{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T11:15:39Z","timestamp":1787742939003,"version":"build-2784847793"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Linear mixed models (LMMs) are a commonly used method for genome-wide association studies (GWAS) that aim to detect associations between genetic markers and phenotypic measurements in a population of individuals while accounting for population structure and cryptic relatedness. In a standard GWAS, hundreds of thousands to millions of statistical tests are performed, requiring control for multiple hypothesis testing. Typically, static corrections that penalize the number of tests performed are used to control for the family-wise error rate, which is the probability of making at least one false positive. However, it has been shown that in practice this threshold is too conservative for normally distributed phenotypes and not stringent enough for non-normally distributed phenotypes. Therefore, permutation-based LMM approaches have recently been proposed to provide a more realistic threshold that takes phenotypic distributions into account. In this work, we discuss the advantages of permutation-based GWAS approaches, including new simulations and results from a re-analysis of all publicly available Arabidopsis phenotypes from the AraPheno database.<\/jats:p>","DOI":"10.1093\/jxb\/erae280","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T23:01:06Z","timestamp":1719961266000},"page":"5377-5389","source":"Crossref","is-referenced-by-count":6,"title":["The benefits of permutation-based genome-wide association studies"],"prefix":"10.1093","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2773-2426","authenticated-orcid":false,"given":"Maura","family":"John","sequence":"first","affiliation":[{"name":"Technical University of Munich, Campus Straubing for Biotechnology and Sustainability, Bioinformatics , Petersgasse 18, 94315 Straubing ,","place":["Germany"]},{"name":"Weihenstephan-Triesdorf University of Applied Sciences, Bioinformatics , Petersgasse 18, 94315 Straubing ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0831-1463","authenticated-orcid":false,"given":"Arthur","family":"Korte","sequence":"additional","affiliation":[{"name":"University of W\u00fcrzburg, Faculty of Biology, Julius-von-Sachs Institute , Julius-von-Sachs-Platz 3, 97082 W\u00fcrzburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2085-4591","authenticated-orcid":false,"given":"Dominik G","family":"Grimm","sequence":"additional","affiliation":[{"name":"Technical University of Munich, Campus Straubing for Biotechnology and Sustainability, Bioinformatics , Petersgasse 18, 94315 Straubing ,","place":["Germany"]},{"name":"Weihenstephan-Triesdorf University of Applied Sciences, Bioinformatics , Petersgasse 18, 94315 Straubing ,","place":["Germany"]},{"name":"Technical University of Munich, TUM School of Computation, Information and Technology , Boltzmannstra\u00dfe 3, 85748 Garching ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"2024121110593198100_CIT0001","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1080\/01621459.1954.10501232","article-title":"A test of goodness of fit","volume":"49","author":"Anderson","year":"1954","journal-title":"Journal of the American Statistical Association"},{"key":"2024121110593198100_CIT0002","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1111\/tpj.14659","article-title":"Imputation of 3 million SNPs in the Arabidopsis regional mapping population","volume":"102","author":"Arouisse","year":"2020","journal-title":"The Plant Journal"},{"key":"2024121110593198100_CIT0003","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1214\/20-STS778","article-title":"The box\u2013cox transformation: review and extensions","volume":"36","author":"Atkinson","year":"2021","journal-title":"Statistical Science"},{"key":"2024121110593198100_CIT0004","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":"2024121110593198100_CIT0005","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12870-019-2217-9","article-title":"Genome-wide association study identified candidate genes controlling continuous storage root formation and bulking in hexaploid sweetpotato","volume":"20","author":"Bararyenya","year":"2020","journal-title":"BMC Plant Biology"},{"key":"2024121110593198100_CIT0006","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society Series B"},{"key":"2024121110593198100_CIT0007","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1136\/bmj.310.6973.170","article-title":"Multiple significance tests: the Bonferroni method","volume":"310","author":"Bland","year":"1995","journal-title":"British Medical Journal"},{"key":"2024121110593198100_CIT0008","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":"2024121110593198100_CIT0009","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1534\/genetics.116.193987","article-title":"Controlling the rate of GWAS false discoveries","volume":"205","author":"Brzyski","year":"2017","journal-title":"Genetics"},{"key":"2024121110593198100_CIT0010","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1756-0381-7-9","article-title":"An adaptive permutation approach for genome-wide association study: evaluation and recommendations for use","volume":"7","author":"Che","year":"2014","journal-title":"BioData Mining"},{"key":"2024121110593198100_CIT0011","first-page":"693","article-title":"A less conservative method to adjust for familywise error rate in neuropsychological research: the holm\u2019s sequential Bonferroni