Mapping the landscape of cell type-dependent genetic regulation of DNA methylation across human tissues

DNA methylation (DNAm) is an epigenetic modification involved in gene regulation. DNAm quantitative trait loci (mQTLs) have been identified in many tissues, but bulk-tissue studies obscure cell type-specific effects. Here, we present the first multi-tissue landscape of cell type-dependent regulation of DNAm in humans by mapping cell type-interaction mQTLs (imQTLs) across seven tissue types (breast, colon, lung, ovary, prostate, kidney, and whole blood), identifying 3,150 imQTLs. Inter-individual variability in cell type proportion, rather than mean proportion, was most associated with imQTL discovery. The cell type with the most imQTLs tended to have interaction effects directionally consistent with mQTL marginal effects from bulk-tissue. imQTLs exhibited biologically relevant effect sharing across related cell types. Compared to cell-agnostic mQTLs, imQTLs exhibited stronger enrichment in regulatory elements and higher colocalization with eQTLs and GWAS loci. Our cell type deconvolution-based approach provides a scalable alternative to single-cell DNAm profiling for uncovering the cellular contexts of genetic regulation of DNAm.