Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements

Grundberg, Elin and Meduri, Eshwar and Sandling, Johanna K and Hedman, Asa K and Keildson, Sarah and Buil, Alfonso and Busche, Stephan and Yuan, Wei and Nisbet, James and Sekowska, Magdalena and Wilk, Alicja and Barrett, Amy and Small, Kerrin S and Ge, Bing and Caron, Maxime and Shin, So-Youn and Lathrop, Mark and Dermitzakis, Emmanouil T and McCarthy, Mark I and Spector, Timothy D and Bell, Jordana T and Deloukas, Panos and Tsaprouni, Loukia (2013) Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. American journal of human genetics, 93 (5). pp. 876-890. ISSN 1537-6605

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Official URL: http://www.cell.com/AJHG/abstract/S0002-9297(13)00...

Abstract

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(2)median = 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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Article

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https://doi.org/10.1016/j.ajhg.2013.10.004

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