{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T13:03:29Z","timestamp":1785503009191,"version":"3.56.0"},"reference-count":21,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Big Data"],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:p>\n                    Delirium is a prevalent neuropsychiatric syndrome affecting up to 50% of hospitalized elderly patients, associated with increased mortality, cognitive decline, and health care costs exceeding $164 billion annually. Despite its clinical burden, the genetic architecture underlying susceptibility to delirium remains poorly characterized. We developed an agentic artificial intelligence pipeline integrating genome-wide association study (GWAS) data from FinnGen Release 12 (6854 cases; 384,461 controls) with causal transcriptome-wide association study (cTWAS) using brain-specific eQTL data from Genotype-Tissue Expression. Spatial transcriptomics analysis (gsMap) was performed on the human dorsolateral prefrontal cortex to characterize layer-specific expression patterns. Deep learning models (Enformer, SpliceTransformer) were applied to predict functional consequences of identified variants. GWAS identified a strongly associated locus on chromosome 19q13.32, with lead variant rs429358 (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 2.79 \u00d7 10\n                    <jats:sup>\u221270<\/jats:sup>\n                    ) defining the apolipoprotein E (\n                    <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                    ) \u03b54 allele. cTWAS analysis identified two causal genes:\n                    <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                    (posterior inclusion probabilities [PIP] = 0.871,\n                    <jats:italic toggle=\"yes\">Z<\/jats:italic>\n                    = \u22128.44) and\n                    <jats:italic toggle=\"yes\">ZNF226<\/jats:italic>\n                    (PIP = 0.604,\n                    <jats:italic toggle=\"yes\">Z<\/jats:italic>\n                    = 5.63), exhibiting opposite directional effects.\n                    <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                    downregulation increased susceptibility to delirium, while\n                    <jats:italic toggle=\"yes\">ZNF226<\/jats:italic>\n                    upregulation conferred an elevated risk. Spatial transcriptomics revealed significant GWAS enrichment in Layer 5 (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    &lt; 0.001), with distinct layer-specific expression patterns for both genes. Enformer predicted that rs429358 substantially altered chromatin accessibility at promoter regions (H3K4me3 SNP Activity Difference = 0.30). SpliceTransformer identified significant splice site perturbations (maximum \u0394 = 0.45). This study provides a comprehensive genetic dissection of delirium through agentic artificial intelligence-driven multiomics integration. We identify\n                    <jats:italic toggle=\"yes\">APOE<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">ZNF226<\/jats:italic>\n                    as causal genes with distinct mechanisms and spatial expression patterns. These findings establish a molecular framework for understanding delirium pathophysiology and identify potential therapeutic targets.\n                  <\/jats:p>","DOI":"10.1177\/2167647x261463929","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T10:13:11Z","timestamp":1782727991000},"page":"280-290","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Agentic Artificial Intelligence-Driven Explainable Deep Learning for Deciphering Noncoding Pathogenic Mechanisms of Delirium Through Genomic Big Data Integration"],"prefix":"10.1177","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0355-4422","authenticated-orcid":false,"given":"Jidong","family":"Yang","sequence":"first","affiliation":[{"name":"Intensive Care Unit\/Operating Room, Luzhou Maternal &amp; Child Health Hospital (Luzhou Second People\u2019s Hospital), Luzhou, China."},{"name":"The University of Newcastle, Newcastle, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiong","family":"Wang","sequence":"additional","affiliation":[{"name":"Intensive Care Unit\/Operating Room, Luzhou Maternal &amp; Child Health Hospital (Luzhou Second People\u2019s Hospital), Luzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishuang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Medical Affairs and Education, Luzhou Mental Hospital (Luzhou Mental Health Center), Luzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfu","family":"Tang","sequence":"additional","affiliation":[{"name":"Intensive Care Unit\/Operating Room, Luzhou Maternal &amp; Child Health Hospital (Luzhou Second People\u2019s Hospital), Luzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Cai","sequence":"additional","affiliation":[{"name":"Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7375-8010","authenticated-orcid":false,"given":"Yuting","family":"Xue","sequence":"additional","affiliation":[{"name":"Intensive Care Unit\/Operating Room, Luzhou Maternal &amp; Child Health Hospital (Luzhou Second People\u2019s Hospital), Luzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"e_1_3_2_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00223-4"},{"key":"e_1_3_2_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60688-1"},{"key":"e_1_3_2_4_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.12067"},{"key":"e_1_3_2_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2020.2273"},{"key":"e_1_3_2_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(15)00101-5"},{"key":"e_1_3_2_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/gps.4823"},{"key":"e_1_3_2_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/JGP.0b013e3181ab8c84"},{"key":"e_1_3_2_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000251925.18961.CA"},{"key":"e_1_3_2_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00870-7"},{"key":"e_1_3_2_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaz1776"},{"key":"e_1_3_2_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08757-x"},{"key":"e_1_3_2_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00787-0"},{"key":"e_1_3_2_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-021-01252-x"},{"key":"e_1_3_2_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53088-6"},{"key":"e_1_3_2_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-019-0228-7"},{"key":"e_1_3_2_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2014.08.025"},{"key":"e_1_3_2_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2493-4"},{"key":"e_1_3_2_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCC.0b013e328357effa"},{"key":"e_1_3_2_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00014"},{"key":"e_1_3_2_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21683"},{"key":"e_1_3_2_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-019-0566-x"}],"container-title":["Big Data"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/2167647X261463929","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/2167647X261463929","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/2167647X261463929","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T12:17:17Z","timestamp":1785500237000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/2167647X261463929"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":21,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,8,1]]}},"alternative-id":["10.1177\/2167647X261463929"],"URL":"https:\/\/doi.org\/10.1177\/2167647x261463929","relation":{},"ISSN":["2167-6461","2167-647X"],"issn-type":[{"value":"2167-6461","type":"print"},{"value":"2167-647X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]}}}