DNA methylation patterns are important for establishing cell, tissue, and organism phenotypes, but little is known about their contribution to natural human variation. To determine their contribution to variability, we have generated genome-scale DNA methylation profiles of three human populations (Caucasian-American, African-American, and Han Chinese-American) and examined the differentially methylated CpG sites. The distinctly methylated genes identified suggest an influence of DNA methylation on phenotype differences, such as susceptibility to certain diseases and pathogens, and response to drugs and environmental agents. DNA methylation differences can be partially traced back to genetic variation, suggesting that differentially methylated CpG sites serve as evolutionarily established mediators between the genetic code and phenotypic variability. Notably, one-third of the DNA methylation differences were not associated with any genetic variation, suggesting that variation in population-specific sites takes place at the genetic and epigenetic levels, highlighting the contribution of epigenetic modification to natural human variation

The research leading to these results received funding from the European Research Council (ERC) grant EPINORC under agreement number268626,ERC StartingGrant(260372),NIHgrantsCA138461 and GM61388 (Pharmacogenomics Research Network), the MICINN Projects SAF2011-22803 andBFU2011-28549,the CellexFoundation, the European Community’s Seventh Framework Programme (FP7/2007-2013) from grant HEALTH-F5-2011-282510 (BLUEPRINT), and the Health and Science Departments of the Generalitat de Catalunya. I.H.H. is a fellow of the Generalitat de Catalunya (FI 2011). T.M.B. and M.E. are ICREA Research Professors