Epigenome-Wide Association Study of Blood Proteome in the Atherosclerosis Risk in Communities Study

Authors

• Yang Li
• Aditya Surapaneni
• Zulema Rodriguez-Hernandez
• Pascal Schlosser
• Eugene P Rhee
• Eric Boerwinkle
• Bing Yu
• Megan L Grove
• Kelly V Ruggles
• Josef Coresh
• Morgan Grams

Language

English

Publication Date

4-9-2026

Journal

Human Genetics and Genomics Advances

DOI

10.1016/j.xhgg.2026.100585

PMID

41782372

PMCID

PMC13014933

PubMedCentral® Full Text Version

Post-print

Abstract

Characterizing the relationship between DNA methylation and circulating proteins is critical to understanding the epigenetic regulation of the human plasma proteome. Here, we performed an epigenome-wide association study of 5,032 circulating proteins in 1,449 White and 315 Black participants from the Atherosclerosis Risk in Communities cohort. We identified 12,500 significant protein quantitative trait methylation (pQTM)-protein associations involving 1,647 proteins. Among 7,796 unique pQTMs, 14.7% were classified as cis-pQTMs, which were enriched for fundamental cellular processes, whereas trans-pQTMs were predominantly linked to immune-related functions. Trans-pQTMs also exhibited stronger associations with demographic, lifestyle, and clinical traits as compared with cis-pQTMs. We identified proteins such as GM2A and EPHB6, whose expression appears to be strongly associated with DNA methylation, suggesting potential as targets for epigenetic-based therapeutic interventions. These findings demonstrate the extensive impact of DNA methylation on the circulating proteome through cis- and trans-regulatory mechanisms and underscore the influence of population-level traits on epigenetic regulation. These findings highlight a broad impact of DNA methylation on circulating proteins through both cis- and trans-regulatory mechanisms and the roles of population-level phenotypes.

Keywords

Humans, Atherosclerosis, Genome-Wide Association Study, DNA Methylation, Proteome, Epigenesis, Genetic, Female, Male, Epigenome, Middle Aged, Blood Proteins, epigenome-wide association study, blood proteome, trans-pQTM, cis-pQTM

Published Open-Access

yes

Recommended Citation

Li, Yang; Surapaneni, Aditya; Rodriguez-Hernandez, Zulema; et al., "Epigenome-Wide Association Study of Blood Proteome in the Atherosclerosis Risk in Communities Study" (2026). Faculty, Staff and Student Publications. 1436.
https://digitalcommons.library.tmc.edu/uthsph_docs/1436