omicsPrint: detection of data linkage errors in multiple omics studies

Iterson, Maarten van; Cats, Davy; Hop, Paul J.; Heijmans, Bastiaan T.

doi:10.1093/bioinformatics/bty062

Cited by 29 publications

(24 citation statements)

References 11 publications

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“…For all samples, Illumina 450k array data passed quality control using MethylAid [32]. Sample mix-ups between donors were excluded on the basis of inferred genotypes using OmicsPrint [33]. Probes with detection P value > 0.01, bead number < 3 or zero intensity in at least one sample were removed (46718 probes were removed, resulting in a final data set of 440292 CpGs).…”

Section: Methodsmentioning

confidence: 99%

Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites

Dekkers

Neele

Jukema

et al. 2019

Epigenetics & Chromatin

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Background Macrophages and their precursors monocytes play a key role in inflammation and chronic inflammatory disorders. Monocyte-to-macrophage differentiation and activation programs are accompanied by significant epigenetic remodeling where DNA methylation associates with cell identity. Here we show that DNA methylation changes characteristic for monocyte-to-macrophage differentiation occur at transcription factor binding sites, and, in contrast to what was previously described, are generally highly localized and encompass both losses and gains of DNA methylation. Results We compared genome-wide DNA methylation across 440,292 CpG sites between human monocytes, naïve macrophages and macrophages further activated toward a pro-inflammatory state (using LPS/IFNγ), an anti-inflammatory state (IL-4) or foam cells (oxLDL and acLDL). Moreover, we integrated these data with public whole-genome sequencing data on monocytes and macrophages to demarcate differentially methylated regions. Our analysis showed that differential DNA methylation was most pronounced during monocyte-to-macrophage differentiation, was typically restricted to single CpGs or very short regions, and co-localized with lineage-specific enhancers irrespective of whether it concerns gain or loss of methylation. Furthermore, differentially methylated CpGs were located at sites characterized by increased binding of transcription factors known to be involved in monocyte-to-macrophage differentiation including C/EBP and ETS for gain and AP-1 for loss of methylation. Conclusion Our study highlights the involvement of subtle, yet highly localized remodeling of DNA methylation at regulatory regions in cell differentiation. Electronic supplementary material The online version of this article (10.1186/s13072-019-0279-4) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites

Dekkers

Neele

Jukema

et al. 2019

Epigenetics & Chromatin

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“…Proper data linkage of SNP, RNAseq, and DNA methylation array data within individuals was verified using the omicsPrint package [86].…”

Section: Probe Filteringmentioning

confidence: 99%

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

et al. 2020

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Background: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. Results: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation. Conclusion: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.

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“…MethylAid was applied with the default EPIC array-specific quality filter thresholds for EPIC arrays. The R package omicsPrint [81] was used to call genotypes based on methylation probes and to verify sample relationships based on those single nucleotide polymorphisms (SNPs) (e.g., the zygosity of twins and samples from the same individual). We checked for sample mismatches between methylation data and genotype data by computing the correlation between SNP genotypes called by omicsPrint based on methylation probes and genotypes based on genome-wide SNP arrays.…”

Section: Methodsmentioning

confidence: 99%

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

et al. 2019

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Breastfeeding has long-term benefits for children that may be mediated via the epigenome. This pathway has been hypothesized, but the number of empirical studies in humans is small and mostly done by using peripheral blood as the DNA source. We performed an epigenome-wide association study (EWAS) in buccal cells collected around age nine (mean = 9.5) from 1006 twins recruited by the Netherlands Twin Register (NTR). An age-stratified analysis examined if effects attenuate with age (median split at 10 years; n<10 = 517, mean age = 7.9; n>10 = 489, mean age = 11.2). We performed replication analyses in two independent cohorts from the NTR (buccal cells) and the Avon Longitudinal Study of Parents and Children (ALSPAC) (peripheral blood), and we tested loci previously associated with breastfeeding in epigenetic studies. Genome-wide DNA methylation was assessed with the Illumina Infinium MethylationEPIC BeadChip (Illumina, San Diego, CA, USA) in the NTR and with the HumanMethylation450 Bead Chip in the ALSPAC. The duration of breastfeeding was dichotomized (‘never‘ vs. ‘ever’). In the total sample, no robustly associated epigenome-wide significant CpGs were identified (α = 6.34 × 10–8). In the sub-group of children younger than 10 years, four significant CpGs were associated with breastfeeding after adjusting for child and maternal characteristics. In children older than 10 years, methylation differences at these CpGs were smaller and non-significant. The findings did not replicate in the NTR sample (n = 98; mean age = 7.5 years), and no nearby sites were associated with breastfeeding in the ALSPAC study (n = 938; mean age = 7.4). Of the CpG sites previously reported in the literature, three were associated with breastfeeding in children younger than 10 years, thus showing that these CpGs are associated with breastfeeding in buccal and blood cells. Our study is the first to show that breastfeeding is associated with epigenetic variation in buccal cells in children. Further studies are needed to investigate if methylation differences at these loci are caused by breastfeeding or by other unmeasured confounders, as well as what mechanism drives changes in associations with age.

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omicsPrint: detection of data linkage errors in multiple omics studies

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 29 publications

References 11 publications

Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites

Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

DNA Methylation Signatures of Breastfeeding in Buccal Cells Collected in Mid-Childhood

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