Abstract
The risk of Type 1 diabetes comprises both genetic and environmental components. We investigated whether genetic susceptibility could be mediated by changes in DNA methylation, an epigenetic mechanism that potentially plays a role in autoimmune diabetes. Using data from a non-diabetic population comprising blood samples taken at birth (n=844), childhood (n=911) and adolescence (n=907), we evaluated the association between 65 top GWAS single nucleotide polymorphisms (SNPs) and genome-wide DNA methylation levels interrogating 99% RefSeq genes. We identified 159 proximal SNP-cytosine phosphate guanine (CpG) pairs (cis), and 7 distal SNP-CpG associations (trans) at birth, childhood, and adolescence. We also found systematic enrichment for DNA methylation related SNPs to be associated with T1D across the genome, after controlling for the SNPs’ genomic characteristics. For each of the proximal CpG site identified, we used the principles of Mendelian Randomization to infer the putative causal relationship between DNA methylation levels and T1D. With genetic colocalization analysis, we discovered 10 CpGs at 5 loci, including ITGB3BP, AFF3, PTPN2, CTSH and CTLA4, where DNA methylation is potentially on the causal pathway to T1D. Nine out of ten SNP – CpG associations showed similar patterns in an independent T1D cohort (n=45). Our data imply that DNA methylation mediate the polygenic risk of T1D and dissecting their molecular mechanisms may uncover novel disease aetiologies.
Significance statement So far genome wide association studies identified 62 loci contributing to the genetic risk of Type 1 diabetes. However, the underlying mechanisms mediating genetic susceptibilities are largely unknown. DNA methylation is an epigenetic mechanism, which can be influenced by genetic polymorphisms and is potentially causal to Type 1 diabetes by altering chromatin conformation and gene expression. We investigated the causal relationships between type 1 diabetes-associated loci and DNA methylation. Our data suggest that methylation potentially mediates the genetic risk at 5 loci. These effects were consistently detected in a non-diabetic population at birth, childhood and adolescence, and the majority of which were replicated in a type 1 diabetes cohort. Dissecting their molecular mechanisms may uncover novel mechanisms of disease aetiology.
Footnotes
- Abbreviations
- ARIES
- Accessible Resource for Integrated Epigenomic Studies
- ALSPAC
- Avon Longitudinal Study of Parents and Children
- BOX
- Bart’s Oxford family study of Type 1 Diabetes
- CpG
- Cytosine-phosphate-guanine dinucleotides
- GWAS
- Genome-wide association study
- HLA
- Human leukocyte antigen
- JLIM
- Joint likelihood mapping
- LD
- Linkage disequilibrium
- SNP
- Single nucleotide polymorphism
- T1D
- Type 1 diabetes
- MAF
- Minor allele frequency
- MR
- Mendelian Randomization
- mQTL
- methylation quantitative trait loci
- RA
- Rheumatoid arthritis
- 2SMR
- Two Sample Mendelian Randomization