{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T11:47:32Z","timestamp":1772624852521,"version":"3.50.1"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Office of the Vice Chancellor for Research and Graduate Education"},{"DOI":"10.13039\/100008028","name":"School of Medicine and Public Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008028","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Population Health Sciences"},{"DOI":"10.13039\/100007015","name":"University of Wisconsin-Madison","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Understanding gene-environment and gene\u2013gene interactions is important for studying complex diseases. Case-only analysis has been proposed to improve power for detecting interactions. However, case-only analysis relies on key assumptions, including correct specification of the disease risk model and marginal independence between variables. In this study, we systematically investigate the challenges of case-only analysis using polygenic risk scores (PRS) as genetic variables in large biobanks. Through simulations, we demonstrate that the false positive control of PRS-based case-only analysis depends on the log-linear disease risk model and weak main effects, and that it is prone to false positives under other commonly used disease risk models. We then conduct case-only analyses for breast cancer, prostate cancer, class 3 obesity, and short stature in the UK Biobank, using PRS derived from non-overlapping chromosome sets (e.g. even-numbered and odd-numbered chromosomes) that are unlikely to interact with each other. The resulting case-only regression estimates consistently show negative shifts compared to population-based estimates, suggesting false positives driven by collider bias due to model misspecification. Furthermore, correlations between chromosome set-specific PRS, likely driven by assortative mating or population stratification, suggest additional sources of confounding. Our results underscore the challenges of applying PRS-based case-only analysis in large biobank settings and highlight the need for caution when interpreting case-only results.<\/jats:p>","DOI":"10.1093\/genetics\/iyag006","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T20:47:17Z","timestamp":1768337237000},"source":"Crossref","is-referenced-by-count":0,"title":["Challenges to case-only analysis for interaction detection using polygenic risk scores: model assumptions and biases in large biobanks"],"prefix":"10.1093","volume":"232","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-8859","authenticated-orcid":false,"given":"Wenmin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Statistics, University of Manitoba , Winnipeg, Manitoba R3T 2N2 ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4514-0969","authenticated-orcid":false,"given":"Qiongshi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin\u2013Madison , Madison, WI 53726 ,","place":["United States"]},{"name":"Department of Statistics, University of Wisconsin\u2013Madison , Madison, WI 53706 ,","place":["United States"]},{"name":"Center for Demography of Health and Aging, University of Wisconsin\u2013Madison , Madison, WI 53706 ,","place":["United States"]},{"name":"Center for Genomic Science Innovation, University of Wisconsin\u2013Madison , Madison, WI 53706 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5664-5698","authenticated-orcid":false,"given":"Tianyuan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Medical Informatics, University of Wisconsin\u2013Madison , Madison, WI 53726 ,","place":["United States"]},{"name":"Center for Demography of Health and Aging, University of Wisconsin\u2013Madison , Madison, WI 53706 ,","place":["United States"]},{"name":"Center for Genomic Science Innovation, University of Wisconsin\u2013Madison , Madison, WI 53706 ,","place":["United States"]},{"name":"Department of Population Health Sciences, University of Wisconsin\u2013Madison , Madison, WI 53726 ,","place":["United States"]},{"name":"Center for Precision Medicine, University of Wisconsin\u2013Madison , Madison, WI 53705 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"2026030400563469200_iyag006-B1","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"1000 Genomes Project Consortium","year":"2015","journal-title":"Nature"},{"key":"2026030400563469200_iyag006-B2","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1016\/j.ajhg.2012.04.017","article-title":"Inclusion of gene-gene and gene-environment interactions unlikely to dramatically improve risk prediction for complex diseases","volume":"90","author":"Aschard","year":"2012","journal-title":"Am J Hum Genet."},{"key":"2026030400563469200_iyag006-B3","first-page":"173","article-title":"Statistical analysis of molecular epidemiology studies employing case-series","volume":"3","author":"Begg","year":"1994","journal-title":"Cancer Epidemiol Biomarkers Prev."