Abstract
Background The identification of expression quantitative trait methylation (eQTMs), defined as correlations between gene expression and DNA methylation levels, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis-eQTMs in child blood, using data from 832 children of the Human Early Life Exposome (HELIX) project.
Methods Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (transcription start site (TSS) within a window of 1 Mb) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, and cohort.
Results We identified 63,831 autosomal cis-eQTMs, representing 35,228 unique CpGs and 11,071 unique transcript clusters (TCs, genes). 74.3% of these cis-eQTMs were located at <250 kb, 60.0% showed an inverse relationship and 23.9% had at least one genetic variant associated with the methylation and expression levels. They were enriched for active blood regulatory regions. Adjusting for cellular composition decreased the number of cis-eQTMs to 37.7%, suggesting that some of them were cell type-specific. The overlap of child blood cis-eQTMs with those described in adults was small, and child and adult shared cis-eQTMs tended to be proximal to the TSS, enriched for genetic variants and with lower cell type specificity. Only half of the cis-eQTMs could be captured through annotation to the closest gene.
Conclusions This catalogue of blood autosomal cis-eQTMs in children can help the biological interpretation of EWAS findings, and is publicly available at https://helixomics.isglobal.org/.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Abbreviations
- BivFlnx
- flanking bivalent region
- CpG
- cytosine nucleotide followed by a guanine nucleotide
- eQTM
- expression quantitative trait methylation
- eQTL
- expression quantitative trait locus
- Enh
- enhancer
- EnhBiv
- bivalent enhancer
- EnhG
- genic enhancer
- EWAS
- epigenome-wide association study
- FC
- fold change
- FDR
- false discovery rate
- GO
- gene ontology
- GWAS
- genome-wide association study
- HELIX
- Human Early-Life Exposome project
- Het
- heterochromatin
- IQR
- interquartile range
- meQTL
- methylation quantitative trait locus
- OR
- odds ratio
- Quies
- quiescent region
- ReprPC
- repressed Polycomb
- ReprPCWk
- weak repressed polycomb
- SE
- standard error
- SNP
- single nucleotide polymorphism
- TC
- transcript cluster
- TSS
- transcription start site
- TssA
- active transcription start site
- TssAFlnk
- flanking active transcription start site
- TssBiv
- bivalent transcription start site
- TSS200
- proximal promoter, from TSS to 200 bp
- TSS1500
- distal promoter, from 200 bp to 1,500 bp
- Tx
- transcription region
- TxFlnk
- transcription at 5’ and 3’
- TxWk
- weak transcription region
- 3’UTR
- 3’ untranslated region
- 5’UTR
- 5’ untranslated region
- ZNF.Rpts
- zinc finger genes and repeats