However, there are many difficulties and computational challenges in achieving this goal (7). One of the major difficulties comes from the unclear role of non-coding genetic variants in the relevant processes underlying disease/trait association. These variants could affect many biological activities including transcription, splicing, post-transcriptional regulation, translation initiation/elongation and post-translational modification (8). Previously, conservation information was frequently used to prioritize the functional importance of non-coding genetic variation (9,10). At the transcription regulation level, mutations in the promoter regions may impact the recruitment of RNA polymerase and other regulators, especially the binding of transcriptional factors (TFs) to the promoter region to initiate gene transcription. Tools such as is-rSNP (11), sTRAP (12) and regSNPs (13) have been successfully developed to evaluate the binding affinity affected by genetic variation. However, although algorithms that solely used TF motifs are effective in finding regulatory elements in the immediate promoter regions but may inevitably introduce a large number of false positives in the distal promoter/enhancer regions where the searching space becomes substantially larger. More and more studies showed that mutations within the distal regulatory elements, such
