Genome-wide association studies (GWAS) are providing a flood of data associating genetic variants with common phenotypes (1). A confounding factor in such studies is linkage disequilibrium (LD), which allows many variants at the same locus to be associated with a phenotype even if only one of them is causal. Within genes, prioritizing the likely causal variant is relatively straightforward; variants are easily annotated as synonymous, missense or nonsense, changing the consensus sequence at splice sites, or residing in introns or UTRs. Often, however, GWAS associations lie far from known genes or transcribed regions, presumably in distal tissue-specific enhancers. One of the most striking examples of such a finding is the gene desert at 8q24, within which are regions specifically and independently linked to prostate, breast, ovarian, colorectal and bladder cancer. These variants have been shown to correspond to cell-type-specific distal enhancers for the MYC oncogene (2,3). Recent systematic comparisons of expression quantitative trait loci (eQTL) and GWAS suggest that the association of intergenic variants with complex phenotyes is a result of alteration of gene expression regulatory elements (4,5).
