{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T23:40:30Z","timestamp":1774914030667,"version":"3.50.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2018,3,2]],"date-time":"2018-03-02T00:00:00Z","timestamp":1519948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"funder":[{"name":"Icahn Institute for Genomics and Multiscale Biology","award":["R01 GM114472"],"award-info":[{"award-number":["R01 GM114472"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nash Family Research Scholar"},{"name":"Department of Scientific Computing"},{"DOI":"10.13039\/100007277","name":"Icahn School of Medicine at Mount Sinai","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007277","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>For many traits, causal loci uncovered by genetic mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this \u2018missing heritability\u2019 have been proposed. Single nucleotide polymorphism (SNP)\u2013SNP interaction (epistasis), as one of the compelling models, has been widely studied. However, the genome-wide scan of epistasis, especially for quantitative traits, poses huge computational challenges. Moreover, covariate adjustment is largely ignored in epistasis analysis due to the massive extra computational undertaking.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In the current study, we found striking differences among epistasis models using both simulation data and real biological data, suggesting that not only can covariate adjustment remove confounding bias, it can also improve power. Furthermore, we derived mathematical formulas, which enable the exhaustive epistasis scan together with full covariate adjustment to be expressed in terms of large matrix operation, therefore substantially improving the computational efficiency (\u223c104\u00d7 faster than existing methods). We call the new method MatrixEpistasis. With MatrixEpistasis, we re-analyze a large real yeast dataset comprising 11\u00a0623 SNPs, 1008 segregants and 46 quantitative traits with covariates fully adjusted and detect thousands of novel putative epistasis with P-values\u2009&amp;lt;\u20091.48e-10.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>The method is implemented in R and available at https:\/\/github.com\/fanglab\/MatrixEpistasis.<\/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\/bty094","type":"journal-article","created":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T04:11:38Z","timestamp":1519877498000},"page":"2341-2348","source":"Crossref","is-referenced-by-count":23,"title":["MatrixEpistasis: ultrafast, exhaustive epistasis scan for quantitative traits with covariate adjustment"],"prefix":"10.1093","volume":"34","author":[{"given":"Shijia","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}]},{"given":"Gang","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}]}],"member":"286","published-online":{"date-parts":[[2018,3,2]]},"reference":[{"key":"2023012712595097300_bty094-B1","doi-asserted-by":"crossref","first-page":"i19","DOI":"10.1093\/bioinformatics\/btu261","article-title":"EPIQ\u2014efficient detection of SNP\u2013SNP epistatic interactions for quantitative traits","volume":"30","author":"Arkin","year":"2014","journal-title":"Bioinformatics"},{"key":"2023012712595097300_bty094-B2","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1002\/gepi.20629","article-title":"Rapid testing of gene-gene interactions in genome-wide association studies of binary and quantitative phenotypes","volume":"35","author":"Bhattacharya","year":"2011","journal-title":"Genetic Epidemiol"},{"key":"2023012712595097300_bty094-B3","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nature11867","article-title":"Finding the sources of missing heritability in a yeast cross","volume":"494","author":"Bloom","year":"2013","journal-title":"Nature"},{"key":"2023012712595097300_bty094-B4","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nature03865","article-title":"Genetic interactions between polymorphisms that affect gene expression in yeast","volume":"436","author":"Brem","year":"2005","journal-title":"Nature"},{"key":"2023012712595097300_bty094-B5","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1073\/pnas.0408709102","article-title":"The landscape of genetic complexity across 5,700 gene expression traits in yeast","volume":"102","author":"Brem","year":"2005","journal-title":"Proc. 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