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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.

SUBMITTER: Elliott HR

PROVIDER: S-EPMC5860189 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Elliott Hannah R HR Shihab Hashem A HA Lockett Gabrielle A GA Holloway John W JW Holloway John W JW McRae Allan F AF Smith George Davey GD Ring Susan M SM Gaunt Tom R TR Relton Caroline L CL

Diabetes 20170228 6

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 ...[more]

PMID: 28246294

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Project description:ObjectiveThis study aimed to explore shared genetic etiology and the causality between smoking status and type 2 diabetes (T2D), cardiovascular diseases (CVDs), and related metabolic traits.MethodsUsing summary statistics from publicly available genome-wide association studies (GWASs), we estimated genetic correlations between smoking status and T2D, 6 major CVDs, and 8 related metabolic traits with linkage disequilibrium score regression (LDSC) analysis; identified shared genetic loci with large-scale genome-wide cross-trait meta-analysis; explored potential shared biological mechanisms with a series of post-GWAS analyses; and determined causality with Mendelian randomization (MR).ResultsWe found significant positive genetic associations with smoking status for T2D (Rg = 0.170, p = 9.39 × 10-22), coronary artery disease (CAD) (Rg = 0.234, p = 1.96 × 10-27), myocardial infarction (MI) (Rg = 0.226, p = 1.08 × 10-17), and heart failure (HF) (Rg = 0.276, p = 8.43 × 10-20). Cross-trait meta-analysis and transcriptome-wide association analysis of smoking status identified 210 loci (32 novel loci) and 354 gene-tissue pairs jointly associated with T2D, 63 loci (12 novel loci) and 37 gene-tissue pairs with CAD, 38 loci (6 novel loci) and 17 gene-tissue pairs with MI, and 28 loci (3 novel loci) and one gene-tissue pair with HF. The shared loci were enriched in the exo-/endocrine, cardiovascular, nervous, digestive, and genital systems. Furthermore, we observed that smoking status was causally related to a higher risk of T2D (β = 0.385, p = 3.31 × 10-3), CAD (β = 0.670, p = 7.86 × 10-11), MI (β = 0.725, p = 2.32 × 10-9), and HF (β = 0.520, p = 1.53 × 10-6).ConclusionsOur findings provide strong evidence on shared genetic etiology and causal associations between smoking status and T2D, CAD, MI, and HF, underscoring the potential shared biological mechanisms underlying the link between smoking and T2D and CVDs. This work opens up a new way of more effective and timely prevention of smoking-related T2D and CVDs.

Dataset Information

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

Publications

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

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