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. 2013;8(2):e55923.
doi: 10.1371/journal.pone.0055923. Epub 2013 Feb 19.

The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue

Alexander W Drong  1 , George Nicholson, Asa K Hedman, Eshwar Meduri, Elin Grundberg, Kerrin S Small, So-Youn Shin, Jordana T Bell, Fredrik Karpe, Nicole Soranzo, Tim D Spector, Mark I McCarthy, Panos Deloukas, Mattias Rantalainen, Cecilia M Lindgren; MolPAGE Consortia
Affiliations

The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue

Alexander W Drong et al. PLoS One. 2013.

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.

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Conflict of interest statement

Competing Interests: This work was supported by the Wellcome Trust (090532/Z/09/Z) and the European Community's Sixth Framework Programme, MolPAGE Consortium (LSHG-CT-2004-512066), which included both academic and commercial partners. The latter, included Epigenomics AG, whose involvement in MolPAGE was funded on a 50/50 basis. Epigenomics took no patents on the work and has no active products in the field of diabetes and obesity. None of the authors own stocks or shares of Epigenomics AG, are employed or members of the board of Epigenomics AG, or have received research grants, travel grants, or any gifts of any kind from Epigenomics AG. This does not alter the authors‚ adherence to all the PLOS ONE policies on sharing data and materials. AWD is a Wellcome Trust Student (093933Z/10/Z). JTB was funded by a Sir Henry Wellcome Trust postdoctoral fellowship. NS is supported by the Wellcome Trust (Core Grant Number 091746/Z/10/Z). PD is supported by the Wellcome Trust core grant 098051 which also covered costs for methylation profiling with the 27K methylation array, carried out by the Genotyping Facility at the Wellcome Trust Sanger Institute. MR is a MRC biomedical informatics fellow (Medical Research Council, fellowship G0802460). CML is a Wellcome Trust Research Career Development Fellow (086596/Z/08/Z).

Figures

Figure 1
Figure 1. Patterns of CpG Methylation in abdominal SAT. A:
DMH data show a bimodal pattern consistent with hypo- and hypermethylation. B: CpG sites close to TSS’s on the X chromosome are hemimethylated in females. C: CpG sites close to TSS’s of Imprinted Genes are hemimethylated D: Lower methylation is observed around TSS’s (black line shows 300 bp sliding window median methylation score).
Figure 2
Figure 2. Flowchart showing the analysis pipeline.
Top: Association of DMH Methylation Score with phenotypes. Bottom: Primary cis-meQTL association study, followed by replication study. Left: Association of DMH probe sets with significant meQTLs with mRNA expression. Right: Text mining of meQTLs significant in the primary study.
Figure 3
Figure 3. Genome-wide meQTL analysis. A:
Cis-meQTL quantile-quantile plot showing enrichment of association signal. Grey bands correspond to 95% confidence intervals. B: Significant meQTL are located close to CpG sites.
Figure 4
Figure 4. Boxplots showing methylation level plotted against genotype for the 5 replicated meQTLs in both the primary study (left panels) and replication study (right panels).
All SNPs passed quality control filtering and association with methylation levels in both data sets.
Figure 5
Figure 5. –log10 P values of the 5 replicated meQTLs against genomic position, with the top SNP indexed and indicated by a diamond.
Estimated recombination rates are shown in blue, and SNP LD is given by colour as shown in the legends (LD data from 1000 Genomes Nov 2010 CEU genotypes).
See this image and copyright information in PMC

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References

    1. Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A (2009) An operational definition of epigenetics. Genes & development 23: 781. - PMC - PubMed
    1. Richards EJ (2006) Inherited epigenetic variation-revisiting soft inheritance. Nat Rev Genet 7: 395–401. - PubMed
    1. Kerkel K, Spadola A, Yuan E, Kosek J, Jiang L, et al. (2008) Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat Genet 40: 904–908. - PubMed
    1. Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, et al. (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 12: R10. - PMC - PubMed
    1. Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, et al. (2010) Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genetics 6: e1000952. - PMC - PubMed

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