Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

• Main Authors: Paul, Dirk S., Teschendorff, Andrew E., Dang, Mary A.N., Lowe, Robert, Hawa, Mohammed I., Ecker, Simone, Beyan, Huriya, Cunningham, Stephanie, Fouts, Alexandra R., Ramelius, Anita, Burden, Frances, Farrow, Samantha, Rowlston, Sophia, Rehnstrom, Karola, Frontini, Mattia, Downes, Kate, Busche, Stephan, Cheung, Warren A., Ge, Bing, Simon, Marie-Michelle, Bujold, David, Kwan, Tony, Bourque, Guillaume, Datta, Avik, Lowy, Ernesto, Clarke, Laura, Flicek, Paul, Libertini, Emanuele, Heath, Simon, Gut, Marta, Gut, Ivo G, Ouwehand, Willem H., Pastinen, Tomi, Soranzo, Nicole, Hofer, Sabine E., Karges, Beate, Meissner, Thomas, Boehm, Bernhard O., Cilio, Corrado, Elding Larsson, Helena, Lernmark, Åke, Steck, Andrea K., Rakyan, Vardhman K., Beck, Stephan, Leslie, R. David
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2018
• Subjects: Epigenomics; Disease Genetics; DRNTU::Science::Medicine
• Online Access: https://hdl.handle.net/10356/89962; http://hdl.handle.net/10220/47168
• Institution: Nanyang Technological University

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.