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Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation.

ABSTRACT: 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 the variable CpGs are 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 covariation 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.

SUBMITTER: Islam SA

PROVIDER: S-EPMC6314079 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation.

Islam Sumaiya A SA Goodman Sarah J SJ MacIsaac Julia L JL Obradović Jelena J Barr Ronald G RG Boyce W Thomas WT Kobor Michael S MS

Epigenetics & chromatin 20190102 1

<h4>Background</h4>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 c ...[more]

PMID: 30602389

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Project description:Quantifying the natural inter-individual variation in DNA methylation patterns is important for identifying its contribution to phenotypic variation, but also for understanding how the environment affects variability, and for incorporation into statistical analyses. The inter-individual variation in DNA methylation patterns in female cattle and the effect that a prenatal stressor has on such variability have yet to be quantified. Thus, the objective of this study was to utilize methylation data from mature Brahman females to quantify the inter-individual variation in DNA methylation. Pregnant Brahman cows were transported for 2 h durations at days 60 ± 5; 80 ± 5; 100 ± 5; 120 ± 5; and 140 ± 5 of gestation. A non-transport group was maintained as a control. Leukocytes, amygdala, and anterior pituitary glands were harvested from eight cows born from the non-transport group (Control) and six from the transport group (PNS) at 5 years of age. The DNA harvested from the anterior pituitary contained the greatest variability in DNA methylation of cytosine-phosphate-guanine (mCpG) sites from both the PNS and Control groups, and the amygdala had the least. Numerous variable mCpG sites were associated with retrotransposable elements and highly repetitive regions of the genome. Some of the genomic features that had high variation in DNA methylation are involved in immune responses, signaling, responses to stimuli, and metabolic processes. The small overlap of highly variable CpG sites and features between tissues and leukocytes supports the role of variable DNA methylation in regulating tissue-specific gene expression. Many of the CpG sites that exhibited high variability in DNA methylation were common between the PNS and Control groups within a tissue, but there was little overlap in genomic features with high variability. The interaction between the prenatal environment and the genome could be responsible for the differences in location of the variable DNA methylation.

Project description:BackgroundDNA methylation is an epigenetic event that may regulate gene expression. Because of this regulation role, aberrant DNA methylation is often associated with many diseases. Within-sample DNA co-methylation is the similarity of methylation in nearby cytosine sites of a chromosome. It is important to study co-methylation patterns. However, it is not well studied yet, and it is unclear to us what co-methylation patterns normal DNA samples have. Are the co-methylation patterns of the same tissue across several samples different? Are the co-methylation patterns of various tissues of the same sample different? To answer these questions, we conduct analyses using two sets of data: 3-sample-1-tissue (3S1T) and 1-sample-8-tissue (1S8T).ResultsTo study the co-methylation patterns of the two datasets, 3S1T and 1S8T, we investigate the following questions: How often does one methylation state change to other methylation states and how is this change associated with chromosome distance? Based on the 3S1T data, we find there is not significant co-methylation difference among the same spleen tissues of three different samples. However, the analysis results of 1S8T data show that there were significant differences among eight tissues of one sample. For both 3S1T and 1S8T data, we find that the no/low methylation state A and high/full methylation state D tend to remain the same along a chromosome region. We also find that the low/partial methylation state B and partial/high methylation state C tend to change to higher methylation states along a chromosome. Finally, we find that lengths of most co-methylation regions are very short with only a few hundred base pairs. In fact, only a small proportion of methylated regions are longer than 1000 base pairs.ConclusionsIn this paper, we have addressed a few questions regarding within-sample co-methylation patterns in normal tissues. Our statistical analysis results and answers may help researchers to better understand the biological process of DNA methylation. This may pave the way to develop better analysis methods for future methylation research.

Project description:BackgroundThe discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.ResultsWe conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10-10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.ConclusionOur study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.

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Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation.

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Integration of DNA methylation patterns and genetic variation in human pediatric tissues help inform EWAS design and interpretation.

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