{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T00:46:08Z","timestamp":1740185168415,"version":"3.37.3"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T00:00:00Z","timestamp":1662336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01HG009086"],"award-info":[{"award-number":["U01HG009086"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006537","name":"Vanderbilt University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006537","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Analysis of whole-genome sequencing (WGS) for genetics is still a challenge due to the lack of accurate functional annotation of non-coding variants, especially the rare ones. As eQTLs have been extensively implicated in the genetics of human diseases, we hypothesize that rare non-coding variants discovered in WGS play a regulatory role in predisposing disease risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>With thousands of tissue- and cell-type-specific epigenomic features, we propose TVAR. This multi-label learning-based deep neural network predicts the functionality of non-coding variants in the genome based on eQTLs across 49 human tissues in the GTEx project. TVAR learns the relationships between high-dimensional epigenomics and eQTLs across tissues, taking the correlation among tissues into account to understand shared and tissue-specific eQTL effects. As a result, TVAR outputs tissue-specific annotations, with an average AUROC of 0.77 across these tissues. We evaluate TVAR\u2019s performance on four complex diseases (coronary artery disease, breast cancer, Type 2 diabetes and Schizophrenia), using TVAR\u2019s tissue-specific annotations, and observe its superior performance in predicting functional variants for both common and rare variants, compared with five existing state-of-the-art tools. We further evaluate TVAR\u2019s G-score, a scoring scheme across all tissues, on ClinVar, fine-mapped GWAS loci, Massive Parallel Reporter Assay (MPRA) validated variants and observe the consistently better performance of TVAR compared with other competing tools.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The TVAR source code and its scores on the ClinVar catalog, fine mapped GWAS Loci, high confidence eQTLs from GTEx dataset, and MPRA validated functional variants are available at https:\/\/github.com\/haiyang1986\/TVAR.<\/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\/btac608","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T17:58:45Z","timestamp":1662400725000},"page":"4697-4704","source":"Crossref","is-referenced-by-count":5,"title":["TVAR: assessing tissue-specific functional effects of non-coding variants with deep learning"],"prefix":"10.1093","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1161-4337","authenticated-orcid":false,"given":"Hai","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Computer Science and Engineering, East China University of Science and Technology , Shanghai 200237, China"},{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5691-1303","authenticated-orcid":false,"given":"Ying","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Zhong","sequence":"additional","affiliation":[{"name":"Vanderbilt Genetics Institute, Vanderbilt University , Nashville, TN 37232, USA"},{"name":"Department of Medicine, Vanderbilt University Medical Center , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2129-168X","authenticated-orcid":false,"given":"Bingshan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology & Biophysics, Vanderbilt University , Nashville, TN 37232, USA"},{"name":"Vanderbilt Genetics Institute, Vanderbilt University , Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"2022101415192451800_btac608-B1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrg3891","article-title":"The role of regulatory variation in complex traits and disease","volume":"16","author":"Albert","year":"2015","journal-title":"Nat. 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