期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 93, 期 5, 页码 876-890出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.10.004
关键词
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资金
- Wellcome Trust (WT) [098051]
- Center for Inherited Disease Research as part of a National Eye Institute, National Institutes of Health (NIH)
- WT [081917/Z/07/Z, 083270/Z/07/Z]
- European Community
- core funding for the WT Centre for Human Genetics [090532]
- National Institute for Health Research (NIHR) Clinical Research Facility at Guy's & St. Thomas' National Health Service (NHS) Foundation Trust
- NIHR Biomedical Research Centre based at Guy's and St. Thomas' NHS Foundation Trust
- King's College London
- European Research Council
- Swedish Research Council [C0025601]
- Canadian Institutes of Health Research Canadian Epigenetics, Environment, and Health Research Consortium [EP1-120608]
- Medical Research Council [G0600717B, MC_UU_12012/5/B, G0600717, MC_UU_12012/1, G9824984] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10140] Funding Source: researchfish
- MRC [G9824984, MC_UU_12012/1, G0600717] Funding Source: UKRI
- Wellcome Trust [081917/Z/07/Z, 083270/Z/07/Z] Funding Source: Wellcome Trust
Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.
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