Prenatal exposure to residential green space and cord blood DNA methylation: epigenome wide association studies in the ENVIRONAGE cohort

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Background and aim DNA methylation may be an underlying mechanism between green space and health. Although newborn DNA methylation is sensitive to environmental influences during prenatal life, the impact of green space has not been studied yet. This study evaluated whether prenatal exposure to residential green space is associated with cord blood DNA methylation. Methods We conducted epigenome-wide association studies using data from two subpopulations (N=198 and 349) of the ENVIRONAGE cohort. Cord blood DNA methylation was measured by Illumina HumanMethylation 450K and EPIC BeadChip arrays, respectively in the two subpopulations. High (vegetation >3m), low (vegetation <3m) and total (including both) green space exposure was estimated within 100 and 1000 m distance around the maternal residence using high-resolution data. We used linear mixed models to identify differentially methylated sites, and two different approaches (ENmix-combp and DMRcate) to identify differentially methylated regions. Functional analysis was performed by associating green space with cord expression of the genes mapped to the identified signals. Results Prenatal exposure to total, low and high residential green space within 100 and 1000 m was associated with six differentially methylated regions (annotated to COL9A3, GPR27, LINC00612, LINC01973, PARD6G-AS1, ZNF274 genes), in common to the two subsets. Methylation at 7 CpGs was associated with prenatal exposure to total and high green space at 100 and 1000 m distance, with no overlap between the two subsets. Expression level of the FSTL3 gene decreased with prenatal exposure to total green space at 1000 m buffer. Conclusions Our results demonstrate that prenatal residential exposure to green space is associated with cord blood DNA methylation, mainly at loci organized in regions, and that these signals may have functional relevance. Keywords: Residential green space, Epigenomics, Gene expression