Liu, JunCarnero-Montoro, Elenavan Dongen, JennyLent, SamanthaNedeljkovic, IvanaLigthart, SymenTsai, Pei-ChienMartin, Tiphaine CMandaviya, Pooja RJansen, RickPeters, Marjolein JDuijts, LiesbethJaddoe, Vincent W VTiemeier, HenningFelix, Janine FWillemsen, Gonnekede Geus, Eco J CChu, Audrey YLevy, DanielHwang, Shih-JenBressler, JanGondalia, RahulSalfati, Elias LHerder, ChristianHidalgo, Bertha ATanaka, ToshikoMoore, Ann ZenobiaLemaitre, Rozenn NJhun, Min ASmith, Jennifer ASotoodehnia, NonaBandinelli, StefaniaFerrucci, LuigiArnett, Donna KGrallert, HaraldAssimes, Themistocles LHou, LifangBaccarelli, AndreaWhitsel, Eric Avan Dijk, Ko WillemsAmin, NajafUitterlinden, André GSijbrands, Eric J GFranco, Oscar HDehghan, AbbasSpector, Tim DDupuis, JoséeHivert, Marie-FranceRotter, Jerome IMeigs, James BPankow, James Svan Meurs, Joyce B JIsaacs, AaronBoomsma, Dorret IBell, Jordana TDemirkan, Ayşevan Duijn, Cornelia M2023-01-252023-01-252019-06-13http://hdl.handle.net/10668/14112Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AdultAgedAged, 80 and overComputer SimulationCpG IslandsDNA MethylationDiabetes Mellitus, Type 2Epigenesis, GeneticEpigenomicsFemaleGene Expression ProfilingGene Expression RegulationGenome-Wide Association StudyGlucoseHomeostasisHumansInsulinMaleMetabolic Networks and PathwaysMiddle AgedObesityPolymorphism, Single NucleotideYoung Adultresearch article31197173open access10.1038/s41467-019-10487-42041-1723PMC6565679https://www.nature.com/articles/s41467-019-10487-4.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565679/pdf