-wide association of myocardial infarction with DNA methylation sites at loci related to cardiovascular disease.Clinical epigenetics · 2017Trial
- DNA methylation as a biomarker of prenatal exposures: current challenges and opportunities.Environmental epigenetics · 2026Review
- Methodological and Biological Factors Influencing Global DNA Methylation Results Measured by LINE-1 Pyrosequencing Assay in Colorectal Tissue and Liquid Biopsy Samples.International journal of molecular sciences · 2022Article
- Autoimmune gastritis induces aberrant DNA methylation reflecting its carcinogenic potential.Journal of gastroenterology · 2022Article
- DNA methylation analysis of cord blood samples in neonates born to gestational diabetes mothers diagnosed before 24 gestational weeks.BMJ open diabetes research & care · 2022Article
- Likelihood-based deconvolution of bulk gene expression data using single-cell references.Genome research · 2021Article
- DNA Methylation Analysis Identifies Differentially Methylated Sites Associated with Early-Onset Intracranial Atherosclerotic Stenosis.Journal of atherosclerosis and thrombosis · 2020Article
- DNA methylome profiling of all-cause mortality in comparison with age-associated methylation patterns.Clinical epigenetics · 2019Article
- DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid.Cancers · 2018Article
- Letter to the editor: blood processing and sample storage have negligible effects on methylation.Clinical epigenetics · 2018Article
- Exploring the influence from whole blood DNA extraction methods on Infinium 450K DNA methylation.PloS one · 2018Article
- DNA-Methylation and Body Composition in Preschool Children: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study.Scientific reports · 2017Article
- Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies.NPJ genomic medicine · 2017Article
- Intraindividual dynamics of transcriptome and genome-wide stability of DNA methylation.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
23 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Differences in DNA collection protocols may be a potential confounder in epigenome-wide association studies (EWAS) using a large number of blood specimens from multiple biobanks and/or cohorts. Here we show that pre-analytical procedures involved in DNA collection can induce systematic bias in the DNA methylation profiles of blood cells that can be adjusted by cell-type composition variables. In Experiment 1, whole blood from 16 volunteers was collected to examine the effect of a 24 h storage period at 4°C on DNA methylation profiles as measured using the Infinium HumanMethylation450 BeadChip array. Our statistical analysis showed that the P-value distribution of more than 450,000 CpG sites was similar to the theoretical distribution (in quantile-quantile plot, λ = 1.03) when comparing two control replicates, which was remarkably deviated from the theoretical distribution (λ = 1.50) when comparing control and storage conditions. We then considered cell-type composition as a possible cause of the observed bias in DNA methylation profiles and found that the bias associated with the cold storage condition was largely decreased (λ adjusted = 1.14) by taking into account a cell-type composition variable. As such, we compared four respective sample collection protocols used in large-scale Japanese biobanks or cohorts as well as two control replicates. Systematic biases in DNA methylation profiles were observed between control and three of four protocols without adjustment of cell-type composition (λ = 1.12-1.45) and no remarkable biases were seen after adjusting for cell-type composition in all four protocols (λ adjusted = 1.00-1.17). These results revealed important implications for comparing DNA methylation profiles between blood specimens from different sources and may lead to discovery of disease-associated DNA methylation markers and the development of DNA methylation profile-based predictive risk models.
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