Language
English
Publication Date
3-1-2026
Journal
Briefings in Bioinformatics
DOI
10.1093/bib/bbag142
PMID
41902502
PMCID
PMC13032028
PubMedCentral® Posted Date
3-28-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Population stratification is one of the source of inflation in epigenome-wide association studies (EWAS) when not properly accounted for. To address this, we developed methylation population scores (MPSs) to predict genetic principal components (GPCs) using a feature selection approach. We used multi-ethnic DNA methylation data from Illumina EPIC arrays across five cohorts, including MESA (n = 929), CARDIA (n = 1123), JHS (n = 1365), ARIC (n = 2338), and HCHS/SOL (n = 1475), randomly splitting participants into training (85%) and test (15%) sets. Within each cohort, associations between GPCs and CpG sites were estimated using linear regression adjusting for age, sex, smoking and alcohol use, race/ethnicity, body mass index, and cell type proportions, followed by meta-analysis and selection of CpGs with FDR < 0.05. We then applied a two-stage weighted least squares Lasso regression to construct MPSs, adjusting for the aforementioned covariates. In the test dataset, MPSs showed strong correlation with GPCs, with R² ranging from 0.27 (MPS7 vs. GPC7) to 0.98 (MPS1 vs. GPC1). Visualization demonstrated that MPSs recapitulated the pattern shown by GPCs in differentiating self-reported White, Black, and Hispanic/Latino groups and outperformed methylation-based principal components constructed using alternative published methods. Additionally, MPSs showed comparable performance to GPCs in reducing inflation in EWAS. Overall, MPSs uses supervised learning with covariate adjustment to capture genetic structure across diverse populations, and provide a reliable estimate of population structure in the data and can complement GPCs when genetic data are absent.
Keywords
Humans, DNA Methylation, CpG Islands, Epigenome, Genome-Wide Association Study, Female, Male, Middle Aged, Epigenomics, Epigenesis, Genetic, Principal Component Analysis, population stratification, DNA methylation, epigenome-wide association study (EWAS)
Published Open-Access
yes
Recommended Citation
Wang, Ziqing; Taylor, Kent D; Rotter, Jerome I; et al., "Estimating Population Structure Using Epigenome-Wide Methylation Data" (2026). The Brown Foundation: Institute of Molecular Medicine. 56.
https://digitalcommons.library.tmc.edu/molecular_med/56