},{"key":"2026030400563469200_iyag006-B4","doi-asserted-by":"publisher","first-page":"2211","DOI":"10.1056\/NEJMoa1000367","article-title":"Body-mass index and mortality among 1.46 million white adults","volume":"363","author":"Berrington de Gonzalez","year":"2010","journal-title":"N Engl J Med."},{"key":"2026030400563469200_iyag006-B5","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41586-018-0579-z","article-title":"The UK biobank resource with deep phenotyping and genomic data","volume":"562","author":"Bycroft","year":"2018","journal-title":"Nature"},{"key":"2026030400563469200_iyag006-B6","doi-asserted-by":"publisher","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":"2026030400563469200_iyag006-B7","doi-asserted-by":"publisher","first-page":"4210","DOI":"10.1210\/jc.2008-0509","article-title":"Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the growth hormone research society, the Lawson Wilkins pediatric endocrine society, and the European society for paediatric endocrinology workshop","volume":"93","author":"Cohen","year":"2008","journal-title":"J Clin Endocrinol Metab."},{"key":"2026030400563469200_iyag006-B8","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1093\/aje\/kwr368","article-title":"Gene-environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes","volume":"175","author":"Cornelis","year":"2012","journal-title":"Am J Epidemiol."},{"key":"2026030400563469200_iyag006-B9","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1111\/j.1469-1809.1965.tb00500.x","article-title":"The inheritance of liability to certain diseases, estimated from the incidence among relatives","volume":"29","author":"Falconer","year":"1965","journal-title":"Ann Hum Genet."},{"key":"2026030400563469200_iyag006-B10","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1093\/aje\/kwx246","article-title":"Comparison of sociodemographic and health-related characteristics of UK biobank participants with those of the general population","volume":"186","author":"Fry","year":"2017","journal-title":"Am J Epidemiol."},{"key":"2026030400563469200_iyag006-B11","doi-asserted-by":"publisher","first-page":"1776","DOI":"10.1038\/s41467-019-09718-5","article-title":"Polygenic prediction via Bayesian regression and continuous shrinkage priors","volume":"10","author":"Ge","year":"2019","journal-title":"Nat Commun."},{"key":"2026030400563469200_iyag006-B12","doi-asserted-by":"publisher","first-page":"e1000008","DOI":"10.1371\/journal.pgen.1000008","article-title":"Data and theory point to mainly additive genetic variance for complex traits","volume":"4","author":"Hill","year":"2008","journal-title":"PLoS Genet."},{"key":"2026030400563469200_iyag006-B13","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/s41588-022-01062-7","article-title":"Within-Sibship genome-wide association analyses decrease bias in estimates of direct genetic effects","volume":"54","author":"Howe","year":"2022","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B14","doi-asserted-by":"publisher","first-page":"8111","DOI":"10.1038\/ncomms9111","article-title":"Improved imputation of low-frequency and rare variants using the Uk10k haplotype reference panel","volume":"6","author":"Huang","year":"2015","journal-title":"Nat Commun."},{"key":"2026030400563469200_iyag006-B15","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/nrg1578","article-title":"Gene-environment interactions in human diseases","volume":"6","author":"Hunter","year":"2005","journal-title":"Nat Rev Genet."},{"key":"2026030400563469200_iyag006-B16","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1038\/s41588-021-00954-4","article-title":"A generalized linear mixed model association tool for biobank-scale data","volume":"53","author":"Jiang","year":"2021","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B17","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/oxfordjournals.aje.a008915","article-title":"Nontraditional epidemiologic approaches in the analysis of gene environment interaction: case-control studies with no controls!","volume":"144","author":"Khoury","year":"1996","journal-title":"Am J Epidemiol."},{"key":"2026030400563469200_iyag006-B18","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1159\/000099183","article-title":"Exploiting gene-environment interaction to detect genetic associations","volume":"63","author":"Kraft","year":"2007","journal-title":"Hum Hered."