HGG Adv. 2025 Dec 4:100552. doi: 10.1016/j.xhgg.2025.100552. Online ahead of 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 (EWAS) meta-analysis in AA participants from the Jackson Heart Study (JHS, n=1604) and the Multi-Ethnic Study of Atherosclerosis (MESA, n=179) with Illumina EPIC (850k) 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 not been previously reported in literature. Replication was performed in a separate sample of AA participants with 450k array data, which lacks many CpGs present in the 850k 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 and 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).
PMID:41351263 | DOI:10.1016/j.xhgg.2025.100552
