{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T11:52:59Z","timestamp":1774007579701,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Traditional genome-wide association studies (GWAS) aim to uncover the genetic variants associated with a single phenotype of interest (typically a disease), and to elucidate its genotypic architecture. However, many of today\u2019s GWAS simultaneously measure multiple related phenotypes, leading to the possibility of pursuing the reverse aim of elucidating the \u201cphenotypic architecture\u201d of a single genetic variant. In other words, we may ask what combination of measured phenotypes is associated with a given genotypic variant. ReverseGWAS is an algorithmic platform for answering such questions in the context of large-scale multi-phenotype GWAS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrate the effectiveness of ReverseGWAS on simulated data, showing its ability to identify logical combinations of phenotypes with a reasonable amount of noise. We then apply it to a selection of combined phenotypes from the UK Biobank, obtaining 719 candidate associations using autoimmune diseases and 205 using common ICD10 codes. We find that the majority of these associations (546\/719 and 111\/205, respectively) successfully replicate in an independent cohort, FinnGen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The source code of ReverseGWAS is freely available to non-commercial users as an installable R package at https:\/\/github.com\/Leonardini\/rgwas.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btag079","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T12:43:14Z","timestamp":1770986594000},"source":"Crossref","is-referenced-by-count":0,"title":["<tt>ReverseGWAS<\/tt>\n                    identifies combined phenotypes associated with a genotype in GWA studies"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6619-6013","authenticated-orcid":false,"given":"Leonid","family":"Chindelevitch","sequence":"first","affiliation":[{"name":"MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College , London W2 1NY,","place":["United Kingdom"]}]},{"given":"\u00c5sa K","family":"Hedman","sequence":"additional","affiliation":[{"name":"Inflammation and Immunology, Pfizer Research and Development , Cambridge, MA 02139,","place":["United States"]}]},{"given":"Dmitri","family":"Bichko","sequence":"additional","affiliation":[{"name":"Inflammation and Immunology, Pfizer Research and Development , Cambridge, MA 02139,","place":["United States"]}]},{"given":"Daniel","family":"Ziemek","sequence":"additional","affiliation":[{"name":"Inflammation and Immunology, Pfizer Research and Development , Cambridge, MA 02139,","place":["United States"]}]}],"member":"286","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"2026032005262983200_btag079-B1","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/nature05911","article-title":"Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls","volume":"447","author":"Burton","year":"2007","journal-title":"Nature"},{"key":"2026032005262983200_btag079-B2","doi-asserted-by":"crossref","first-page":"e1011245","DOI":"10.1371\/journal.pgen.1011245","article-title":"A novel method for multiple phenotype association studies based on genotype and phenotype network","volume":"20","author":"Cao","year":"2024","journal-title":"PLoS Genet"},{"key":"2026032005262983200_btag079-B3","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41586-021-03552-w","article-title":"Interpreting type 1 diabetes risk with genetics and single-cell epigenomics","volume":"594","author":"Chiou","year":"2021","journal-title":"Nature"},{"key":"2026032005262983200_btag079-B4","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/ng.782","article-title":"A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease","volume":"43","author":"Coronary Artery Disease Genetics Consortium","year":"2011","journal-title":"Nat Genet"},{"key":"2026032005262983200_btag079-B5","doi-asserted-by":"crossref","first-page":"e1008009","DOI":"10.1371\/journal.pgen.1008009","article-title":"Reverse GWAS: using genetics to identify and model phenotypic subtypes","volume":"15","author":"Dahl","year":"2019","journal-title":"PLoS Genet"},{"key":"2026032005262983200_btag079-B6","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1126\/science.1135245","article-title":"A genome-wide association study identifies IL23R as an inflammatory bowel disease gene","volume":"314","author":"Duerr","year":"2006","journal-title":"Science"},{"key":"2026032005262983200_btag079-B7","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/ng.717","article-title":"Genome-wide meta-analysis increases to 71 the number of confirmed Crohn\u2019s disease susceptibility loci","volume":"42","author":"Franke","year":"2010","journal-title":"Nat Genet"},{"key":"2026032005262983200_btag079-B8","doi-asserted-by":"crossref","first-page":"4644","DOI":"10.4049\/jimmunol.1100272","article-title":"Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function","volume":"188","author":"Garg","year":"2012","journal-title":"J Immunol"},{"key":"2026032005262983200_btag079-B9","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1093\/bioinformatics\/bts610","article-title":"GWASTools: an R\/Bioconductor package for quality control and analysis of genome-wide association studies","volume":"28","author":"Gogarten","year":"2012","journal-title":"Bioinformatics"},{"key":"2026032005262983200_btag079-B10","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.1002\/cphg.95","article-title":"Genetic risk scores","volume":"104","author":"Igo","year":"2019","journal-title":"Curr Protoc Hum Genet"},{"key":"2026032005262983200_btag079-B11","first-page":"159","article-title":"An optimal algorithm for approximating a piecewise linear function","volume":"9","author":"Imai","year":"1986","journal-title":"J Inf Process"},{"key":"2026032005262983200_btag079-B12","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1038\/s41588-018-0222-9","article-title":"Genetics of blood lipids among 300,000 multi-ethnic participants of the Million Veteran Program","volume":"50","author":"Klarin","year":"2018","journal-title":"Nat Genet"},{"key":"2026032005262983200_btag079-B13","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"2026032005262983200_btag079-B14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.biopsych.2020.09.026","article-title":"Pleiotropy and cross-disorder genetics among psychiatric disorders","volume":"89","author":"Lee","year":"2021","journal-title":"Biol