{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T00:45:20Z","timestamp":1740185120040,"version":"3.37.3"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T00:00:00Z","timestamp":1592870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"SNSF","doi-asserted-by":"publisher","award":["155913"],"award-info":[{"award-number":["155913"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alfried Krupp Prize"},{"DOI":"10.13039\/501100005306","name":"Alfried Krupp von Bohlen und Halbach-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005306","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Correlating genetic loci with a disease phenotype is a common approach to improve our understanding of the genetics underlying complex diseases. Standard analyses mostly ignore two aspects, namely genetic heterogeneity and interactions between loci. Genetic heterogeneity, the phenomenon that genetic variants at different loci lead to the same phenotype, promises to increase statistical power by aggregating low-signal variants. Incorporating interactions between loci results in a computational and statistical bottleneck due to the vast amount of candidate interactions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We propose a novel method SiNIMin that addresses these two aspects by finding pairs of interacting genes that are, upon combination, associated with a phenotype of interest under a model of genetic heterogeneity. We guide the interaction search using biological prior knowledge in the form of protein\u2013protein interaction networks. Our method controls type I error and outperforms state-of-the-art methods with respect to statistical power. Additionally, we find novel associations for multiple Arabidopsis thaliana phenotypes, and, with an adapted variant of SiNIMin, for a study of rare variants in migraine patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Code available at https:\/\/github.com\/BorgwardtLab\/SiNIMin.<\/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\/btaa581","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T11:11:35Z","timestamp":1592219495000},"page":"57-65","source":"Crossref","is-referenced-by-count":8,"title":["Network-guided search for genetic heterogeneity between gene pairs"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0194-1809","authenticated-orcid":false,"given":"Anja C","family":"Gumpinger","sequence":"first","affiliation":[{"name":"Department of Biosystems Science and Engineering, ETH Z\u00fcrich , Basel 4058, Switzerland"},{"name":"SIB Swiss Institute of Bioinformatics , Lausanne 1015, Switzerland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4335-0302","authenticated-orcid":false,"given":"Bastian","family":"Rieck","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering, ETH Z\u00fcrich , Basel 4058, Switzerland"},{"name":"SIB Swiss Institute of Bioinformatics , Lausanne 1015, Switzerland"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2085-4591","authenticated-orcid":false,"given":"Dominik G","family":"Grimm","sequence":"additional","affiliation":[{"name":"Technical University of Munich, TUM Campus Straubing for Biotechnology and Sustainability , Bioinformatics, Straubing 94315, Germany"},{"name":"Weihenstephan-Triesdorf University of Applied Sciences , Bioinformatics, Straubing 94315, Germany"}]},{"name":"International Headache Genetics Consortium","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7221-2393","authenticated-orcid":false,"given":"Karsten","family":"Borgwardt","sequence":"additional","affiliation":[{"name":"Department of Biosystems Science and Engineering, ETH Z\u00fcrich , Basel 4058, Switzerland"},{"name":"SIB Swiss Institute of Bioinformatics , Lausanne 1015, Switzerland"}]}],"member":"286","published-online":{"date-parts":[[2020,6,23]]},"reference":[{"key":"2023051510483356200_btaa581-B8","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1126\/science.1203877","article-title":"Evidence for network evolution in an Arabidopsis interactome map","volume":"333","year":"2011","journal-title":"Science"},{"key":"2023051510483356200_btaa581-B1","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nature08800","article-title":"Genome-wide association study of 107 phenotypes in Arabidopsis thaliana inbred lines","volume":"465","author":"Atwell","year":"2010","journal-title":"Nature"},{"key":"2023051510483356200_btaa581-B2","doi-asserted-by":"crossref","first-page":"i171","DOI":"10.1093\/bioinformatics\/btt238","article-title":"Efficient network-guided multi-locus association mapping with graph cuts","volume":"29","author":"Azencott","year":"2013","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B3","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/dvg.22877","article-title":"The Arabidopsis information resource: making and mining the \u201cgold standard\u201d