Abstract
Background DNA methylation (DNAm) is a critical epigenetic mark impacting gene expression, and differential DNAm in the brain is associated with a number of psychiatric diseases. However, access to brain tissues to assess DNAm is essentially limited to post-mortem samples. The use of surrogate tissues, such as blood and saliva, has become common in identifying methylation changes associated with psychiatric disease. However, there is no literature showing direct association of DNAm between brain and peripheral tissues within individuals to support the validity of such surrogate tissues. In this study, we determined the extent to which these peripheral tissues can be used as surrogates for DNAm in the brain. Methods DNA from blood, saliva, and live brain tissue samples from 12 treatment refractory epilepsy patients undergoing brain resection were collected. Genome-wide methylation was assessed with the Infinium HumanMethylation450 BeadChip array. Data were processed and analyzed with the R package RnBeads. Tissue relatedness was analyzed with Pearson correlation. Subsets of CpGs within different genomic regions, including promoter, genic, and intergenic regions, were evaluated for their degree of DNAm similarity. Results Blood and saliva showed a high degree of correlation for DNAm (r2=0.97), and saliva DNAm was revealed to be more similar to brain DNAm (r2=0.86) than was blood (r2=0.82; p Discussion Genome-wide analysis of DNAm from both saliva and blood revealed a high degree of correlation with live brain DNAm within individuals, but saliva was more highly correlated. This indicates that saliva is a suitable surrogate for DNAm in the brain.
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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