Abstract
Differential DNA methylation in the brain is associated with many psychiatric diseases, but access to brain tissues is essentially limited to postmortem samples. The use of surrogate tissues has become common in identifying methylation changes associated with psychiatric disease. In this study, we determined the extent to which peripheral tissues can be used as surrogates for DNA methylation in the brain. Blood, saliva, buccal, and live brain tissue samples from 27 patients with medically intractable epilepsy undergoing brain resection were collected (age range 5–61 years). Genome-wide methylation was assessed with the Infinium HumanMethylation450 (n = 12) and HumanMethylationEPIC BeadChip arrays (n = 21). For the EPIC methylation data averaged for each CpG across subjects, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.86) and buccal–brain (r = 0.85) comparisons. However, within individual CpGs, blood had the highest proportion of CpGs correlated to brain at nominally significant levels (20.8%), as compared to buccal tissue (17.4%) and saliva (15.1%). For each CpG and each gene, levels of brain-peripheral tissue correlation varied widely. This indicates that to determine the most useful surrogate tissue for representing brain DNA methylation, the patterns specific to the genomic region of interest must be considered. To assist in that objective, we have developed a website, IMAGE-CpG, that allows researchers to interrogate DNA methylation levels and degree of cross-tissue correlation in user-defined locations across the genome.
Highlights
1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Using human postmortem brain tissues, epigenetic studies among psychiatric populations have found differential DNA methylation (DNAm) changes in both candidate gene studies and genome-wide analyses, including in schizophrenia[1], bipolar disorder[2], and major depressive disorder (MDD)[3], but access to brain tissue for psychiatric disorders is limited by a small number of postmortem brain samples
To determine the degree of similarity in genome-wide DNAm between brain and peripheral tissues, a multidimensional scaling (MDS) plot was constructed with all the samples for both datasets
The MDS plot with the EPIC dataset revealed the brain samples clustering separately from all peripheral tissues with the peripheral tissues clustered as expected based on their cellular compositions (Fig. 1)
Summary
Using human postmortem brain tissues, epigenetic studies among psychiatric populations have found differential DNA methylation (DNAm) changes in both candidate gene studies and genome-wide analyses, including in schizophrenia[1], bipolar disorder[2], and major depressive disorder (MDD)[3], but access to brain tissue for psychiatric disorders is limited by a small number of postmortem brain samples. Considerations remain regarding the stability and the biological implications of measurements done on postmortem tissues, as the levels of global DNAm have been shown to change in relation to postmortem interval[4,5]. Several studies have begun to address the degree to which DNAm of peripheral tissues correspond to that of the brain. Earlier studies approached this using an acrossindividual method. Horvath et al.[13] found high levels of
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