Faculty, Staff and Student Publications

Language

English

Publication Date

1-15-2026

Journal

Human Genetics and Genomics Advances

DOI

10.1016/j.xhgg.2025.100552

PMID

41351263

PMCID

PMC12903085

PubMedCentral® Posted Date

12-4-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Despite considerable advances in identifying risk factors for obesity, gaps remain in our understanding about its etiology. Genetic variants explain only a small portion of variation in obesity-related traits such as body mass index (BMI). Epigenetic regulation, which controls gene expression and is influenced by environmental and genetic factors, may account for additional variability in BMI. Epigenetic studies of BMI have largely been conducted in European ancestry populations, despite the disproportionate burden of obesity in African Americans (AAs). We conducted a sex-stratified BMI epigenome-wide association study meta-analysis in AA participants from the Jackson Heart Study (n = 1,604) and the Multi-Ethnic Study of Atherosclerosis (n = 179) with Illumina EPIC (850,000) array data. Linear regression models with methylation as the outcome and continuous BMI as the predictor were stratified by study and sex and meta-analyzed. We identified 208 methylation sites (CpGs, p < 8.72 × 10−8) significantly associated with BMI; 151 had not been previously reported in the literature. Replication was performed in a separate sample of AA participants with 450,000 array data, which lacks many CpGs present in the 850,000 array. Replication testing was possible for only 29 of the 151 CpGs; 19 were statistically significant (p < 1.72 × 10−3). Sex-specific results showed 4 female-only and 3 male-only BMI-CpGs not identified in the sex-combined results. Differentially methylated region (DMR) analysis resulted in 66 DMRs, including several regions near genes previously implicated for obesity (e.g., SOCS3, TGFB1). Further analyses showed enrichment of genes and traits related to the immune system and inflammation-related pathways (e.g., the IL-6/JAK/STAT pathway).

Keywords

Aged, Female, Humans, Male, Middle Aged, Black or African American, Body Mass Index, CpG Islands, DNA Methylation, Epigenesis, Genetic, Epigenome, Genome-Wide Association Study, Obesity, epigenetics, methylation, genetics, obesity, BMI, African American, inflammation, immune system

Published Open-Access

yes

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