annotated reference plant genome","volume":"53","author":"Berardini","year":"2015","journal-title":"Genesis"},{"key":"2023051510483356200_btaa581-B4","doi-asserted-by":"crossref","first-page":"i438","DOI":"10.1093\/bioinformatics\/bty246","article-title":"Association mapping in biomedical time series via statistically significant shapelet mining","volume":"34","author":"Bock","year":"2018","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B5","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/dneu.22022","article-title":"The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation","volume":"72","author":"Bond","year":"2012","journal-title":"Dev. Neurobiol"},{"key":"2023051510483356200_btaa581-B6","first-page":"3","article-title":"Teoria statistica delle classi e calcolo delle probabilita","volume":"8","author":"Bonferroni","year":"1936","journal-title":"Pubblicazioni Del R Istituto Superiore di Scienze Economiche e Commericiali di Firenze"},{"key":"2023051510483356200_btaa581-B7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13742-015-0047-8","article-title":"Second-generation plink: rising to the challenge of larger and richer datasets","volume":"4","author":"Chang","year":"2015","journal-title":"Gigascience"},{"key":"2023051510483356200_btaa581-B9","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1093\/hmg\/11.20.2463","article-title":"Epistasis: what it means, what it doesn\u2019t mean, and statistical methods to detect it in humans","volume":"11","author":"Cordell","year":"2002","journal-title":"Hum. Mol. Genet"},{"key":"2023051510483356200_btaa581-B10","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1055\/s-2006-923935","article-title":"Jasmonate biosynthesis in Arabidopsis thaliana\u2014enzymes, products, regulation","volume":"8","author":"Delker","year":"2006","journal-title":"Plant Biol"},{"first-page":"410","year":"2016","author":"Fowkes","key":"2023051510483356200_btaa581-B11"},{"key":"2023051510483356200_btaa581-B12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1105\/tpc.16.00551","article-title":"easyGWAS: a cloud-based platform for comparing the results of genome-wide association studies","volume":"29","author":"Grimm","year":"2017","journal-title":"Plant Cell"},{"key":"2023051510483356200_btaa581-B13","doi-asserted-by":"crossref","first-page":"796e","DOI":"10.1097\/PRS.0000000000000696","article-title":"Electron microscopic and proteomic comparison of terminal branches of the trigeminal nerve in patients with and without migraine headaches","volume":"134","author":"Guyuron","year":"2014","journal-title":"Plastic Reconstruct. Surg"},{"key":"2023051510483356200_btaa581-B14","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nmeth.4514","article-title":"NetSig: network-based discovery from cancer genomes","volume":"15","author":"Horn","year":"2018","journal-title":"Nat. Methods"},{"key":"2023051510483356200_btaa581-B15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/nrg1578","article-title":"Gene\u2013environment interactions in human diseases","volume":"6","author":"Hunter","year":"2005","journal-title":"Nat. Rev. Genet"},{"key":"2023051510483356200_btaa581-B16","doi-asserted-by":"crossref","first-page":"D353","DOI":"10.1093\/nar\/gkw1092","article-title":"KEGG: new perspectives on genomes, pathways, diseases and drugs","volume":"45","author":"Kanehisa","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023051510483356200_btaa581-B17","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1126\/science.2570460","article-title":"Identification of the cystic fibrosis gene: genetic analysis","volume":"245","author":"Kerem","year":"1989","journal-title":"Science"},{"key":"2023051510483356200_btaa581-B18","doi-asserted-by":"crossref","first-page":"D1003","DOI":"10.1093\/nar\/gku1200","article-title":"Araport: the Arabidopsis information portal","volume":"43","author":"Krishnakumar","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023051510483356200_btaa581-B19","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.molcel.2015.05.008","article-title":"The cancer cell map initiative: defining the hallmark networks of cancer","volume":"58","author":"Krogan","year":"2015","journal-title":"Mol. Cell"},{"key":"2023051510483356200_btaa581-B20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12918-018-0543-4","article-title":"GxGrare: gene\u2013gene interaction analysis method for rare variants from high-throughput sequencing data","volume":"12","author":"Kwon","year":"2018","journal-title":"BMC Syst. Biol"},{"key":"2023051510483356200_btaa581-B21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s11103-007-9135-1","article-title":"Yeast two-hybrid map of Arabidopsis TFIID","volume":"64","author":"Lawit","year":"2007","journal-title":"Plant