procedure","volume":"32","author":"Eichstaedt","year":"2013","journal-title":"NeuroRehabilitation"},{"key":"2024121110593198100_CIT0012","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/ejhg.2015.269","article-title":"The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants","volume":"24","author":"Fadista","year":"2016","journal-title":"European Journal of Human Genetics"},{"key":"2024121110593198100_CIT0013","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.chembiol.2018.04.004","article-title":"Linking genomic and metabolomic natural variation uncovers nematode pheromone biosynthesis","volume":"25","author":"Falcke","year":"2018","journal-title":"Cell Chemical Biology"},{"key":"2024121110593198100_CIT0014","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":"The Plant Cell"},{"key":"2024121110593198100_CIT0015","first-page":"93","article-title":"Methods and tools in genome-wide association studies","volume-title":"Computational cell biology. Methods in Molecular Biology","author":"Gumpinger","year":"2018"},{"key":"2024121110593198100_CIT0016","doi-asserted-by":"crossref","first-page":"4186","DOI":"10.1016\/j.celrep.2019.11.051","article-title":"The Arabidopsis transcriptome responds specifically and dynamically to high light stress","volume":"29","author":"Huang","year":"2019","journal-title":"Cell Reports"},{"key":"2024121110593198100_CIT0017","doi-asserted-by":"crossref","first-page":"ii5","DOI":"10.1093\/bioinformatics\/btac455","article-title":"Efficient permutation-based genome-wide association studies for normal and skewed phenotypic distributions","volume":"38","author":"John","year":"2022","journal-title":"Bioinformatics"},{"key":"2024121110593198100_CIT0018","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/978-1-0716-3354-0_18","article-title":"Predicting gene regulatory interactions using natural genetic variation","volume-title":"Plant gene regulatory networks. Methods in Molecular Biology","author":"John","year":"2023"},{"key":"2024121110593198100_CIT0019","first-page":"2023.11.28.569016","article-title":"permGWAS2: enhanced and accelerated permutation-based genome-wide association studies","author":"John","year":"2023","journal-title":"bioRxiv"},{"key":"2024121110593198100_CIT0020","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/ng.548","article-title":"Variance component model to account for sample structure in genome-wide association studies","volume":"42","author":"Kang","year":"2010","journal-title":"Nature Genetics"},{"key":"2024121110593198100_CIT0021","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1534\/genetics.107.080101","article-title":"Efficient control of population structure in model organism association mapping","volume":"178","author":"Kang","year":"2008","journal-title":"Genetics"},{"key":"2024121110593198100_CIT0022","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/ng2115","article-title":"Recombination and linkage disequilibrium in Arabidopsis thaliana","volume":"39","author":"Kim","year":"2007","journal-title":"Nature Genetics"},{"key":"2024121110593198100_CIT0023","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1746-4811-9-29","article-title":"The advantages and limitations of trait analysis with GWAS: a review","volume":"9","author":"Korte","year":"2013","journal-title":"Plant Methods"},{"key":"2024121110593198100_CIT0024","article-title":"Yield Spain 2009 (1st experiment)","author":"Li","year":"2016"},{"key":"2024121110593198100_CIT0025","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1534\/genetics.113.157628","article-title":"Genetic variation for life history sensitivity to seasonal warming in Arabidopsis thaliana","volume":"196","author":"Li","year":"2014","journal-title":"Genetics"},{"key":"2024121110593198100_CIT0026","doi-asserted-by":"crossref","first-page":"21199","DOI":"10.1073\/pnas.1007431107","article-title":"Association mapping of local climate-sensitive quantitative trait loci in Arabidopsis thaliana","volume":"107","author":"Li","year":"2010","journal-title":"Proceedings of the National Academy of Sciences, USA"},{"key":"2024121110593198100_CIT0027","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1038\/ng.3117","article-title":"Genomic analyses provide insights into the history of tomato breeding","volume":"46","author":"Lin","year":"2014","journal-title":"Nature Genetics"},{"key":"2024121110593198100_CIT0028","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":"Nature Methods"},{"key":"2024121110593198100_CIT0029","doi-asserted-by":"crossref","first-page":"15562","DOI":"10.1038\/srep15562","article-title":"Genome-wide association study of 29 morphological traits in Aegilops tauschii","volume":"5","author":"Liu","year":"2015","journal-title":"Scientific Reports"},{"key":"2024121110593198100_CIT0030","doi-asserted-by":"crossref","first-page":"i240","DOI":"10.1093\/bioinformatics\/btv263","article-title":"Genome-wide detection of intervals of genetic heterogeneity associated with complex traits","volume":"31","author":"Llinares-L\u00f3pez","year":"2015","journal-title":"Bioinformatics"},{"key":"2024121110593198100_CIT0031","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/ng.3190","article-title":"Efficient Bayesian mixed-model analysis increases association power in large cohorts","volume":"47","author":"Loh","year":"2015","journal-title":"Nature Genetics"},{"key":"2024121110593198100_CIT0032","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1080\/10618600.2014.960084","article-title":"Are you normal? The problem of confounded residual structures in hierarchical linear models","volume":"24","author":"Loy","year":"2015","journal-title":"Journal