Role of DNA Methylation in Type 2 Diabetes Etiology: Using Genotype as a Causal Anchor

Diabetes. 2017 Jun;66(6):1713-1722. doi: 10.2337/db16-0874. Epub 2017 Feb 28.

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 etiology of type 2 diabetes. Illumina HumanMethylation450 BeadChip data were generated on 1,018 young individuals from the Avon Longitudinal Study of Parents and Children (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 noncausal 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Cohort Studies
  • CpG Islands
  • DNA Methylation / genetics*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genotype
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • Male
  • Polymorphism, Single Nucleotide
  • Prospective Studies
  • Quantitative Trait Loci

Substances

  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human