Mol. Biol"},{"key":"2023051510483356200_btaa581-B22","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/biostatistics\/kxs014","article-title":"Optimal tests for rare variant effects in sequencing association studies","volume":"13","author":"Lee","year":"2012","journal-title":"Biostatistics"},{"key":"2023051510483356200_btaa581-B23","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.ajhg.2011.02.002","article-title":"Estimating missing heritability for disease from genome-wide association studies","volume":"88","author":"Lee","year":"2011","journal-title":"Am. J. Hum. Genet"},{"key":"2023051510483356200_btaa581-B24","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ajhg.2008.06.024","article-title":"Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data","volume":"83","author":"Li","year":"2008","journal-title":"Am. J. Hum. Genet"},{"key":"2023051510483356200_btaa581-B25","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nmeth.4083","article-title":"A scored human protein\u2013protein interaction network to catalyze genomic interpretation","volume":"14","author":"Li","year":"2017","journal-title":"Nat. Methods"},{"key":"2023051510483356200_btaa581-B26","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/nmeth.1681","article-title":"Fast linear mixed models for genome-wide association studies","volume":"8","author":"Lippert","year":"2011","journal-title":"Nat. Methods"},{"key":"2023051510483356200_btaa581-B27","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.1093\/bioinformatics\/btu504","article-title":"Greater power and computational efficiency for kernel-based association testing of sets of genetic variants","volume":"30","author":"Lippert","year":"2014","journal-title":"Bioinformatics"},{"first-page":"725","year":"2015","author":"Llinares-L\u00f3pez","key":"2023051510483356200_btaa581-B28"},{"key":"2023051510483356200_btaa581-B29","doi-asserted-by":"crossref","first-page":"i240","DOI":"10.1093\/bioinformatics\/btv263","article-title":"Genome-wide detection of intervals of genetic\u00a0heterogeneity associated with complex traits","volume":"31","author":"Llinares-L\u00f3pez","year":"2015","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B30","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1093\/bioinformatics\/btx071","article-title":"Genome-wide genetic heterogeneity discovery with categorical covariates","volume":"33","author":"Llinares-L\u00f3pez","year":"2017","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B31","doi-asserted-by":"crossref","first-page":"2680","DOI":"10.1093\/bioinformatics\/bty1020","article-title":"CASMAP: detection of statistically significant combinations of snps in association mapping","volume":"35","author":"Llinares-L\u00f3pez","year":"2019","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B32","doi-asserted-by":"crossref","first-page":"3097","DOI":"10.1038\/s41467-018-05452-6","article-title":"Genome-wide identification of directed gene networks using large-scale population genomics data","volume":"9","author":"Luijk","year":"2018","journal-title":"Nat. Commun"},{"key":"2023051510483356200_btaa581-B33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/ng0592-99","article-title":"The Huntington\u2019s disease candidate region exhibits many different haplotypes","volume":"1","author":"MacDonald","year":"1992","journal-title":"Nat. Genet"},{"key":"2023051510483356200_btaa581-B34","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the missing heritability of complex diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"2023051510483356200_btaa581-B35","first-page":"719","article-title":"Statistical aspects of the analysis of data from retrospective studies of disease","volume":"22","author":"Mantel","year":"1959","journal-title":"J. Natl. Cancer Inst"},{"key":"2023051510483356200_btaa581-B36","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.cell.2010.03.032","article-title":"Genetic heterogeneity in human disease","volume":"141","author":"McClellan","year":"2010","journal-title":"Cell"},{"key":"2023051510483356200_btaa581-B37","doi-asserted-by":"crossref","first-page":"e1005580","DOI":"10.1371\/journal.pcbi.1005580","article-title":"Incorporating networks in a probabilistic graphical model to find drivers for complex human diseases","volume":"13","author":"Mezlini","year":"2017","journal-title":"PLoS Comput. Biol"},{"first-page":"422","year":"2014","author":"Minato","key":"2023051510483356200_btaa581-B38"},{"key":"2023051510483356200_btaa581-B39","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1002\/gepi.20450","article-title":"An evaluation of statistical approaches to rare variant analysis in genetic association studies","volume":"34","author":"Morris","year":"2010","journal-title":"Genet. Epidemiol"},{"key":"2023051510483356200_btaa581-B40","doi-asserted-by":"crossref","first-page":"D1016","DOI":"10.1093\/nar\/gkq1147","article-title":"COXPRESdb: