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Cell Metab. 2015 Jun 2;21(6):905-17. doi: 10.1016/j.cmet.2015.04.025.

Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice.

Author information

1
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2
Center for Synthetic & Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China.
3
Department of Biology, California State University, Northridge, Northridge, CA 91330, USA.
4
Department of Bioinformatics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.
6
Department of Genetics, University of North Carolina, Kannapolis, NC 28081, USA.
7
Department of Medicine, University of Virginia, Charlottesville, VA 22904, USA.
8
Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
9
Departments of Human Genetics and Pediatrics, McGill University, Montreal, QC 514, Canada.
10
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: matteop@mcdb.ucla.edu.

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.

PMID:
26039453
PMCID:
PMC4454894
DOI:
10.1016/j.cmet.2015.04.025
[Indexed for MEDLINE]
Free PMC Article

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