Concordant and discordant DNA methylation signatures of aging in human blood and brain

Abstract

BackgroundDNA methylation is an epigenetic mark that balances plasticity with stability. While DNA methylation exhibits tissue specificity, it can also vary with age and potentially environmental exposures. In studies of DNA methylation, samples from specific tissues, especially brain, are frequently limited and so surrogate tissues are often used. As yet, we do not fully understand how DNA methylation profiles of these surrogate tissues relate to the profiles of the central tissue of interest.ResultsWe have adapted principal component analysis to analyze data from the Illumina 450K Human Methylation array using a set of 17 individuals with 3 brain regions and whole blood. All of the top five principal components in our analysis were associated with a variable of interest: principal component 1 (PC1) differentiated brain from blood, PCs 2 and 3 were representative of tissue composition within brain and blood, respectively, and PCs 4 and 5 were associated with age of the individual (PC4 in brain and PC5 in both brain and blood). We validated our age-related PCs in four independent sample sets, including additional brain and blood samples and liver and buccal cells. Gene ontology analysis of all five PCs showed enrichment for processes that inform on the functions of each PC.ConclusionsPrincipal component analysis (PCA) allows simultaneous and independent analysis of tissue composition and other phenotypes of interest. We discovered an epigenetic signature of age that is not associated with cell type composition and required no correction for cellular heterogeneity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0011-y) contains supplementary material, which is available to authorized users.

Epigenome-wide profiling of DNA methylation in paired samples of adipose tissue and blood

“…Second, the age of the study subjects is similar, ranging from 44 to 50 years. As age is shown to be associated with DNA methylation profile and gene expression, 19,31 the narrow range minimizes its potential confounding. Third, both internal cross-validation and external validation studies were conducted and confirmed the finding that the first principal component of epigenome-wide variations differentiates adipose tissue from blood.…”

“…18 Another study found that the top axes of methylomic variations across blood and brain are related to the tissue type, anatomical regions of the brain, and age. 19 In addition to comparison across non-pathological tissues, studies have also been conducted to examine the tumor and nontumor tissues. Comparing soft-tissue sarcoma tumor or cell line and non-neoplastic fat samples, Rener et al identified a set of CpG sites that differentiates the subphenotypes.…”

“…There are studies of tissue-specific DNA methylation directly comparing human brain with blood, 18,19 adipose tissue with skeletal muscle, 7 and blood with atrium tissue. 20 In addition to pair-wise comparison between two tissues, tissue-specific methylation patterns have also been studied across multiple tissue types or primary cell lines from various tissues, including peripheral tissues, such as blood and buccal swabs, and internal tissues obtained with invasive procedures.…”

Methylome analysis for spina bifida shows SOX18 hypomethylation as risk factor with evidence for a complex (epi)genetic interplay to affect neural tube development

“…The father is carrier of the BMP4 deletion methylation of the same gene set would be observed in brain or spinal cord tissue of MMC patients. But concordant methylation alterations in brain and blood suggest that blood methylation might be representative for brain methylation [38][39][40][41][42]. Hannon et al generated an online tool which allows to investigate the correlation of DNA methylation of blood and four brain regions for all probes present on the HM450k [43].…”

How to interpret epigenetic association studies: a guide for clinicians

“…35 There are very scarce data about the correlation of epigenetic marks in blood and the skeleton, but, in view of other studies, caution is recommended before extrapolating blood signatures to bone signatures. Investigators exploring the correlation of DNA methylation between blood and solid tissues found that the dominant difference (470%) in DNA methylation across samples depends on the source tissue, 36 and o3% of CpG sites show r 2 40.5 between blood and solid tissues such as brain or muscle. 37,38 Therefore, the reader should not assume that epigenetic marks in blood reflect the skeletal epigenome, unless such a correlation is confirmed experimentally.…”