Genome-wide DNA Methylation Comparison between Live Human Brain and Peripheral Tissues within Individuals
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE111165 | GEO | 2019/02/19
REPOSITORIES: GEO
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Project description:Neuroepigenetics considers genetic sequences and the interplay with environmental influences to elucidate vulnerability risk for various neurological and psychiatric disorders. However, evaluating DNA methylation of brain tissue is challenging owing to the issue of tissue specificity. Consequently, peripheral surrogate tissues were used, resulting in limited progress compared with other epigenetic studies, such as cancer research. Therefore, we developed databases to establish correlations between the brain and peripheral tissues in the same individuals. Four tissues, resected brain tissue, blood, saliva, and buccal mucosa (buccal), were collected from 19 patients (aged 13–73 years) who underwent neurosurgery. Moreover, their genome-wide DNA methylation was assessed using the Infinium HumanMethylationEPIC BeadChip arrays to determine the cross-tissue correlation of each combination. These correlation analyses were conducted with all methylation sites and with variable CpGs, and with when these were adjusted for cellular proportions. For the averaged data for each CpG across individuals, the saliva–brain correlation (r = 0.90) was higher than that for blood–brain (r = 0.87) and buccal–brain (r = 0.88) comparisons. Among individual CpGs, blood had the highest proportion of CpGs correlated to the brain at nominally significant levels (19.0%), followed by saliva (14.4%) and buccal (9.8%). These results were similar to the previous IMAGE-CpG results; however, the correlation analysis between the correlation coefficients of the datasets revealed a relatively low degree of correlation (brain vs. blood: r = 0.27, saliva; r = 0.18, and buccal; r = 0.24). To the best of our knowledge, this is the fourth study in the literature initiating the development of databases for correlations between the brain and peripheral tissues in the same individuals. We present the first database developed from an Asian population, specifically Japanese samples (AMAZE-CpG), which would contribute to interpreting individual epigenetic study results from various Asian populations.
2023-02-16 | GSE214901 | GEO
Project description:DNA methylation has become increasingly recognized in the etiology of psychiatric disorders. Because brain tissue is not accessible in living humans, epigenetic studies are most often conducted in blood. Saliva is often collected for genotyping studies but is rarely used to examine DNA methylation because the proportion of epithelial cells and leukocytes varies extensively between individuals. The goal of this study was to evaluate whether saliva DNA is informative for studies of psychiatric disorders. Saliva and blood methylation was clearly distinguishable though there was positive correlation overall. There was little correlation in CpG sites within relevant candidate genes. Correlated CpG sites were more likely to occur in areas of low CpG density (i.e. CpG shores and open seas). There was more variability in CpG sites from saliva than blood, which may reflect its heterogeneity. Thus, this study provides a framework for using DNA methylation from saliva and suggests that DNA methylation of saliva may offer distinct opportunities for epidemiological and longitudinal studies of psychiatric traits.
2014-09-24 | GSE61653 | GEO
Project description:DNA methylation has become increasingly recognized in the etiology of psychiatric disorders. Because brain tissue is not accessible in living humans, epigenetic studies are most often conducted in blood. Saliva is often collected for genotyping studies but is rarely used to examine DNA methylation because the proportion of epithelial cells and leukocytes varies extensively between individuals. The goal of this study was to evaluate whether saliva DNA is informative for studies of psychiatric disorders. Saliva and blood methylation was clearly distinguishable though there was positive correlation overall. There was little correlation in CpG sites within relevant candidate genes. Correlated CpG sites were more likely to occur in areas of low CpG density (i.e. CpG shores and open seas). There was more variability in CpG sites from saliva than blood, which may reflect its heterogeneity. Thus, this study provides a framework for using DNA methylation from saliva and suggests that DNA methylation of saliva may offer distinct opportunities for epidemiological and longitudinal studies of psychiatric traits. DNA methylation was assessed in saliva and blood samples from 64 adult African Americans. Both saliva and blood samples were collected from each participant. Saliva was stored in Oragene DNA sample collection kits (DNA Genotek), and blood was collected in EDTA vacuum tubes. DNA was extracted using the Puregene Genomic DNA kit (Invitrogen). DNA methylation was interrogated for each sample using the HumanMethylation450 BeadChip (Illumina). Analyses for tissue-specific DNA patterns were conducted using linear regression adjusted for appropriate covariates, including estimated cellular proportions. The estimated proportion of epithelial cells in saliva DNA ranged from 3-99% (median 26%). In blood, the estimated proportion of lymphocytes ranged from 25-70% (median 48%) and neutrophils ranged from 42-84% (median 58%). Methylation of 68.8% of all CpG sites differed relative to epithelial cell proportion (FDR<.05). Our results provide a framework for methylation studies in DNA extracted from saliva and highlight the importance of controlling for the proportion of epithelial and leukocyte cells. This presents an attractive opportunity for investigators that have already collected salivary DNA for genetic studies of psychiatric traits.
