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Here, we present GENDULF (GENetic moDULators identiFication), one of the first methods to facilitate prediction of disease modifiers using healthy and diseased tissue gene expression data. GENDULF is designed for monogenic diseases in which the mechanism is loss of function leading to reduced expression of the mutated gene. When applied to cystic fibrosis, GENDULF successfully identifies multiple, previously established disease modifiers, including\n                    <jats:italic>EHF<\/jats:italic>\n                    ,\n                    <jats:italic>SLC6A14<\/jats:italic>\n                    , and\n                    <jats:italic>CLCA1<\/jats:italic>\n                    . It is then utilized in spinal muscular atrophy (SMA) and predicts\n                    <jats:italic>U2AF1<\/jats:italic>\n                    as a modifier whose low expression correlates with higher SMN2 pre\u2010mRNA exon 7 retention. Indeed, knockdown of U2AF1 in SMA patient\u2010derived cells leads to increased full\u2010length SMN2 transcript and SMN protein expression. Taking advantage of the increasing availability of transcriptomic data, GENDULF is a novel addition to existing strategies for prediction of genetic disease modifiers, providing insights into disease pathogenesis and uncovering novel therapeutic targets.\n                  <\/jats:p>","DOI":"10.15252\/msb.20209701","type":"journal-article","created":{"date-parts":[[2020,12,8]],"date-time":"2020-12-08T07:31:39Z","timestamp":1607412699000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-8735","authenticated-orcid":false,"given":"Noam","family":"Auslander","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel M","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivette","family":"Zelaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3607-6552","authenticated-orcid":false,"given":"Hiren","family":"Karathia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas O.","family":"Crawford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-8033","authenticated-orcid":false,"given":"Alejandro A","family":"Sch\u00e4ffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5088-6012","authenticated-orcid":false,"given":"Charlotte J","family":"Sumner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7862-3940","authenticated-orcid":false,"given":"Eytan","family":"Ruppin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,8]]},"reference":[{"key":"BFMSB20209701_CR1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","volume":"550","author":"F Aguet","year":"2017","unstructured":"Aguet F, Brown AA, Castel SE, Davis JR, He Y, Jo B, Mohammadi P, Park YS, Parsana P, Segr\u00e8 AV et al (2017) Genetic effects on gene expression across human tissues. 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