Résumé
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.
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•DNA methylation is variable among individuals and is influenced by genetic variation•DNA methylation is associated with complex metabolic and molecular traits•Many associations to DNA methylation are not identified using traditional GWAS•Genetic variation in the gene Mtrr affects DNA methylation throughout the genome
DNA methylation influences multiple biological processes but has typically not been considered in genome-wide association studies. Studying 90 mouse inbred strains, Orozco et al. show that DNA methylation is highly variable among individuals and associated with molecular and clinical traits that are precursors to heart disease, diabetes, and osteoporosis.