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

Jody Ye; Tom G. Richardson; Wendy L. McArdle; Caroline L. Relton; Kathleen M. Gillespie; Matthew Suderman; Gibran Hemani

doi:10.1016/j.jaut.2018.06.005

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

Jody Ye^*, Tom G. Richardson, Wendy L. McArdle, Caroline L. Relton, Kathleen M. Gillespie, Matthew Suderman, Gibran Hemani

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal)

5 Citations (Scopus)

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Abstract

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.

Original language	English
Pages (from-to)	66-75
Number of pages	10
Journal	Journal of Autoimmunity
Volume	93
Early online date	29 Jun 2018
DOIs	https://doi.org/10.1016/j.jaut.2018.06.005
Publication status	Published - 1 Sep 2018

Keywords

DNA methylation
Epigenetics
Mendelian randomization
Type 1 diabetes

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Projects

1 Finished

(IEU) Epigenetics: Environment, Embodiment & Equality (E4)

Relton, C. L.

1/01/16 → 31/12/19

Project: Research

Equipment

Illumina Array

Susan M Ring (Manager)

Bristol Population Health Science Institute

Facility/equipment: Facility

Cite this

Ye, J., Richardson, T. G., McArdle, W. L., Relton, C. L., Gillespie, K. M., Suderman, M., & Hemani, G. (2018). Identification of loci where DNA methylation potentially mediates genetic risk of type 1 diabetes. Journal of Autoimmunity, 93, 66-75. https://doi.org/10.1016/j.jaut.2018.06.005

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abstract = "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.",

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