{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T15:09:57Z","timestamp":1772118597404,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>For complex traits such as lung disease in Cystic Fibrosis (CF), Gene x Gene or Gene x Environment interactions can impact disease severity but these remain largely unknown. Unaccounted\u2010for genetic interactions introduce a distributional shift in the quantitative trait across the genotypic groups. Joint location and scale tests, or full distributional differences across genotype groups can account for unknown genetic interactions and increase power for gene identification compared with the conventional association test. Here we propose a new joint location and scale test (JLS), a quantile regression\u2010basd JLS (qJLS), that addresses previous limitations. Specifically, qJLS is free of distributional assumptions, thus applies to non\u2010Gaussian traits; is as powerful as the existing JLS tests under Gaussian traits; and is computationally efficient for genome\u2010wide association studies (GWAS). Our simulation studies, which model unknown genetic interactions, demonstrate that qJLS is robust to skewed and heavy\u2010tailed error distributions and is as powerful as other JLS tests in the literature under normality. Without any unknown genetic interaction, qJLS shows a large increase in power with non\u2010Gaussian traits over conventional association tests and is slightly less powerful under normality. We apply the qJLS method to the Canadian CF Gene Modifier Study (n\u2009=\u20091,997) and identified a genome\u2010wide significant variant, rs9513900 on chromosome 13, that had not previously been reported to contribute to CF lung disease. qJLS provides a powerful alternative to conventional genetic association tests, where interactions may contribute to a quantitative trait.<\/jats:p>","DOI":"10.1002\/gepi.70013","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T07:07:22Z","timestamp":1750144042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Robust Association Test Leveraging Unknown Genetic Interactions: Application to Cystic Fibrosis Lung Disease"],"prefix":"10.1002","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0966-0991","authenticated-orcid":false,"given":"Sangook","family":"Kim","sequence":"first","affiliation":[{"name":"Biostatistics Division, Dalla Lana School of Public Health University of Toronto Toronto ON Canada"},{"name":"Genetics and Genome Biology The Hospital for Sick Children Toronto ON Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Chung","family":"Lin","sequence":"additional","affiliation":[{"name":"Biostatistics Division, Dalla Lana School of Public Health University of Toronto Toronto ON Canada"},{"name":"Genetics and Genome Biology The Hospital for Sick Children Toronto ON Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa J.","family":"Strug","sequence":"additional","affiliation":[{"name":"Biostatistics Division, Dalla Lana School of Public Health University of Toronto Toronto ON Canada"},{"name":"Genetics and Genome Biology The Hospital for Sick Children Toronto ON Canada"},{"name":"Department of Statistical Sciences University of Toronto Toronto ON Canada"},{"name":"Department of Computer Science University of Toronto Toronto ON Canada"},{"name":"The Centre for Applied Genomics The Hospital for Sick Children Toronto Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21716"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1098\/rspa.1937.0109"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10519-009-9281-0"},{"key":"e_1_2_9_5_1","volume-title":"Statistics in Biology; Statistical Methods for Research in the Natural Sciences","author":"Bliss C. 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