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Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)66-75
Number of pages10
JournalJournal of Autoimmunity
Early online date29 Jun 2018
DateAccepted/In press - 19 Jun 2018
DateE-pub ahead of print - 29 Jun 2018
DatePublished (current) - 1 Sep 2018


The risk of Type 1 Diabetes (T1D) comprises both genetic and environmental components. We investigated whether genetic susceptibility to T1D could be mediated by changes in DNA methylation, an epigenetic mechanism that potentially plays a role in autoimmune diabetes. From enrichment analysis, we found that there was a common genetic influence for both DNA methylation and T1D across the genome, implying that methylation could be either on the causal pathway to T1D or a non-causal biomarker of T1D genetic risk. Using data from a general population comprising blood samples taken at birth (n = 844), childhood (n = 846) and adolescence (n = 907), we then evaluated the associations between 64 top GWAS single nucleotide polymorphisms (SNPs) and DNA methylation levels at 55 non-HLA loci. We identified 95 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis) and 1 distal SNP-CpG association (trans) consistently at birth, childhood, and adolescence. Combining genetic co-localization and Mendelian Randomization analysis, we provided evidence that at 5 loci, ITGB3BP, AFF3, PTPN2, CTSH and CTLA4, DNA methylation is potentially mediating the genetic risk of T1D mainly by influencing local gene expression.

    Research areas

  • DNA methylation, Epigenetics, Mendelian randomization, Type 1 diabetes

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