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DOI: 10.1016/j.ebiom.2024.105096; PMCID: PMC11004697


BACKGROUND: Type 2 diabetes (T2D) susceptibility is influenced by genetic and environmental factors. Previous findings suggest DNA methylation as a potential mechanism in T2D pathogenesis and progression.

METHODS: We profiled DNA methylation in 248 blood samples from participants of European ancestry from 7 twin cohorts using a methylation sequencing platform targeting regulatory genomic regions encompassing 2,048,698 CpG sites.

FINDINGS: We find and replicate 3 previously unreported T2D differentially methylated CpG positions (T2D-DMPs) at FDR 5% in RGL3, NGB and OTX2, and 20 signals at FDR 25%, of which 14 replicated. Integrating genetic variation and T2D-discordant monozygotic twin analyses, we identify both genetic-based and genetic-independent T2D-DMPs. The signals annotate to genes with established GWAS and EWAS links to T2D and its complications, including blood pressure (RGL3) and eye disease (OTX2).

INTERPRETATION: The results help to improve our understanding of T2D disease pathogenesis and progression and may provide biomarkers for its complications.

FUNDING: Funding acknowledgements for each cohort can be found in the Supplementary Note.

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MeSH Keywords

Humans; Diabetes Mellitus, Type 2; DNA Methylation; CpG Islands; Female; Male; Genome-Wide Association Study; Genetic Predisposition to Disease; Middle Aged; Epigenesis, Genetic; Otx Transcription Factors; Diabetes Complications; Gene Expression Profiling


DNA methylation; Genetics; Twins; Type 2 diabetes.


This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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