{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T00:45:07Z","timestamp":1740185107646,"version":"3.37.3"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2019,10,7]],"date-time":"2019-10-07T00:00:00Z","timestamp":1570406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"McCormick Genomic and Proteomic Center"},{"name":"MGPC"},{"DOI":"10.13039\/100007108","name":"The George Washington University","doi-asserted-by":"crossref","award":["MGPC_PG2018","UL1TR000075"],"award-info":[{"award-number":["MGPC_PG2018","UL1TR000075"]}],"id":[{"id":"10.13039\/100007108","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Center for Advancing Translational Sciences or the National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>By testing for associations between DNA genotypes and gene expression levels, expression quantitative trait locus (eQTL) analyses have been instrumental in understanding how thousands of single nucleotide variants (SNVs) may affect gene expression. As compared to DNA genotypes, RNA genetic variation represents a phenotypic trait that reflects the actual allele content of the studied system. RNA genetic variation at expressed SNV loci can be estimated using the proportion of alleles bearing the variant nucleotide (variant allele fraction, VAFRNA). VAFRNA is a continuous measure which allows for precise allele quantitation in loci where the RNA alleles do not scale with the genotype count. We describe a method to correlate VAFRNA with gene expression and assess its ability to identify genetically regulated expression solely from RNA-sequencing (RNA-seq) datasets.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We introduce ReQTL, an eQTL modification which substitutes the DNA allele count for the variant allele fraction at expressed SNV loci in the transcriptome (VAFRNA). We exemplify the method on sets of RNA-seq data from human tissues obtained though the Genotype-Tissue Expression (GTEx) project and demonstrate that ReQTL analyses are computationally feasible and can identify a subset of expressed eQTL loci.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>A toolkit to perform ReQTL analyses is available at https:\/\/github.com\/HorvathLab\/ReQTL.<\/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\/btz750","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T19:27:59Z","timestamp":1569958079000},"page":"1351-1359","source":"Crossref","is-referenced-by-count":11,"title":["ReQTL: identifying correlations between expressed SNVs and gene expression using RNA-sequencing data"],"prefix":"10.1093","volume":"36","author":[{"given":"Liam F","family":"Spurr","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute , Boston, MA 02215, USA"},{"name":"Cancer Program, The Broad Institute of MIT and Harvard , Cambridge, MA 02142, USA"},{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nawaf","family":"Alomran","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pavlos","family":"Bousounis","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dacian","family":"Reece-Stremtan","sequence":"additional","affiliation":[{"name":"Computer Applications Support Services, School of Medicine and Health Sciences, The George Washington University , Washington, DC 20037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N M","family":"Prashant","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"S\u0142owi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Mathematics & Living Systems Institute, University of Exeter , Exeter EX4 4QD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muzi","family":"Li","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine"},{"name":"Department of Biostatistics and Bioinformatics, School of Medicine and Health Sciences, George Washington University , Washington, DC 20037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin","family":"Sein","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Asher","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keith A","family":"Crandall","sequence":"additional","affiliation":[{"name":"Computational Biology Institute, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University , Washington, DC 20052, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krasimira","family":"Tsaneva-Atanasova","sequence":"additional","affiliation":[{"name":"Department of Mathematics & Living Systems Institute, University of Exeter , Exeter EX4 4QD, UK"},{"name":"EPSRC Centre for Predictive Modelling in Healthcare, University of Exeter , Exeter EX4 4QJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anelia","family":"Horvath","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Medicine, McCormick Genomics and Proteomics Center"},{"name":"Department of Biochemistry and Molecular Medicine"},{"name":"Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University , Washington, DC 20037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,10,7]]},"reference":[{"key":"2023060910275027900_btz750-B1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"Aguet","year":"2017","journal-title":"Nature"},{"key":"2023060910275027900_btz750-B2","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. Rev. Genet"},{"key":"2023060910275027900_btz750-B3","doi-asserted-by":"crossref","first-page":"e1440","DOI":"10.1002\/wrna.1440","article-title":"RNA uridylation: a key posttranscriptional modification shaping the coding and noncoding transcriptome","volume":"9","author":"De Almeida","year":"2018","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"2023060910275027900_btz750-B4","first-page":"e1003997","volume-title":"PLoS