},{"key":"2026030400563469200_iyag006-B19","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/s41588-021-00783-5","article-title":"The polygenic score catalog as an open database for reproducibility and systematic evaluation","volume":"53","author":"Lambert","year":"2021","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B20","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/nature14177","article-title":"Genetic studies of body mass index yield new insights for obesity biology","volume":"518","author":"Locke","year":"2015","journal-title":"Nature"},{"key":"2026030400563469200_iyag006-B21","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1210\/clinem\/dgab215","article-title":"A polygenic risk score to predict future adult short stature among children","volume":"106","author":"Lu","year":"2021","journal-title":"J Clin Endocrinol Metab."},{"key":"2026030400563469200_iyag006-B22","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.ajcnut.2025.01.021","article-title":"Characterization of gene\u2013environment interactions for vitamin D through variance quantitative trait loci: a UK biobank-based genetic epidemiology study","volume":"121","author":"Lu","year":"2025","journal-title":"Am J Clin Nutr."},{"key":"2026030400563469200_iyag006-B23","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyac158","article-title":"Genetic determinants of polygenic prediction accuracy within a population","volume":"222","author":"Lu","year":"2022","journal-title":"Genetics"},{"key":"2026030400563469200_iyag006-B24","doi-asserted-by":"publisher","first-page":"2867","DOI":"10.1093\/bioinformatics\/btq559","article-title":"Robust relationship inference in genome-wide association studies","volume":"26","author":"Manichaikul","year":"2010","journal-title":"Bioinformatics (Oxford, England)"},{"key":"2026030400563469200_iyag006-B25","doi-asserted-by":"publisher","first-page":"6383","DOI":"10.1038\/s41467-020-19966-5","article-title":"The role of polygenic risk and susceptibility genes in breast cancer over the course of life","volume":"11","author":"Mars","year":"2020","journal-title":"Nat Commun."},{"key":"2026030400563469200_iyag006-B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2022.100118","article-title":"Genome-wide risk prediction of common diseases across ancestries in one million people","volume":"2","author":"Mars","year":"2022","journal-title":"Cell Genom."},{"key":"2026030400563469200_iyag006-B27","doi-asserted-by":"publisher","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":"2026030400563469200_iyag006-B28","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1038\/ng.3643","article-title":"A reference panel of 64,976 haplotypes for genotype imputation","volume":"48","author":"McCarthy","year":"2016","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B29","doi-asserted-by":"publisher","first-page":"2013","DOI":"10.1093\/aje\/kwz175","article-title":"Case-only analysis of gene-environment interactions using polygenic risk scores","volume":"188","author":"Meisner","year":"2019","journal-title":"Am J Epidemiol."},{"key":"2026030400563469200_iyag006-B30","doi-asserted-by":"publisher","first-page":"e2212959119","DOI":"10.1073\/pnas.2212959119","article-title":"A quantile integral linear model to quantify genetic effects on phenotypic variability","volume":"119","author":"Miao","year":"2022","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2026030400563469200_iyag006-B31","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/nature24284","article-title":"Association analysis identifies 65 new breast cancer risk loci","volume":"551","author":"Michailidou","year":"2017","journal-title":"Nature"},{"key":"2026030400563469200_iyag006-B32","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511803161","volume-title":"Causality","author":"Pearl","year":"2009"},{"key":"2026030400563469200_iyag006-B33","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1002\/sim.4780130206","article-title":"Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case-control studies","volume":"13","author":"Piegorsch","year":"1994","journal-title":"Stat Med."},{"key":"2026030400563469200_iyag006-B34","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1038\/s41588-021-00846-7","article-title":"Genetic analyses identify widespread sex-differential participation bias","volume":"53","author":"Pirastu","year":"2021","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B35","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1016\/S0140-6736(09)60318-4","article-title":"Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies","volume":"373","author":"Prospective Studies Collaboration","year":"2009","journal-title":"Lancet (London, England)"},{"key":"2026030400563469200_iyag006-B36","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am J Hum Genet."},{"key":"2026030400563469200_iyag006-B37","doi-asserted-by":"crossref","DOI":"10.1201\/b10722","volume-title":"Introduction to functional equations","author":"Sahoo","year":"2011"},{"key":"2026030400563469200_iyag006-B38","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1093\/oxfordjournals.aje.a010093","article-title":"Potential misinterpretation of the case-only study to assess gene-environment interaction","volume":"150","author":"Schmidt","year":"1999","journal-title":"Am J Epidemiol."