{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T04:46:00Z","timestamp":1785818760852,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T00:00:00Z","timestamp":1785628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 114-2320-B-039-017"],"award-info":[{"award-number":["NSTC 114-2320-B-039-017"]}]},{"award":["NSTC 114-2320-B-039-017"],"award-info":[{"award-number":["NSTC 114-2320-B-039-017"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["DMR-115-001"],"award-info":[{"award-number":["DMR-115-001"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]},{"award":["DMR-115-001"],"award-info":[{"award-number":["DMR-115-001"]}],"id":[{"id":"https:\/\/ror.org\/0368s4g32","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSH-2026-C-021"],"award-info":[{"award-number":["CSH-2026-C-021"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CSH-2026-C-021"],"award-info":[{"award-number":["CSH-2026-C-021"]}],"id":[{"id":"https:\/\/ror.org\/01abtsn51","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic lung diseases, including asthma, chronic obstructive pulmonary disease, bronchiectasis, and idiopathic pulmonary fibrosis, are clinically distinct but share epithelial injury, host-defense, inflammatory, and remodeling processes. We integrated European-ancestry genome-wide association study (GWAS) summary statistics for these four diseases using genomic structural equation modeling to construct a multivariate chronic lung disease (mvCLD) factor. Variant-level association testing was combined with genomic control assessment, locus annotation, GWAS-by-subtraction, fine-mapping, transcriptomic prioritization, pathway enrichment, single-cell spatial mapping, and heritability partitioning. For discovery, across 6,255,777 autosomal variants, mvCLD identified 2067 genome-wide significant variants, 30 loci, and 53 lead variants. Five lead variants were genome-wide significant for mvCLD but not for any component disease and showed high-confidence fine-mapping support. For gene prioritization, transcriptomic and gene-level analyses prioritized 21 candidate genes, including ORMDL3, GSDMB, IL18RAP, IL18R1, IL1R1, SMAD3, and CLEC16A. In exploratory functional analyses, enrichment analyses converged on interleukin, cytokine-receptor, JAK-STAT, interleukin-4\/interleukin-13, thymic stromal lymphopoietin, asthma, and lung fibrosis pathways. Exploratory single-cell spatial mapping, based on a mouse embryonic atlas, showed the strongest overall enrichment in the lung annotation, although cross-dataset cell-type and tissue analyses did not reach significance after false discovery rate correction; heritability partitioning implicated conserved and active regulatory elements. These findings support a shared epithelial\u2013immune and cytokine-regulatory genetic architecture across major chronic lung diseases and nominate biologically coherent candidate genes and pathways for future functional and translational studies.<\/jats:p>","DOI":"10.3390\/ijms27156946","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6946","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Multivariate Genomics Identifies Shared Epithelial\u2013Immune and Cytokine-Regulatory Mechanisms Across Major Chronic Lung Diseases"],"prefix":"10.3390","volume":"27","author":[{"given":"Chung-Chih","family":"Liao","sequence":"first","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Integrated Chinese and Western Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke-Ru","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yuanlin Christian Hospital, Changhua 51052, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-8510","authenticated-orcid":false,"given":"Jung-Miao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Chinese Medicine, China Medical University Hospital, Taichung 40447, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/s41591-025-04077-9","article-title":"Global, regional, and national burden of chronic respiratory diseases and impact of the COVID-19 pandemic, 1990\u20132023: A Global Burden of Disease study","volume":"32","author":"Oh","year":"2026","journal-title":"Nat. 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