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It has been hypothesized that altered transcription factor (TF) binding events are a central mechanism by which cis-regulatory variants impact gene expression levels. However, we lack a computational framework to understand and quantify such mechanistic contributions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We present TF2Exp, a gene-based framework to predict the impact of altered TF-binding events on gene expression levels. Using data from lymphoblastoid cell lines, TF2Exp models were applied successfully to predict the expression levels of 3196 genes. Alterations within DNase I hypersensitive, CTCF-bound and tissue-specific TF-bound regions were the greatest contributing features to the models. TF2Exp models performed as well as models based on common variants, both in cross-validation and external validation. Combining TF alteration and common variant features can further improve model performance. Unlike variant-based models, TF2Exp models have the unique advantage to evaluate the functional impact of variants in linkage disequilibrium and uncommon variants. We find that adding TF-binding events altered only by uncommon variants could increase the number of predictable genes (R2 &amp;gt; 0.05). Taken together, TF2Exp represents a key step towards interpreting the functional roles of cis-regulatory variants in the human genome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The code and model training results are publicly available at https:\/\/github.com\/wqshi\/TF2Exp.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Supplementary information<\/jats:title>\n                    <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty992","type":"journal-article","created":{"date-parts":[[2018,12,10]],"date-time":"2018-12-10T23:17:45Z","timestamp":1544483865000},"page":"2610-2617","source":"Crossref","is-referenced-by-count":12,"title":["Gene expression models based on transcription factor binding events confer insight into functional\n                    <i>cis<\/i>\n                    -regulatory variants"],"prefix":"10.1093","volume":"35","author":[{"given":"Wenqiang","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children\u2019s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada"},{"name":"Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC, Canada"},{"name":"Beijing Institute of Microbiology and Epidemiology, Beijing, China"}]},{"given":"Oriol","family":"Fornes","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children\u2019s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada"}]},{"given":"Wyeth W","family":"Wasserman","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, BC Children\u2019s Hospital Research Institute, University of British Columbia, Vancouver, BC, Canada"}]}],"member":"286","published-online":{"date-parts":[[2018,12,12]]},"reference":[{"key":"2023062713151529800_bty992-B1","article-title":"The Ensembl gene annotation system","volume":"2016","author":"Aken","year":"2016","journal-title":"Database J. 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