of Computational and Graphical Statistics"},{"key":"2024121110593198100_CIT0033","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1186\/1753-6561-3-S1-S14","article-title":"Pre-selection of most significant SNPs for the estimation of genomic breeding values","volume":"3","author":"Macciotta","year":"2009","journal-title":"BMC Proceedings"},{"key":"2024121110593198100_CIT0034","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/ng.3595","article-title":"Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing","volume":"48","author":"Nicod","year":"2016","journal-title":"Nature Genetics"},{"issue":"52","key":"2024121110593198100_CIT0035","doi-asserted-by":"crossref","first-page":"145","DOI":"10.2307\/621706","article-title":"The assumptions of the linear regression model","author":"Poole","year":"1971","journal-title":"Transactions of the Institute of British Geographers"},{"key":"2024121110593198100_CIT0036","doi-asserted-by":"crossref","first-page":"e3000244","DOI":"10.1371\/journal.pbio.3000244","article-title":"Genome-wide sexually antagonistic variants reveal long-standing constraints on sexual dimorphism in fruit flies","volume":"17","author":"Ruzicka","year":"2019","journal-title":"PLoS Biology"},{"key":"2024121110593198100_CIT0037","doi-asserted-by":"crossref","first-page":"15603","DOI":"10.1038\/ncomms15603","article-title":"Natural allelic variation of FRO2 modulates Arabidopsis root growth under iron deficiency","volume":"8","author":"Satbhai","year":"2017","journal-title":"Nature Communications"},{"key":"2024121110593198100_CIT0038","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s13059-021-02354-7","article-title":"Limited haplotype diversity underlies polygenic trait architecture across 70 years of wheat breeding","volume":"22","author":"Scott","year":"2021","journal-title":"Genome Biology"},{"key":"2024121110593198100_CIT0039","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":"2016","journal-title":"Nucleic Acids Research"},{"key":"2024121110593198100_CIT0040","doi-asserted-by":"crossref","first-page":"200","DOI":"10.12688\/f1000research.2-200.v1","article-title":"Issues with data transformation in genome-wide association studies for phenotypic variability","volume":"2","author":"Shen","year":"2013","journal-title":"F1000Research"},{"key":"2024121110593198100_CIT0041","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.ajhg.2013.06.017","article-title":"What is the significance of difference in phenotypic variability across SNP genotypes","volume":"93","author":"Sun","year":"2013","journal-title":"American Journal of Human Genetics"},{"key":"2024121110593198100_CIT0042","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fgene.2020.00022","article-title":"Genome-wide association mapping to identify genetic loci for cold tolerance and cold recovery during germination in rice","volume":"11","author":"Thapa","year":"2020","journal-title":"Frontiers in Genetics"},{"key":"2024121110593198100_CIT0043","first-page":"D1063","article-title":"AraPheno and the araGWAS catalog 2020: a major database update including RNA-Seq and knockout mutation data for Arabidopsis thaliana","volume":"48","author":"Togninalli","year":"2020","journal-title":"Nucleic Acids Research"},{"key":"2024121110593198100_CIT0044","volume-title":"Resampling-based multiple testing: Examples and methods for p-value adjustment","author":"Westfall","year":"1993"},{"key":"2024121110593198100_CIT0045","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11295-021-01511-0","article-title":"Genome-wide association study of myrtle rust (Austropuccinia psidii) resistance in Eucalyptus obliqua (subgenus Eucalyptus)","volume":"17","author":"Yong","year":"2021","journal-title":"Tree Genetics and Genomes"},{"key":"2024121110593198100_CIT0046","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s11540-019-09437-w","article-title":"Genome-wide association study of resistance to potato common scab","volume":"63","author":"Yuan","year":"2020","journal-title":"Potato Research"},{"key":"2024121110593198100_CIT0047","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/ncomms1467","article-title":"Genome-wide association mapping reveals a rich genetic architecture of complex traits in Oryza sativa","volume":"2","author":"Zhao","year":"2011","journal-title":"Nature Communications"}],"container-title":["Journal of Experimental Botany"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jxb\/advance-article-pdf\/doi\/10.1093\/jxb\/erae280\/58622371\/erae280.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jxb\/article-pdf\/75\/17\/5377\/61030527\/erae280.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jxb\/article-pdf\/75\/17\/5377\/61030527\/erae280.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T17:42:32Z","timestamp":1733938952000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jxb\/article\/75\/17\/5377\/7703222"}},"subtitle":[],"editor":[{"given":"Martin","family":"Janda","sequence":"additional","affiliation":[{"name":"University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice ,","place":["Czech Republic"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,2]]},"references-count":47,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,7,2]]},"published-print":{"date-parts":[[2024,9,11]]}},"URL":"https:\/\/doi.org\/10.1093\/jxb\/erae280","relation":{},"ISSN":["0022-0957","1460-2431"],"issn-type":[{"value":"0022-0957","type":"print"},{"value":"1460-2431","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,9,11]]},"published":{"date-parts":[[2024,7,2]]}}}