Altered transcription factor binding events predict personalized gene expression and confer insight into functional cis-regulatory variants

Deciphering the functional roles of cis-regulatory variants is a critical challenge in genome analysis and interpretation. We hypothesize that altered transcription factor (TF) binding events are a central mechanism by which cis-regulatory variants impact gene expression. We present TF2Exp, the first gene-based framework (to our knowledge) to predict the impact of altered TF binding on personalized gene expression based on cis-regulatory variants. Using data from lymphoblastoid cell lines, TF2Exp models achieved suitable performance for 3,060 genes. Alterations within DNase I hypersensitive, CTCF-bound, and tissue-specific TF-bound regions were the greatest contributors to the models. Our cis-regulatory variant-based TF2Exp models performed as well as the state-of-the-art SNP-based models, both in cross-validation and external validation. In addition, unlike SNP-based models, our TF2Exp models have the unique advantages to evaluate impact of uncommon variants and distinguish the functional roles of variants in linkage disequilibrium, showing broader utility for future human genetic studies.