Abstract
Genetic variants that associate with DNA methylation at CpG sites (methylation quantitative trait loci, meQTLs) offer a potential biological mechanism of action for disease associated SNPs. We investigated whether meQTLs exist in abdominal subcutaneous adipose tissue (SAT) and if CpG methylation associates with metabolic syndrome (MetSyn) phenotypes. We profiled 27,718 genomic regions in abdominal SAT samples of 38 unrelated individuals using differential methylation hybridization (DMH) together with genotypes at 5,227,243 SNPs and expression of 17,209 mRNA transcripts. Validation and replication of significant meQTLs was pursued in an independent cohort of 181 female twins. We find that, at 5% false discovery rate, methylation levels of 149 DMH regions associate with at least one SNP in a ±500 kilobase cis-region in our primary study. We sought to validate 19 of these in the replication study and find that five of these significantly associate with the corresponding meQTL SNPs from the primary study. We find that none of the 149 meQTL top SNPs is a significant expression quantitative trait locus in our expression data, but we observed association between expression levels of two mRNA transcripts and cis-methylation status. Our results indicate that DNA CpG methylation in abdominal SAT is partly under genetic control. This study provides a starting point for future investigations of DNA methylation in adipose tissue.
Highlights
There is growing interest in the role of epigenetic factors in predisposition to common, and especially metabolic, diseases
Global methylation patterns measured by differential methylation hybridization (DMH) in our study showed bimodality, with a ‘‘hypomethylated mode’’ at lower and a ‘‘hypermethylated mode’’ at higher methylation score (Figure 1A)
While the Illumina 27 k array probes are mainly located in promoter regions, the DMH array targets a larger number of intra- and intergenic regions: 9,253 of the 12,500 genes targeted by the DMH array are probed by the Illumina 27 k array (74.0%) [4,5], only 3,629 probed sites directly overlap (13.1%)
Summary
There is growing interest in the role of epigenetic factors in predisposition to common, and especially metabolic, diseases. Epigenetic effects are mitotically heritable alterations in gene expression that occur without alterations in the DNA sequence [1], but rather through molecular alterations such as histone modifications and DNA methylation. These epigenetic marks are generally not inherited across generations [2], but DNA sequence variants that associate with methylation, known as methylation quantitative trait loci (meQTLs), have been found throughout the genome for a number of tissues [3,4,5,6]. Tissue availability is generally a problem, but Participant characteristics
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