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

Elliott, Hannah R., Shihab, Hashem A., Lockett, Gabrielle A., Holloway, John W., McRae, Allan F., Smith, George Davey, Ring, Susan M., Gaunt, Tom R. and Relton, Caroline L. (2017) Role of DNA methylation in type 2 diabetes etiology: using genotype as a causal anchor. Diabetes, 66 6: 1713-1722. doi:10.2337/db16-0874


Author Elliott, Hannah R.
Shihab, Hashem A.
Lockett, Gabrielle A.
Holloway, John W.
McRae, Allan F.
Smith, George Davey
Ring, Susan M.
Gaunt, Tom R.
Relton, Caroline L.
Title Role of DNA methylation in type 2 diabetes etiology: using genotype as a causal anchor
Journal name Diabetes   Check publisher's open access policy
ISSN 0012-1797
1939-327X
Publication date 2017-06-01
Sub-type Article (original research)
DOI 10.2337/db16-0874
Open Access Status Not yet assessed
Volume 66
Issue 6
Start page 1713
End page 1722
Total pages 10
Place of publication Arlington, VA, United States
Publisher American Diabetes Association
Language eng
Subject 2724 Internal Medicine
2712 Endocrinology, Diabetes and Metabolism
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 DNAmethylationmeasured 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.
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1010374
1046880
496667
R01 AI091905
R01 AI121226
R01 HL082925
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
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