Genet.","author":"Atak","year":"2013"},{"key":"2023060910275027900_btz750-B5","doi-asserted-by":"crossref","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr. Protoc. Bioinf"},{"key":"2023060910275027900_btz750-B6","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nmeth.4106","article-title":"Simulation-based comprehensive benchmarking of RNA-seq aligners","volume":"14","author":"Baruzzo","year":"2017","journal-title":"Nat. Methods"},{"key":"2023060910275027900_btz750-B7","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1534\/g3.114.015784","article-title":"Mapping bias overestimates reference allele frequencies at the HLA genes in the 1000 Genomes Project Phase I Data","volume":"5","author":"Brandt","year":"2015","journal-title":"G3 (Bethesda)"},{"key":"2023060910275027900_btz750-B8","doi-asserted-by":"crossref","first-page":"980.","DOI":"10.1016\/j.cell.2017.10.031","article-title":"SnapShot: discovering genetic regulatory variants by QTL analysis","volume":"171","author":"Brandt","year":"2017","journal-title":"Cell"},{"key":"2023060910275027900_btz750-B9","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.3390\/ijms18081652","article-title":"Transcriptome Profiling in Human Diseases: new Advances and Perspectives","volume":"18","author":"Casamassimi","year":"2017","journal-title":"Int. J. Mol. Sci"},{"key":"2023060910275027900_btz750-B10","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s13059-015-0762-6","article-title":"Tools and best practices for data processing in allelic expression analysis","volume":"16","author":"Castel","year":"2015","journal-title":"Genome Biol"},{"key":"2023060910275027900_btz750-B11","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1146\/annurev-genet-120215-035120","article-title":"Monoallelic gene expression in mammals","volume":"50","author":"Chess","year":"2016","journal-title":"Annu. Rev. Genet"},{"key":"2023060910275027900_btz750-B12","doi-asserted-by":"crossref","first-page":"30.","DOI":"10.1186\/s13073-015-0152-4","article-title":"Calling genotypes from public RNA-seq data enables identification of genetic variants that affect gene-expression levels","volume":"7","author":"Deelen","year":"2015","journal-title":"Genome Med"},{"key":"2023060910275027900_btz750-B13","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1093\/bioinformatics\/btp579","article-title":"Effect of read-mapping biases on detecting allele-specific expression from RNA-sequencing data","volume":"25","author":"Degner","year":"2009","journal-title":"Bioinformatics"},{"key":"2023060910275027900_btz750-B14","doi-asserted-by":"crossref","first-page":"120.","DOI":"10.1186\/s13059-017-1250-y","article-title":"Genetic-epigenetic interactions in cis: a major focus in the post-GWAS era","volume":"18","author":"Do","year":"2017","journal-title":"Genome Biol"},{"key":"2023060910275027900_btz750-B15","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"2023060910275027900_btz750-B16","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41576-018-0006-1","article-title":"A-to-I RNA editing \u2013 immune protector and transcriptome diversifier","volume":"19","author":"Eisenberg","year":"2018","journal-title":"Nat. Rev. Genet"},{"key":"2023060910275027900_btz750-B17","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.molmed.2018.01.002","article-title":"A New Chapter in genetic medicine: RNA editing and its role in disease pathogenesis","volume":"24","author":"Gagnidze","year":"2018","journal-title":"Trends Mol. Med"},{"key":"2023060910275027900_btz750-B18","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nmeth.3582","article-title":"WASP: allele-specific software for robust molecular quantitative trait locus discovery","volume":"12","author":"Van de Geijn","year":"2015","journal-title":"Nat. Methods"},{"key":"2023060910275027900_btz750-B21","doi-asserted-by":"crossref","first-page":"59.","DOI":"10.3389\/fcvm.2018.00059","article-title":"Using gene expression to annotate cardiovascular GWAS loci","volume":"5","author":"Heinig","year":"2018","journal-title":"Front. Cardiovasc. Med"},{"key":"2023060910275027900_btz750-B22","doi-asserted-by":"crossref","first-page":"2256.","DOI":"10.1038\/srep02256","article-title":"Novel insights into breast cancer genetic variance through RNA sequencing","volume":"3","author":"Horvath","year":"2013","journal-title":"Sci. Rep"},{"key":"2023060910275027900_btz750-B23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/978-1-4939-6427-7_8","article-title":"Expression QTLs mapping and analysis: a Bayesian perspective","volume":"1488","author":"Imprialou","year":"2017","journal-title":"Methods Mol. Biol"},{"key":"2023060910275027900_btz750-B24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"2023060910275027900_btz750-B25","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.ajhg.2017.05.004","article-title":"Genetic-variation-driven gene-expression changes highlight genes with important functions for kidney disease","volume":"100","author":"Ko","year":"2017","journal-title":"Am. J. Hum. Genet"},{"key":"2023060910275027900_btz750-B26","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jbi.2015.10.010","article-title":"eQTL networks unveil enriched mRNA master integrators downstream of complex disease-associated SNPs","volume":"58","author":"Li","year":"2015","journal-title":"J. Biomed. Inform"},{"key":"2023060910275027900_btz750-B27","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence alignment\/map (SAM) format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023060910275027900_btz750-B29","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/978-1-4939-6427-7_16","article-title":"Systems genetics as a tool to identify master genetic regulators in complex disease","volume":"1488","author":"Moreno-Moral","year":"2017","journal-title":"Methods