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In this study, we analyzed TMFI measured by magnetic resonance imaging in 55,120 UK Biobank participants and found that higher TMFI was significantly associated with all\u2010cause mortality as well as with all major system\u2010specific diseases examined (\n                    <jats:italic>p<\/jats:italic>\n                    values ranged from 2.50\u2009\u00d7\u200910\n                    <jats:sup>\u221288<\/jats:sup>\n                    to 9.97\u2009\u00d7\u200910\n                    <jats:sup>\u221204<\/jats:sup>\n                    ). TMFI also mediated the effects of lifestyle factors on health\u2010related outcomes, with mediation proportions ranging from 6.7% to 71.7%. A genome\u2010wide association study (GWAS) identified 79 lead single nucleotide polymorphisms (SNPs) linked to TMFI, and the polygenic risk score for TMFI was significantly associated with mortality and all incident diseases across examined organ systems in an independent subset of UK Biobank participants of European ancestry who were not included in the TMFI GWAS (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009362,286, all\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). Gene\u2013drug interactions identified multiple drugs that could potentially modulate TMFI. Analysis of single\u2010cell transcriptomic data indicated that myogenic cells were strongly linked to TMFI (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20097.08\u2009\u00d7\u200910\n                    <jats:sup>\u221208<\/jats:sup>\n                    ). Summary\u2010data\u2010based Mendelian randomization and Transcriptome\u2010Wide Association Study analyses revealed numerous genes whose expression in specific tissues was associated with TMFI. Proteomic and metabolomic profiling uncovered a broad array of circulating biomarkers associated with TMFI, many of which mediated the effects of modifiable factors and genetic risk on TMFI. Overall, our results highlight the biological relevance of TMFI to human health and provide insights into the multi\u2010omics mechanisms underlying TMFI, identifying potential targets for interventions.\n                  <\/jats:p>","DOI":"10.1111\/acel.70690","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:58:17Z","timestamp":1788235097000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Analysis Uncover the Effects and Multi\u2010Omics Features of Thigh Muscle Fat Infiltration"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4802-6602","authenticated-orcid":false,"given":"Yiwei","family":"Zhang","sequence":"first","affiliation":[{"name":"Clinical Research Center Zhujiang Hospital, Southern Medical University  Guangzhou Guangdong 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