An atlas of genetic effects on the monocyte methylome across European and African populations.

Elucidating the genetic architecture of DNA methylation (DNAm) is crucial for decoding complex disease etiology. However, current epigenomic studies are often constrained by limited methylation coverage and tissue heterogeneity. Here, we present the first comprehensive, multi-ancestry methylome atlas of purified human monocytes, which play a central role in immune response and inflammation, generated through integrated whole-genome bisulfite sequencing and whole-genome sequencing from 160 African Americans (AA) and 298 European Americans (EA). By analyzing over 25 million CpG sites, we identified 3,634,383 and 3,261,407 CpG sites having cis -methylation quantitative trait loci (meQTLs) in AA and EA populations, respectively, revealing both shared (1,046,098 sites) and population-specific regulatory patterns. Furthermore, we developed population-specific DNAm imputation models, enabling methylome-wide association studies (MWAS) across 2,677,714 and 1,976,046 CpG sites in AA and EA, respectively. These models were validated through multi-ancestry analysis of 41 complex traits from the Million Veteran Program. All meQTLs, MWAS models, and related resources are publicly available at www.gcbhub.org and https://osf.io/gct57/ .