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 - 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 -