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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0874/-/DC1.
- Received July 18, 2016.
- Accepted February 21, 2017.
- © 2017 by the American Diabetes Association.