Examples of local and distant effects of regulatory variants. (a) A local cis-acting variant (red star, top) in a regulatory element (red line) affects allele-specific transcription factor binding affinity and is associated with differential expression of gene A (as shown by the chart, bottom), with possession of a copy of the A allele associated with higher expression than the G allele (hence AA homozygotes having higher expression than AG heterozygotes, with lowest expression in GG homozygotes). (b) The same variant can modulate expression of gene D at a distance through DNA looping that brings the regulatory enhancer element close to the promoter of gene D (gray line) on the same chromosome. (c) An example of a local cis-acting variant modulating expression of a transcription factor encoding gene, Gene E, differential expression of which modulates a set of target genes. Expression of these target genes is found to be associated in trans with the variant upstream of gene E. (d) A local cis-acting variant on chromosome 12 modulates expression of a cytokine gene and is also associated in trans with a set of genes whose expression is regulated through a signaling cascade determined by that cytokine. Such trans associations can be shown on a circos plot (chromosomes labeled 1-22 with arrows pointing to location of gene on a given chromosome).