2014-09-24 | E-GEOD-61653 | biostudies-arrayexpress
Project description:Tissue differences are one of the largest contributors to variability in the human DNA methylome. Despite the tissue specific nature of DNA methylation, the inaccessibility of human brain samples necessitates the frequent use of surrogate tissues such as blood, in studies of associations between DNA methylation and brain function and health. Results from studies of surrogate tissues in humans are difficult to interpret in this context, as the connection between blood-brain DNA methylation is tenuous and not well documented. Here we aimed to provide a resource to the community to aid interpretation of blood based DNA methylation results in the context of brain tissue. We used paired samples from 16 individuals from three brain regions and whole blood, run on the Illumina 450K Human Methylation Array to quantify the concordance of DNA methylation between tissues. From these data we have made available metrics on: the variability of CpGs in our blood and brain samples, the concordance of CpGs between blood and brain, and estimations of how strongly a CpG is affected by cell composition in both blood and brain through the web application BECon (Blood-Brain Epigenetic Concordance; https://redgar598.shinyapps.io/BECon/). We anticipate that BECon will enable biological interpretation of blood based human DNA methylation results, in the context of brain.
2017-08-01 | GSE95049 | GEO
Project description:Prenatal stress exposure is associated with the risk for psychiatric disorders later in life. This may be mediated via enhanced exposure to glucocorticoids (GCs), known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on mRNA expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG sites and in the expression of 3,857 transcripts at FDR ≤ 0.1 and an absolsute change in expression of 1.15. HPC gene expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into four trajectories over HPC-differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting gene expression changes, but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC-challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a poly-epigenetic score that predicted exposure to conditions of excessive prenatal GC in newborn cord blood. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.
2019-03-01 | GSE119846 | GEO
Project description:Prenatal stress exposure is associated with the risk for psychiatric disorders later in life. This may be mediated via enhanced exposure to glucocorticoids (GCs), known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on mRNA expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG sites and in the expression of 3,857 transcripts at FDR ≤ 0.1 and an absolsute change in expression of 1.15. HPC gene expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into four trajectories over HPC-differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting gene expression changes, but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC-challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a poly-epigenetic score that predicted exposure to conditions of excessive prenatal GC in newborn cord blood. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.
2019-03-01 | GSE119843 | GEO
Project description:Prenatal stress exposure is associated with the risk for psychiatric disorders later in life. This may be mediated via enhanced exposure to glucocorticoids (GCs), known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on mRNA expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG sites and in the expression of 3,857 transcripts at FDR ≤ 0.1 and an absolsute change in expression of 1.15. HPC gene expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into four trajectories over HPC-differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting gene expression changes, but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC-challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a poly-epigenetic score that predicted exposure to conditions of excessive prenatal GC in newborn cord blood. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.
