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To address this limitation, we propose a nonlinear high-dimensional inference framework for set-based genetic association analysis that integrates scalable kernel representations with valid statistical inference. The framework combines distance correlation-based sure independence screening to reduce ultra-high dimensional predictors, kernel principal component analysis with Nystr\u00f6m approximation for nonlinear feature extraction, and de-sparsified LASSO to enable asymptotically valid hypothesis testing in high dimensions, together with a two-stage omnibus testing strategy that adaptively aggregates evidence across complementary signal models. Extensive simulation studies demonstrate that the proposed method maintains well-calibrated Type I error and consistently achieves higher power than established set-based approaches, including Sequence Kernel Association Test and adaptive Sum of Powered Score test, particularly under nonlinear and heterogeneous genetic effect scenarios, while remaining competitive in linear settings. Application to Alzheimer\u2019s Disease Neuroimaging Initiative data identifies gene-level associations with brain regional volumes that converge on neuronal excitability, calcium signaling, and cytoskeletal regulation, biological processes centrally implicated in neurodegeneration. Together, this work provides a robust and scalable framework for nonlinear set-based inference in genome-wide studies, expanding the analytical toolbox for dissecting complex genetic contributions to disease.<\/jats:p>","DOI":"10.1093\/bib\/bbag275","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T11:38:00Z","timestamp":1778585880000},"source":"Crossref","is-referenced-by-count":0,"title":["Nonlinear kernel-based high-dimensional inference for set-based genetic association studies"],"prefix":"10.1093","volume":"27","author":[{"given":"Zechen","family":"Zhang","sequence":"first","affiliation":[{"name":"Division of Health Statistics, School of Public Health , Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. China"]},{"name":"Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University , 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meilin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Division of Health Statistics, School of Public Health , Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Health Statistics, School of Public Health , Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuzhao","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Health Statistics, School of Public Health , Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Neurology, Second Hospital of Hebei Medical University , 215 West Heping Road, Shijiazhuang, Hebei 050000 ,","place":["P.R. China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8099-1753","authenticated-orcid":false,"given":"Yuehua","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Statistics and Probability, Michigan State University , 619 Red Cedar Road, East Lansing, MI 48824 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4374-0909","authenticated-orcid":false,"given":"Haitao","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Health Statistics, School of Public Health , Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. China"]},{"name":"Hebei Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University , 361 East Zhongshan Road, Shijiazhuang, Hebei 050017 ,","place":["P.R. 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