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The role of DNA methylation in type 2 diabetes aetiology – using genotype as a causal anchor

The role of DNA methylation in type 2 diabetes aetiology – using genotype as a causal anchor
The role of DNA methylation in type 2 diabetes aetiology – using genotype as a causal anchor
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.
0012-1797
1713-1722
Elliot, Hannah
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Shihab, Hashem
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Lockett, Gabrielle A.
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Holloway, John
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McRae, Allan F.
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Davey-Smith, George
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Ring, Susan M.
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Gaunt, Tom R.
908f92b3-0c63-4f34-bee9-2351778a4e62
Relton, Caroline L.
7a9fe7f7-d14b-4bb7-be71-a3afa6ff8538
Elliot, Hannah
a950f708-80f0-446a-af2e-6c030d4a2559
Shihab, Hashem
bfe7fc7e-580f-4e24-a66d-4f8609b05d4e
Lockett, Gabrielle A.
4d92a28c-f54c-431b-81f6-e82ad9057d7a
Holloway, John
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
McRae, Allan F.
205fcf16-329e-42a9-9e79-54356c5b230c
Davey-Smith, George
6db92889-a8dc-493b-ac13-0d523fff2e66
Ring, Susan M.
75bad926-3425-4723-8774-926e13e9c31c
Gaunt, Tom R.
908f92b3-0c63-4f34-bee9-2351778a4e62
Relton, Caroline L.
7a9fe7f7-d14b-4bb7-be71-a3afa6ff8538

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

Record type: Article

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.

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DB16-0874_R1_The role of DNA methylation in type 2 diabetes aetiology_clean - Accepted Manuscript
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More information

Accepted/In Press date: 21 February 2017
e-pub ahead of print date: 28 February 2017
Published date: June 2017
Additional Information: This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at [insert journal URL: http://diabetes.diabetesjournals.org,
Organisations: Faculty of Medicine, Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 406411
URI: https://eprints.soton.ac.uk/id/eprint/406411
ISSN: 0012-1797
PURE UUID: d3250ffe-56fd-4443-9c3c-79b929141411
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

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Date deposited: 10 Mar 2017 10:46
Last modified: 03 Dec 2019 01:58

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