title: Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice.
abstract: Heritable epigenetic factors can contribute to complex disease etiology. Here we examine the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes, and osteoporosis. We profiled DNA methylation in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics, and 68 clinical traits and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone density, insulin resistance, expression, and protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Luz D
authors.initials: LD
authors.lastname: Orozco
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Morselli
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Liudmilla
authors.initials: L
authors.lastname: Rubbi
authors.affiliation: Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China.
authors.forename: Weilong
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Biology, California State University, Northridge, Northridge, CA 91330, USA.
authors.forename: James
authors.initials: J
authors.lastname: Go
authors.affiliation: Department of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Huwenbo
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lopez
authors.affiliation: Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Furlotte
authors.affiliation: Department of Genetics, University of North Carolina, Kannapolis, NC 28081, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, VA 22904, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Anatole
authors.initials: A
authors.lastname: Ghazalpour
authors.affiliation: Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China.
authors.forename: Michael Q
authors.initials: MQ
authors.lastname: Zhang
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, Montreal, QC 514, Canada.
authors.forename: Renata
authors.initials: R
authors.lastname: Bahous
authors.affiliation: Departments of Human Genetics and Pediatrics, McGill University, Montreal, QC 514, Canada.
authors.forename: Rima
authors.initials: R
authors.lastname: Rozen
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: matteop@mcdb.ucla.edu.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
mesh_terms: D000818:Animals; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D057890:Epigenomics; D055106:Genome-Wide Association Study; D008099:Liver / Q000378:metabolism*; D051379:Mice; D040641:Quantitative Trait Loci / Q000502:physiology*; D013045:Species Specificity