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

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

Author information

1
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K. hannah.elliott@bristol.ac.uk.
2
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K.
3
Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, U.K.
4
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, U.K.
5
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
6
The University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.

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.

PMID:
28246294
PMCID:
PMC5860189
DOI:
10.2337/db16-0874
[Indexed for MEDLINE]
Free PMC Article

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