},{"key":"2026030400563469200_iyag006-B39","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/s41562-023-01579-9","article-title":"Participation bias in the UK biobank distorts genetic associations and downstream analyses","volume":"7","author":"Schoeler","year":"2023","journal-title":"Nat Hum Behav."},{"key":"2026030400563469200_iyag006-B40","doi-asserted-by":"publisher","first-page":"928","DOI":"10.1038\/s41588-018-0142-8","article-title":"Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci","volume":"50","author":"Schumacher","year":"2018","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B41","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1111\/biom.12813","article-title":"Testing for gene\u2013environment interaction under exposure misspecification","volume":"74","author":"Sun","year":"2018","journal-title":"Biometrics"},{"key":"2026030400563469200_iyag006-B42","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1097\/EDE.0b013e31820877c5","article-title":"On the robustness of tests of genetic associations incorporating gene-environment interaction when the environmental exposure is misspecified","volume":"22","author":"Tchetgen","year":"2011","journal-title":"Epidemiology"},{"key":"2026030400563469200_iyag006-B43","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1002\/gepi.20484","article-title":"Case-only gene-environment interaction studies: when does association imply mechanistic interaction?","volume":"34","author":"VanderWeele","year":"2010","journal-title":"Genet Epidemiol."},{"key":"2026030400563469200_iyag006-B44","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaw3538","article-title":"Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK biobank","volume":"5","author":"Wang","year":"2019","journal-title":"Sci Adv."},{"key":"2026030400563469200_iyag006-B45","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1038\/ng.3097","article-title":"Defining the role of common variation in the genomic and biological architecture of adult human height","volume":"46","author":"Wood","year":"2014","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B46","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1097\/00001648-199903000-00014","article-title":"Case-only design to measure gene-gene interaction","volume":"10","author":"Yang","year":"1999","journal-title":"Epidemiology (Cambridge, Mass.)"},{"key":"2026030400563469200_iyag006-B47","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1038\/s41562-018-0476-3","article-title":"Imprint of assortative mating on the human genome","volume":"2","author":"Yengo","year":"2018","journal-title":"Nat Hum Behav."},{"key":"2026030400563469200_iyag006-B48","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btae295","article-title":"SharePro: an accurate and efficient genetic colocalization method accounting for multiple causal signals","volume":"40","author":"Zhang","year":"2024","journal-title":"Bioinformatics"},{"key":"2026030400563469200_iyag006-B49","doi-asserted-by":"publisher","first-page":"9374","DOI":"10.1038\/s41467-024-53818-w","article-title":"Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro","volume":"15","author":"Zhang","year":"2024","journal-title":"Nat Commun."},{"key":"2026030400563469200_iyag006-B50","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","article-title":"Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies","volume":"50","author":"Zhou","year":"2018","journal-title":"Nat Genet."},{"key":"2026030400563469200_iyag006-B51","doi-asserted-by":"publisher","first-page":"3385","DOI":"10.1038\/s41467-024-47806-3","article-title":"An approach to identify gene-environment interactions and reveal new biological insight in Complex traits","volume":"15","author":"Zhu","year":"2024","journal-title":"Nat Commun."}],"container-title":["GENETICS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/genetics\/advance-article-pdf\/doi\/10.1093\/genetics\/iyag006\/66398912\/iyag006.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/232\/3\/iyag006\/66398912\/iyag006.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/genetics\/article-pdf\/232\/3\/iyag006\/66398912\/iyag006.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T05:56:47Z","timestamp":1772603807000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/genetics\/article\/doi\/10.1093\/genetics\/iyag006\/8424708"}},"subtitle":[],"editor":[{"given":"Y","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,1,13]]},"published-print":{"date-parts":[[2026,3,4]]}},"URL":"https:\/\/doi.org\/10.1093\/genetics\/iyag006","relation":{},"ISSN":["1943-2631"],"issn-type":[{"value":"1943-2631","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,3]]},"published":{"date-parts":[[2026,1,13]]},"article-number":"iyag006"}}