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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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124366 | GEO | 2018/12/27

REPOSITORIES: GEO

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Project description:DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis and early development, monozygotic twins show indistinguishable childhood methylation, suggesting DNAm is highly coordinated during the pediatric period. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from 398 boys, aged 3 to 17 years, and find significant age-associated changes in DNAm at 2,078 loci. We report a deficit of such loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. These pediatric age-associated loci overlap significantly with those previously identified in adults (p < 0.001) but most of the pediatric loci are unique, suggesting many are childhood-specific. Meta-analysis (n = 1080) with two adult studies reveals that the methylation changes in 29.5% of the age-associated pediatric loci follow a linear pattern from childhood into adulthood; however, we also find a three-fold higher rate of change in children compared with adults and that a higher proportion of lifelong changes are more accurately modeled as a function of logarithmic age. We therefore conclude that DNAm changes occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies are matched closely for age. Age associated DNA methylation was evaluated at each CpG locus using a fixed-effects linear regression model adjusting for BeadChip as a covariate to account for batch effects. Analysis of variance (ANOVA) was conducted for each CpG locus to assess the age affect at each CpG locus which was subsequently corrected for multiple hypotheses using a Benjamini-Hochberg FDR. SUPPLEMENTARY FILES: * Matrix_AllSampleDetection.txt: Detection P-values for each sample and each loci * Matrix_AllSampleSignal.txt: Signal for Probe A and Probe B for each sample and each loci * Matrix_Non-Normalized_AllSampleBeta.txt: Beta values calculated using GenomeStudio v2010.3 Methylation Module 1.8.5 as Signal of Probe B / (Signal of Probe A + Signal of Probe B + 100) * Matrix_Normalized_AllSampleBetaPrime.txt: Beta Prime values used for analysis calculated from the Probe B and Probe A signals as Beta Prime = Signal of Probe B / (Signal of Probe A + Signal of Probe A)

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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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