Mimosa: A Resource Consisting of Improved Methylome Prediction Models Increases Power to Identify DNA Methylation-Phenotype Associations

Authors

Hunter J Melton
Zichen Zhang
Hong-Wen Deng
Lang Wu
Chong Wu

Publication Date

12-1-2024

Journal

Epigenics

Abstract

Although DNA methylation (DNAm) has been implicated in the pathogenesis of numerous complex diseases, from cancer to cardiovascular disease to autoimmune disease, the exact methylation sites that play key roles in these processes remain elusive. One strategy to identify putative causal CpG sites and enhance disease etiology understanding is to conduct methylome-wide association studies (MWASs), in which predicted DNA methylation that is associated with complex diseases can be identified. However, current MWAS models are primarily trained using the data from single studies, thereby limiting the methylation prediction accuracy and the power of subsequent association studies. Here, we introduce a new resource, MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA), a set of models that substantially improve the prediction accuracy of DNA methylation and subsequent MWAS power through the use of a large summary-level mQTL dataset provided by the Genetics of DNA Methylation Consortium (GoDMC). Through the analyses of GWAS (genome-wide association study) summary statistics for 28 complex traits and diseases, we demonstrate that MIMOSA considerably increases the accuracy of DNA methylation prediction in whole blood, crafts fruitful prediction models for low heritability CpG sites, and determines markedly more CpG site-phenotype associations than preceding methods. Finally, we use MIMOSA to conduct a case study on high cholesterol, pinpointing 146 putatively causal CpG sites.

Keywords

DNA Methylation, Humans, Genome-Wide Association Study, Epigenome, Quantitative Trait Loci, CpG Islands, Phenotype, Models, Genetic

DOI

10.1080/15592294.2024.2370542

PMID

38963888

PMCID

PMC11225927

PubMedCentral® Posted Date

7-4-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes