Genetics and Environment Distinctively Shape the Human Immune Cell Epigenome

^{*Co-first authors}

The epigenome of human immune cells is shaped by both genetics and environmental factors, yet the relative contributions of these influences remain incompletely characterized. Using single-nucleus methylation sequencing and ATAC-seq on 171 PBMC samples from 110 individuals with defined exposures to pathogens and chemicals, we systematically explored how exposures and genetic variation associate with changes in the immune cell epigenome. Distinct exposure-associated differentially methylated regions (eDMRs) and differentially accessible regions were identified, with eDMRs enriched in regulatory regions and genotype-associated DMRs (gDMRs) preferentially located within gene body marks. Disease-associated SNPs were frequently colocalized with methylation QTLs, providing cell-type-specific insights into the genetic basis of immune diseases.

Recommended citation: Wang W^*, Hariharan M^*, Ding W^*, Bartlett A, Barragan C, Castanon R, Wang R, Rothenberg V, Song H, Nery JR, Altshul J, Kenworthy M, Liu H, Tian W, Zhou J, Zeng Q, Chen H, Aldridge A, Gündüz IB, Müller F, Norell T, Broderick TJ, McClain MT, Satterwhite LL, Burke TW, Petzold EA, Woods CW, Fowler VG Jr, Ruffin F, Ecker JR. (2026). "Genetics and environment distinctively shape the human immune cell epigenome." Nature Genetics. 58:392–403. doi:10.1038/s41588-025-02479-6
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