Role of DNA methylation in type 2 diabetes etiology: using genotype as a causal anchor

Hannah Elliott*, Hashem Shihab, Gabrielle A Lockett, John W Holloway, Allan McRae, George Davey Smith, Susan Ring, Tom Gaunt, Caroline Relton

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

22 Citations (Scopus)
193 Downloads (Pure)

Abstract

Several studies have investigated the relationship between genetic variation and DNA methylation with respect to type 2 diabetes but it is unknown if DNA methylation is a mediator in the disease pathway or if it is altered in response to disease state. This study uses genotypic information as a causal anchor to help decipher the likely role of DNA methylation measured in peripheral blood in the aetiology of type 2 diabetes.

Illumina HumanMethylation450 BeadChip data was generated on 1,018 young individuals from the ALSPAC cohort. In stage 1, 118 unique associations between published type 2 diabetes Single Nucleotide Polymorphisms (SNPs) and genome wide methylation (methylation quantitative trait loci; mQTLs) were identified. In stage 2, a further 226 mQTLs were identified between 202 additional independent non-type 2 diabetes SNPs and CpGs identified in stage 1. Where possible, associations were replicated in independent cohorts of similar age.

We discovered that around half of known type 2 diabetes SNPs are associated with variation in DNA methylation and postulated that methylation could either be on a causal pathway to future disease or could be a non-causal biomarker. For one locus (KCNQ1), we were able to provide further evidence that methylation is likely to be on the causal pathway to disease in later life.
Original languageEnglish
Pages (from-to)1713-1722
Number of pages10
JournalDiabetes
Volume66
Issue number6
Early online date28 Feb 2017
DOIs
Publication statusPublished - Jun 2017

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