{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T09:47:28Z","timestamp":1782812848963,"version":"3.54.5"},"reference-count":49,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication driven by inflammatory cascades. Current genetic studies are restricted to single-trait analyses that cannot capture the shared genetic architecture spanning from immune dysregulation to structural myocardial damage. Methods: We applied genomic structural equation modeling to integrate genome-wide association study (GWAS) summary statistics for six phenotypes\u2014sepsis, cardiac troponin I, left ventricular ejection fraction (LVEF), left ventricular diastolic strain rate, right ventricular peak ejection rate, and heart failure\u2014constructing a latent factor for the shared genetic basis of SICM-related phenotypes. Downstream analyses included multivariate GWAS, fine-mapping (SuSiE\/FINEMAP), sparse canonical correlation analysis-based transcriptome-wide association study (sCCA-TWAS) with FOCUS prioritization, MAGMA gene-set enrichment, cell-type enrichment (CELLECT), spatial transcriptomic mapping (gsMap), and stratified LD score regression (S-LDSC). Results: The model showed adequate fit (CFI = 0.936), with left ventricular diastolic strain rate and LVEF anchoring the factor most strongly (\u03bb = 0.811 and 0.636, respectively). Multivariate GWAS identified 4220 lead variants, of which 4197 did not reach genome-wide significance in any constituent single-trait GWAS. Cross-referencing sCCA-TWAS with FOCUS fine-mapping prioritized 39 genes spanning inflammatory transduction, gap junction remodeling, proteostatic defense, and energy sensing. AMPK signaling was recurrently captured across fine-mapping and transcriptome-wide analyses. CELLECT identified cardiac muscle cells as the sole significant cell type. Conclusions: This study provides the first integrative multi-trait genetic framework for the shared genetic basis of SICM-related phenotypes, identifying AMPK as a recurrently captured pleiotropic hub at the inflammation\u2013metabolism intersection and providing a foundation for future biomarker and mechanistic investigations.<\/jats:p>","DOI":"10.3390\/genes17070751","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:26:15Z","timestamp":1782807975000},"page":"751","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic Structural Equation Modeling Reveals Shared Genetic Architecture and Pleiotropic Hub Genes of Sepsis-Induced Cardiomyopathy"],"prefix":"10.3390","volume":"17","author":[{"given":"Min","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The First Clinical Medical College of Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Yu","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Long","sequence":"additional","affiliation":[{"name":"The Second Clinical Medical College, Nanchang University, Nanchang 330006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The First Clinical Medical College of Anhui Medical University, Hefei 230032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and Septic Shock","volume":"392","author":"Cecconi","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1016\/j.chest.2025.08.013","article-title":"Sepsis-Induced Cardiomyopathy: Mechanism, Prevalence, Assessment, Prognosis, and Management","volume":"168","author":"Sato","year":"2025","journal-title":"Chest"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1186\/s13054-022-04208-5","article-title":"A Genome-Wide Association Study of Survival in Patients with Sepsis","volume":"26","author":"Corrales","year":"2022","journal-title":"Crit. 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