Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood

Ruiz-Arenas, Carlos; Hernandez-Ferrer, Carles, 1987-; Vives Usano, Marta, 1990-; Marí, Sergi; Casas Sanahuja, Maribel; Vafeiadi, Marina, 1983-; Vrijheid, Martine; González Ruiz, Juan Ramón; Bustamante Pineda, Mariona

doi:http://dx.doi.org/10.7554/eLife.65310

Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood

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Ruiz-Arenas C, Hernandez-Ferrer C, Vives Usano M, Marí S, Quintela I, Mason D et al. Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children's blood. Elife. 2022 Mar 18;11:e65310. DOI: 10.7554/eLife.65310

Abstract

Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children's 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 (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGene's TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. In 40.4% of the eQTMs, the CpG and the eGene were both associated with at least one genetic variant. The overlap of autosomal cis eQTMs in children's blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. Conclusions: This catalogue of autosomal cis eQTMs in children's blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/ and at Dryad (doi:10.5061/dryad.fxpnvx0t0).