a database to compare gene coexpression in seven model animals","volume":"39","author":"Obayashi","year":"2011","journal-title":"Nucleic Acids Res"},{"first-page":"2279","year":"2016","author":"Papaxanthos","key":"2023051510483356200_btaa581-B41"},{"key":"2023051510483356200_btaa581-B42","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1080\/14786440009463897","article-title":"On the criterion that a given system of deviations from the probable in the case of a correlated system of variables is such that it can be\u00a0reasonably supposed to have arisen from random sampling","volume":"50","author":"Pearson","year":"1900","journal-title":"Lond. Edinburgh Dublin Philos. Mag. J. Sci"},{"key":"2023051510483356200_btaa581-B43","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/s41576-019-0177-4","article-title":"Rare-variant collapsing analyses for complex traits: guidelines and applications","volume":"20","author":"Povysil","year":"2019","journal-title":"Nat. Rev. Genet"},{"key":"2023051510483356200_btaa581-B44","doi-asserted-by":"crossref","first-page":"i972","DOI":"10.1093\/bioinformatics\/bty613","article-title":"Hierarchical HotNet: identifying hierarchies of altered subnetworks","volume":"34","author":"Reyna","year":"2018","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B45","doi-asserted-by":"crossref","first-page":"D1054","DOI":"10.1093\/nar\/gkw986","article-title":"AraPheno: a public database for Arabidopsis thaliana phenotypes","volume":"45","author":"Seren","year":"2017","journal-title":"Nucleic Acids Rese"},{"key":"2023051510483356200_btaa581-B46","doi-asserted-by":"crossref","first-page":"e1005599","DOI":"10.1371\/journal.pcbi.1005599","article-title":"Systematic, network-based characterization of therapeutic target inhibitors","volume":"13","author":"Shen","year":"2017","journal-title":"PLoS Comput. Biol"},{"first-page":"515","year":"1990","author":"Tarone","key":"2023051510483356200_btaa581-B47"},{"key":"2023051510483356200_btaa581-B48","doi-asserted-by":"crossref","first-page":"12996","DOI":"10.1073\/pnas.1302233110","article-title":"Statistical significance of combinatorial regulations","volume":"110","author":"Terada","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023051510483356200_btaa581-B49","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkz925","article-title":"AraPheno and the AraGWAS catalog 2020: a major database update including RNA-Seq and knockout mutation data for Arabidopsis thaliana","author":"Togninalli","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023051510483356200_btaa581-B50","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrg2322","article-title":"Heritability in the genomics era\u2014concepts and misconceptions","volume":"9","author":"Visscher","year":"2008","journal-title":"Nat. Rev. Genet"},{"key":"2023051510483356200_btaa581-B51","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ajhg.2011.11.029","article-title":"Five years of GWAS discovery","volume":"90","author":"Visscher","year":"2012","journal-title":"Am. J. Hum. Genet"},{"volume-title":"Resampling-Based Multiple Testing: Examples and Methods for p-Value Adjustment","year":"1993","author":"Westfall","key":"2023051510483356200_btaa581-B52"},{"key":"2023051510483356200_btaa581-B53","doi-asserted-by":"crossref","first-page":"i484","DOI":"10.1093\/bioinformatics\/bty247","article-title":"Classifying tumors by supervised network propagation","volume":"34","author":"Zhang","year":"2018","journal-title":"Bioinformatics"},{"key":"2023051510483356200_btaa581-B54","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/ejhg.2015.147","article-title":"Genome-wide gene\u2013gene interaction analysis for next-generation sequencing","volume":"24","author":"Zhao","year":"2016","journal-title":"Eur. J. Hum. Genet"},{"key":"2023051510483356200_btaa581-B55","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1073\/pnas.1119675109","article-title":"The mystery of missing heritability: genetic interactions\u00a0create phantom heritability","volume":"109","author":"Zuk","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaa581\/36201236\/btaa581.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/1\/57\/50321675\/btaa581.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/37\/1\/57\/50321675\/btaa581.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T10:51:26Z","timestamp":1684147886000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/37\/1\/57\/5861532"}},"subtitle":[],"editor":[{"given":"Lenore","family":"Cowen","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2020,6,23]]},"references-count":55,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,4,9]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa581","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2021,1,1]]},"published":{"date-parts":[[2020,6,23]]}}}