2019-03-01 | GSE119842 | GEO
Project description:Background: The widespread use of accessible peripheral tissues for epigenetic analyses has prompted increasing interest in the study of tissue-specific DNA methylation (DNAm) variation in human populations. To date, characterizations of inter-individual DNAm variability and DNAm concordance across tissues have been largely performed in adult tissues and therefore are limited in their relevance to DNAm profiles from pediatric samples. Given that DNAm patterns in early life undergo rapid changes and have been linked to a wide range of health outcomes and environmental exposures, direct investigations of tissue-specific DNAm variation in pediatric samples may help inform the design and interpretation of DNAm analyses from early life cohorts. In this study, we present a systematic comparison of genome-wide DNAm patterns between matched pediatric buccal epithelial cells (BECs) and peripheral blood mononuclear cells (PBMCs), two of the most widely used peripheral tissues in human epigenetic studies. Specifically, we assessed DNAm variability, cross-tissue DNAm concordance and genetic determinants of DNAm across two independent early life cohorts encompassing different ages. Results: BECs had greater inter-individual DNAm variability compared to PBMCs and highly variable CpGs were more likely to be positively correlated between the matched tissues compared to less variable CpGs. These sites were enriched for CpGs under genetic influence, suggesting that a substantial proportion of DNAm co-variation between tissues can be attributed to genetic variation. Finally, we demonstrated the relevance of our findings to human epigenetic studies by categorizing CpGs from published DNAm association studies of pediatric BECs and peripheral blood. Conclusions: Taken together, our results highlight a number of important considerations and practical implications in the design and interpretation of EWAS analyses performed in pediatric peripheral tissues.
2018-12-27 | GSE124366 | GEO
Project description:Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain. To investigate this, we interrogated genome-wide DNA methylation in postmortem hippocampus from 32 BD-I patients and 32 age-, sex-, and race-matched non-psychiatric controls from the NIMH Human Brain Collection Core.
2019-12-02 | GSE129428 | GEO
Project description:Background: Measurement of genome-wide DNA methylation (DNAm) has become an important avenue for investigating potentially functional changes in various pathological conditions. Illumina Infinium is a relatively inexpensive and user-friendly DNAm microarray platform used by many researchers to measure DNAm on a large scale. However it has been suggested that a subset of probes may give rise to misleading results due to issues related to probe design. To facilitate biologically significant data interpretation, we set out to enhance probe annotation of the newest HumanMethylation450 BeadChip array (with >485,000 probes covering 99% of RefSeq genes). Results: Annotation that was added or expanded on includes 1) SNPs documented in the probe target, 2) probe binding specificity, 3) CpG classification of target sites and 4) gene feature classification of target sites. Probes with documented SNPs within 10bp of the target site and especially those with documented SNPs at the target CpG, were associated with increased within-tissue variation in DNAm. An example of a probe with a SNP at the target CpG was used to demonstrate how sample genotype can confound the measurement of DNAm. 8.6% of probes were identified as non-specific, in other words, these probes map to multiple locations in silico. DNAm measured from these non-specific probes likely represents a combination of DNAm from multiple genomic sites. The expanded biological annotation demonstrated that based on DNAm, grouping probes by alternative CpG classes rather than UCSC islands provides a more distinctive classification system of CpG sites. Finally variable enrichment for tissue-specific differentially methylated probes was noted across CpG classes and gene feature groups, depending on the tissues that were compared. Conclusion: Probes containing SNPs and non-specific probes may affect the assessment of DNAm using the 450k array. Additionally CpG enrichment classes and to a lesser extent gene feature groups were associated with distinct patterns of DNAm. Thus, we recommend that confounded probes be removed from analyses and that genomic trends be considered in analyses of the Illumina HumanMethylation450 BeadChip. DNAm arrays offer a powerful approach for which thoughtful use of probe content can be utilized to better understand the biological processes affected. Bisulfite converted DNA from 4 buccal, 4 blood and 4 chorionic villus samples was hybridized to the Illumina Infinium HumanMethylation450 BeadChip array.
2013-03-04 | E-GEOD-42409 | biostudies-arrayexpress