Repository logo
 

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Day, Felix R 
Perry, John RB 
Loh, Marie 
Chu, Audrey Y 

Abstract

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

Description

Keywords

Adult, Aged, Blood Glucose, DNA Methylation, Diabetes Mellitus, Type 2, England, Epigenome, Epigenomics, Female, Genetic Association Studies, Humans, Incidence, Male, Middle Aged

Journal Title

Diabetes

Conference Name

Journal ISSN

0012-1797
1939-327X

Volume Title

68

Publisher

American Diabetes Association

Rights

All rights reserved
Sponsorship
Medical Research Council (MC_UU_12015/1)
European Commission (37197)
MRC (MC_PC_13048)
MRC (unknown)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0617-10149)
Medical Research Council (MC_UU_12015/2)
Medical Research Council (MC_UU_12015/5)
European Commission (279143)
Cancer Research Uk (None)
Medical Research Council (MR/L003120/1)
British Heart Foundation (None)
Medical Research Council (G1000143)
Medical Research Council (G0401527)
Medical Research Council (MR/N003284/1)
British Heart Foundation (RG/18/13/33946)
European Commission (282510)
Medical Research Council (G0401527/1)
Cancer Research Uk (None)
Medical Research Council (MC_PC_13048)