title: Role of DNA Methylation in Type 2 Diabetes Etiology: Using Genotype as a Causal Anchor.
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.
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K. hannah.elliott@bristol.ac.uk.
authors.forename: Hannah R
authors.identifier: 0000-0002-1500-3533
authors.initials: HR
authors.lastname: Elliott
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Shihab
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, U.K.
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Lockett
authors.affiliation: Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, U.K.|Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, U.K.
authors.forename: John W
authors.initials: JW
authors.lastname: Holloway
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.|The University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, U.K.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
mesh_terms: D000293:Adolescent; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D040641:Quantitative Trait Loci
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human