Psychiatry"},{"key":"2026032005262983200_btag079-B15","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s13073-020-00742-5","article-title":"Polygenic risk scores: from research tools to clinical instruments","volume":"12","author":"Lewis","year":"2020","journal-title":"Genome Med"},{"key":"2026032005262983200_btag079-B16","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1093\/eurheartj\/ehx254","article-title":"UK biobank: opportunities for cardiovascular research","volume":"40","author":"Littlejohns","year":"2019","journal-title":"Eur Heart J"},{"key":"2026032005262983200_btag079-B17","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41586-019-1457-z","article-title":"Exome sequencing of Finnish isolates enhances rare-variant association power","volume":"572","author":"Locke","year":"2019","journal-title":"Nature"},{"key":"2026032005262983200_btag079-B18","doi-asserted-by":"crossref","first-page":"a008581","DOI":"10.1101\/cshperspect.a008581","article-title":"Personalized medicine and human genetic diversity","volume":"4","author":"Lu","year":"2014","journal-title":"Cold Spring Harb Perspect Med"},{"key":"2026032005262983200_btag079-B19","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/s41588-021-00870-7","article-title":"Computationally efficient whole-genome regression for quantitative and binary traits","volume":"53","author":"Mbatchou","year":"2021","journal-title":"Nat Genet"},{"key":"2026032005262983200_btag079-B20","doi-asserted-by":"crossref","DOI":"10.1002\/9781118627372","volume-title":"Integer and Combinatorial Optimization","author":"Nemhauser","year":"1988"},{"key":"2026032005262983200_btag079-B21","doi-asserted-by":"crossref","first-page":"e34861","DOI":"10.1371\/journal.pone.0034861","article-title":"MultiPhen: joint model of multiple phenotypes can increase discovery in GWAS","volume":"7","author":"O\u2019Reilly","year":"2012","journal-title":"PLoS One"},{"key":"2026032005262983200_btag079-B22","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1001\/jama.299.11.1335","article-title":"How to interpret a genome-wide association study","volume":"299","author":"Pearson","year":"2008","journal-title":"JAMA"},{"key":"2026032005262983200_btag079-B23","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/ng.513","article-title":"Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci","volume":"42","author":"Reveille","year":"2010","journal-title":"Nat. Genet"},{"key":"2026032005262983200_btag079-B24","doi-asserted-by":"crossref","first-page":"4109","DOI":"10.1113\/JP273122","article-title":"Phenome-wide association studies: a new method for functional genomics in humans","volume":"595","author":"Roden","year":"2017","journal-title":"J Physiol"},{"key":"2026032005262983200_btag079-B25","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/s41431-020-00730-8","article-title":"An expanded analysis framework for multivariate GWAS connects inflammatory biomarkers to functional variants and disease","volume":"29","author":"Ruotsalainen","year":"2021","journal-title":"Eur J Hum Genet"},{"key":"2026032005262983200_btag079-B26","volume-title":"Artificial Intelligence: A Modern Approach","author":"Russell","year":"2021","edition":"4th edn."},{"key":"2026032005262983200_btag079-B27","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/s41586-020-2436-0","article-title":"FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease","volume":"584","author":"Saevarsdottir","year":"2020","journal-title":"Nature"},{"key":"2026032005262983200_btag079-B28","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1093\/bioinformatics\/bty810","article-title":"A clustering linear combination approach to jointly analyze multiple phenotypes for GWAS","volume":"35","author":"Sha","year":"2019","journal-title":"Bioinformatics"},{"key":"2026032005262983200_btag079-B29","doi-asserted-by":"crossref","first-page":"e65245","DOI":"10.1371\/journal.pone.0065245","article-title":"A unified framework for association analysis with multiple related phenotypes","volume":"8","author":"Stephens","year":"2013","journal-title":"PLoS One"},{"key":"2026032005262983200_btag079-B30","first-page":"100069","article-title":"Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine-mapping in the MHC and genomewide","volume":"3","author":"Stuart","year":"2022","journal-title":"HGG Adv"},{"key":"2026032005262983200_btag079-B31","doi-asserted-by":"crossref","first-page":"e1001779","DOI":"10.1371\/journal.pmed.1001779","article-title":"UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of Middle and old age","volume":"12","author":"Sudlow","year":"2015","journal-title":"PLoS Med"},{"key":"2026032005262983200_btag079-B32","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1365-2567.2011.03522.x","article-title":"Interleukin-23: as a drug target for autoimmune inflammatory diseases","volume":"135","author":"Tang","year":"2012","journal-title":"Immunology"},{"key":"2026032005262983200_btag079-B33","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41575-023-00768-1","article-title":"IL-12 and IL-23 pathway inhibition in inflammatory bowel disease","volume":"20","author":"Verstockt","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"2026032005262983200_btag079-B100","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-323-90300-4.00095-1","author":"Vierra","year":"2023","journal-title":"Translational Surgery"},{"key":"2026032005262983200_btag079-B34","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/bioinformatics\/btad707","article-title":"Joint analysis of multiple phenotypes for extremely unbalanced case\u2013control association studies using multi-layer network","volume":"39","author":"Xie","year":"2023","journal-title":"Bioinformatics"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btag079\/66966728\/btag079.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/42\/3\/btag079\/66966728\/btag079.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/42\/3\/btag079\/66966728\/btag079.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T09:26:42Z","timestamp":1773998802000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btag079\/8489043"}},"subtitle":[],"editor":[{"given":"Russell","family":"Schwartz","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":35,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,2,28]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btag079","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2026,2,17]]},"article-number":"btag079"}}