TY - JOUR
T1 - Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes
AU - Ye, Jody
AU - Richardson, Tom G.
AU - McArdle, Wendy L.
AU - Relton, Caroline L.
AU - Gillespie, Kathleen M.
AU - Suderman, Matthew
AU - Hemani, Gibran
N1 - Funding Information:
The UK medical Research Council and Wellcome (Grant ref: 102215/2/13/2 ) and the University of Bristol provide core support for ALSPAC. GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) with support from 23andMe. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC -funded ( BB/I025751/1 and BB/I025263/1 ) Accessible Resource for Integrated Epigenomic Studies (ARIES). Methylation data used in the Bart's Oxford Study (BOX) were generated using funding from Diabetes UK ( 14/0004869 ). This publication is the work of the authors; J.Y serves as guarantor for the contents of this paper. J.Y. was funded by a Diabetes Research & Wellness Foundation non-clinical fellowship N-C/2016/Ye . T.G.R. was supported by the Elizabeth Blackwell Institute Proximity to Discovery award EBI 424 . M.S. was supported by the Economic and Social Research Council ES/N000498/1 . G.H. was supported by the Medical Research Council MC_UU_12013/1-9 .
Funding Information:
The UK medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data were generated by Sample Logistics and Genotyping Facilities at the Wellcome Trust Sanger Institute and LabCorp (Laboratory Corporation of America) with support from 23andMe. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC-funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES). Methylation data used in the Bart's Oxford Study (BOX) were generated using funding from Diabetes UK (14/0004869). This publication is the work of the authors; J.Y serves as guarantor for the contents of this paper. J.Y. was funded by a Diabetes Research & Wellness Foundation non-clinical fellowship N-C/2016/Ye. T.G.R. was supported by the Elizabeth Blackwell Institute Proximity to Discovery award EBI 424. M.S. was supported by the Economic and Social Research Council ES/N000498/1. G.H. was supported by the Medical Research Council MC_UU_12013/1-9.
Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - DNA methylation
KW - Epigenetics
KW - Mendelian randomization
KW - Type 1 diabetes
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U2 - 10.1016/j.jaut.2018.06.005
DO - 10.1016/j.jaut.2018.06.005
M3 - Article
C2 - 30146008
AN - SCOPUS:85049308958
SN - 0896-8411
VL - 93
SP - 66
EP - 75
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
ER -
