{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:30:03Z","timestamp":1787567403625,"version":"build-2736575974"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T00:00:00Z","timestamp":1787529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (\n                      <jats:italic>ADH1A, ADH1B, ADH4, ADH6<\/jats:italic>\n                      ) and\n                      <jats:italic>ZNF827<\/jats:italic>\n                      , which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of\n                      <jats:italic>ZNF827<\/jats:italic>\n                      in TAA and\n                      <jats:italic>ADH6<\/jats:italic>\n                      in AAA at both mRNA and protein levels, corroborating the genetic predictions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1795141","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:10:16Z","timestamp":1787562616000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm"],"prefix":"10.3389","volume":"13","author":[{"given":"Hanxi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University","place":["Yiwu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Center for Regeneration and Aging Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University","place":["Yiwu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Jinhua Hospital Affiliated to Zhejiang University","place":["Jinhua, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Jin","sequence":"additional","affiliation":[{"name":"The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Futian Campus","place":["Yiwu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Vascular Surgery, The Second Hospital of Yinzhou District","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e37","DOI":"10.1161\/ATVBAHA.120.313991","article-title":"Aortic aneurysms and dissections series","volume":"40","author":"Shen","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e023601","DOI":"10.1161\/JAHA.121.023601","article-title":"Vascular smooth muscle cells in aortic aneurysm: from genetics to mechanisms","volume":"10","author":"Lu","year":"2021","journal-title":"J Am Heart 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