It is likely that common-variant association studies are giving us our first appreciation check details of how such regulatory, noncoding variation contributes to natural variation in genetically complex disease phenotypes in humans. Further evidence for the regulatory nature of the variants implicated in common-variant association studies comes from the study of expression QTLs (eQTLs) in human tissues. The common variants that are implicated in genome-wide association studies tend also to associate

with quantitative measurements of the expression levels of the same genes, especially when gene expression is measured in the tissue relevant to the disease (Nicolae et al., 2010 and Richards et al., 2012). Progress in the genome-scale analysis of chromatin states now reveals hundreds of thousands of sites across the genome that contain dynamic chromatin marks suggestive of tissue-specific enhancer activity—the ability to regulate the expression of nearby genes in specific tissues (Heintzman et al., 2009, Ernst et al., 2011 and Bernstein et al., 2012).

Enhancer sites tend to exhibit DNase hypersensitivity, suggesting that they are in open, accessible chromatin; they are also flanked by characteristic histone marks, including monomethylation of MDV3100 in vivo H3K4 and acetylation of H3K27 (Heintzman et al., 2009, Ernst et al., 2011 and Thurman et al., 2012). Extensive new data from the ENCODE and Epigenomics Roadmap projects now document many ways in which chromatin states and DNA methylation implement the regulatory instructions

that are encoded in genomic sequence, although with a plasticity that makes them also responsive to cell type, cell state, and environment. Recent studies indicate that associations of disease to common variants in the noncoding regions of genes involve sequence variation in putative enhancers as defined by epigenomic profiling. These relationships follow a tissue-and-disease logic: the common variants that associate to disease phenotypes tend to reside in the tissue-specific enhancers defined experimentally in the tissues thought to be most relevant to each disease (Maurano et al., 2012). Such results reinforce the conclusion that variation in unless gene regulation at many genomic loci contributes to complex, polygenic disease by acting in a tissue-specific manner. The epigenomic profiles available in public resources today are derived from homogenized brain tissues that are mixtures of many cell types, including multiple neuronal and glial cell populations. The utilization of genomic sequence elements is ultimately a property of specific cell types, defined by their developmental lineage and functional properties. It will be important to understand how regulatory DNA elements are utilized by each specific cell population, both under baseline and stimulated conditions.