title: Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements.
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.
authors.affiliation: Wellcome Trust Sanger Institute, CB101SA Hinxton, UK; Department of Twin Research and Genetic Epidemiology, King's College London, SE17EH London, UK. Electronic address: elin.grundberg@mcgill.ca.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Eshwar
authors.initials: E
authors.lastname: Meduri
authors.forename: Johanna K
authors.initials: JK
authors.lastname: Sandling
authors.forename: Asa K
authors.initials: AK
authors.lastname: Hedman
authors.forename: Sarah
authors.initials: S
authors.lastname: Keildson
authors.forename: Alfonso
authors.initials: A
authors.lastname: Buil
authors.forename: Stephan
authors.initials: S
authors.lastname: Busche
authors.forename: Wei
authors.initials: W
authors.lastname: Yuan
authors.forename: James
authors.initials: J
authors.lastname: Nisbet
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sekowska
authors.forename: Alicja
authors.initials: A
authors.lastname: Wilk
authors.forename: Amy
authors.initials: A
authors.lastname: Barrett
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.forename: Maxime
authors.initials: M
authors.lastname: Caron
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
mesh_terms: D000273:Adipose Tissue; D015992:Body Mass Index; D002874:Chromosome Mapping; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D006824:Hybridization, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA; D013447:Sulfites / Q000378:metabolism; D014427:Twins / Q000235:genetics
chemical_list: D013447:Sulfites; C042345:hydrogen sulfite