Mol. Biol"},{"key":"2023060910275027900_btz750-B30","doi-asserted-by":"crossref","first-page":"e161","DOI":"10.1093\/nar\/gkw757","article-title":"RNA2DNAlign: nucleotide resolution allele asymmetries through quantitative assessment of RNA and DNA paired sequencing data","volume":"44","author":"Movassagh","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023060910275027900_btz750-B31","first-page":"1003","article-title":"Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus","volume":"26","author":"Odhams","year":"2017","journal-title":"Hum. Mol. Genet"},{"key":"2023060910275027900_btz750-B32","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1111\/biom.12810","article-title":"Estimation of cis-eQTL effect sizes using a log of linear model","volume":"74","author":"Palowitch","year":"2018","journal-title":"Biometrics"},{"key":"2023060910275027900_btz750-B33","doi-asserted-by":"crossref","first-page":"467.","DOI":"10.1186\/s13059-014-0467-2","article-title":"Allelic mapping bias in RNA-sequencing is not a major confounder in eQTL studies","volume":"15","author":"Panousis","year":"2014","journal-title":"Genome Biol"},{"key":"2023060910275027900_btz750-B34","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1038\/nprot.2016.095","article-title":"Transcript-level expression analysis of RNA-seq experiments with HISAT, StringTie and Ballgown","volume":"11","author":"Pertea","year":"2016","journal-title":"Nat. Protoc"},{"key":"2023060910275027900_btz750-B35","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.ajhg.2013.08.008","article-title":"Reliable identification of genomic variants from RNA-seq data","volume":"93","author":"Piskol","year":"2013","journal-title":"Am. J. Hum. Genet"},{"key":"2023060910275027900_btz750-B36","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3390\/jpm9020018","article-title":"Aligning the aligners: comparison of RNA sequencing data alignment and gene expression quantification tools for clinical breast cancer research","volume":"9","author":"Raplee","year":"2019","journal-title":"J. Pers. Med"},{"key":"2023060910275027900_btz750-B37","doi-asserted-by":"crossref","first-page":"D753","DOI":"10.1093\/nar\/gkv1106","article-title":"dbMAE: the database of autosomal monoallelic expression","volume":"44","author":"Savova","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023060910275027900_btz750-B38","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1093\/bioinformatics\/bts163","article-title":"Matrix eQTL: ultra fast eQTL analysis via large matrix operations","volume":"28","author":"Shabalin","year":"2012","journal-title":"Bioinformatics"},{"key":"2023060910275027900_btz750-B39","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nprot.2011.457","article-title":"Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses","volume":"7","author":"Stegle","year":"2012","journal-title":"Nat. Protoc"},{"key":"2023060910275027900_btz750-B40","doi-asserted-by":"crossref","first-page":"W645","DOI":"10.1093\/nar\/gkl229","article-title":"Applications for protein sequence-function evolution data: mRNA\/protein expression analysis and coding SNP scoring tools","volume":"34","author":"Thomas","year":"2006","journal-title":"Nucleic Acids Res"},{"key":"2023060910275027900_btz750-B41","first-page":"4","article-title":"The genetic architecture of gene expression levels in wild baboons","volume":"25","author":"Tung","year":"2015","journal-title":"Elife"},{"key":"2023060910275027900_btz750-B42","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1111\/cge.13187","article-title":"Genetic association of molecular traits: a help to identify causative variants in complex diseases","volume":"93","author":"Vandiedonck","year":"2018","journal-title":"Clin. Genet"},{"key":"2023060910275027900_btz750-B43","doi-asserted-by":"crossref","first-page":"D135","DOI":"10.1093\/nar\/gky1031","article-title":"LNCipedia 5: towards a reference set of human long non-coding RNAs","volume":"47","author":"Volders","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023060910275027900_btz750-B44","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1534\/genetics.114.167791","article-title":"Novel distal eQTL analysis demonstrates effect of population genetic architecture on detecting and interpreting associations","volume":"198","author":"Weiser","year":"2014","journal-title":"Genetics"},{"key":"2023060910275027900_btz750-B45","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1038\/ng.2756","article-title":"Systematic identification of trans eQTLs as putative drivers of known disease associations","volume":"45","author":"Westra","year":"2013","journal-title":"Nat. Genet"},{"key":"2023060910275027900_btz750-B46","doi-asserted-by":"crossref","first-page":"450.","DOI":"10.1186\/s12864-018-4827-2","article-title":"Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans","volume":"19","author":"Winter","year":"2018","journal-title":"BMC Genomics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz750\/31172707\/btz750.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/5\/1351\/50553059\/bioinformatics_36_5_1351.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/5\/1351\/50553059\/bioinformatics_36_5_1351.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T10:30:42Z","timestamp":1686306642000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/5\/1351\/5582649"}},"subtitle":[],"editor":[{"given":"Inanc","family":"Birol","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,10,7]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz750","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2020,3]]},"published":{"date-parts":[[2019,10,7]]}}}