Elucidating the Epigenetic Landscape of Type 2 Diabetes Mellitus: A Multi-Omics Analysis Revealing Novel CpG Sites and Their Association with Cardiometabolic Traits
- Author:
Ren-Hua CHUNG
1
;
Chun-Chao WANG
;
Djeane Debora ONTHONI
;
Ben-Yang LIAO
;
Tzu-Sheng HSU
;
Eden R. MARTIN
;
Chao A. HSIUNG
;
Wayne Huey-Herng SHEU
;
Hung-Yi CHIOU
Author Information
- Publication Type:Original Article
- From:Diabetes & Metabolism Journal 2026;50(1):153-164
- CountryRepublic of Korea
- Language:English
-
Abstract:
Background:Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease with a significant global burden. Although genome-wide association studies (GWAS) have identified many T2DM-associated variants, most lie in non-coding regions, making it difficult to interpret their functional roles.
Methods:We aimed to identify genetically regulated Cytosine–phosphate–Guanine (CpG) sites associated with T2DM by conducting a methylome-wide association study (MWAS), followed by Mendelian randomization (MR) and functional validation using human pancreatic cells and mouse models. MWAS was performed using summary statistics from large-scale GWAS and a DNA methylation (DNAm) prediction model to test associations between genetically predicted DNAm and T2DM.
Results:We identified 111 CpG sites significantly associated with T2DM in Europeans, including 8 novel sites near genes not previously linked to T2DM. These findings were replicated in independent datasets. Many CpGs also showed associations with cardiometabolic traits, highlighting shared epigenetic mechanisms. Trans-ethnic MR analysis confirmed consistent effects for six CpGs in East Asians. Functional analysis revealed that several CpGs regulate gene expression in human pancreatic α- and β-cells. Among them, 2´-5´-oligoadenylate synthetase like (OASL) expression, regulated by a significant CpG, was differentially expressed in α-cells of T2DM cases compared to controls. Supporting evidence from mouse models suggests a role for OASL in glucose regulation.
Conclusion:Our study identifies novel genetically regulated CpG sites associated with T2DM risk and highlights OASL as a potential epigenetic regulator of glucose metabolism in α-cells. These findings provide mechanistic insights into the epigenetic architecture of T2DM and suggest potential targets for cross-ethnic biomarker development and therapeutic intervention.
