{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T18:25:36Z","timestamp":1786991136105,"version":"build-2736575974"},"reference-count":75,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSERC Discovery Grant","award":["RGPIN-2025-05344"],"award-info":[{"award-number":["RGPIN-2025-05344"]}]},{"name":"a New Frontiers in Research Fund","award":["NFRFE-2023-00291"],"award-info":[{"award-number":["NFRFE-2023-00291"]}]},{"name":"NSERC RTI grant","award":["RTI-2021-00675"],"award-info":[{"award-number":["RTI-2021-00675"]}]},{"name":"NSERC Discovery Grant","award":["RGPIN-2024-06154"],"award-info":[{"award-number":["RGPIN-2024-06154"]}]},{"name":"the Alberta Innovates Graduate Student Scholarship"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Genetic contributions to complex traits are often mediated through coordinated gene\u2013gene interaction networks, yet most existing association frameworks focus on marginal single-gene effects and overlook higher-order dependency structures. Direct modeling of interactions remains challenging due to combinatorial complexity and statistical instability. We introduce Interaction-Bridged Association Study (IBAS), a general framework that incorporates pathway-level interaction patterns into genotype\u2013phenotype association analysis without explicitly enumerating interactions. IBAS leverages transcriptomic reference data to construct low-dimensional representations of pathway activity, which guide SNP-weighting and gene-level association testing within a kernel-based framework. In perturbation-based simulations, IBAS demonstrates improved stability and reproducibility compared to conventional TWAS and gene-based methods, while maintaining well-calibrated Type I error under phenotype permutation. Application to the WTCCC datasets identifies both known and novel genes across multiple complex diseases, including candidates with modest marginal effects missed by standard approaches. These findings are supported by replication in an independent cohort, and analyses across multiple reference tissues revealing both shared and tissue-specific signals. Overall, IBAS provides a statistically robust and computationally tractable framework for incorporating interaction effects into association mapping, extending beyond the single-gene paradigm and enabling more comprehensive characterization of complex trait. IBAS is available on GitHub at:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/QingrunZhangLab\/IBAS\" xlink:type=\"simple\">https:\/\/github.com\/QingrunZhangLab\/IBAS<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014640","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T17:28:16Z","timestamp":1786987696000},"page":"e1014640","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0441-7431","authenticated-orcid":true,"given":"Dinghao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pathum","family":"Kossinna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Ardila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senitha","family":"Kumarapeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5421-3536","authenticated-orcid":true,"given":"M. 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