{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:58:53Z","timestamp":1792112333959,"version":"4.4.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,21]],"date-time":"2024-04-21T00:00:00Z","timestamp":1713657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2703101"],"award-info":[{"award-number":["2022YFC2703101"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971188"],"award-info":[{"award-number":["81971188"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014718","name":"Innovative Research Group Project of the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371422"],"award-info":[{"award-number":["82371422"]}],"id":[{"id":"10.13039\/100014718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2024,8]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We integrated druggable genome data, cis\u2010eQTL\/cis\u2010pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia\u2010related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome\u2010wide MR (Phe\u2010MR) approach and investigated actionable drugs for target genes using available databases.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (\n HP<\/jats:italic>\n ,\n HLA\u2010DRA<\/jats:italic>\n ,\n MAP 3K3<\/jats:italic>\n ,\n MFGE8<\/jats:italic>\n ,\n COL15A1<\/jats:italic>\n , and\n AURKA<\/jats:italic>\n ) were further confirmed by Bayesian colocalization (PPH4\u00a0>\u00a090%). The up\u2010regulation of\n HP<\/jats:italic>\n [higher ALM (beta: 0.012, 95% CI: 0.007\u20130.018,\n P<\/jats:italic>\n \u00a0=\u00a01.2*10\n \u22125<\/jats:sup>\n ) and higher grip strength (OR: 0.96, 95% CI: 0.94\u20130.98,\n P<\/jats:italic>\n \u00a0=\u00a04.2*10\n \u22125<\/jats:sup>\n )],\n MAP 3K3<\/jats:italic>\n [higher ALM (beta: 0.24, 95% CI: 0.21\u20130.26,\n P<\/jats:italic>\n \u00a0=\u00a01.8*10\n \u221294<\/jats:sup>\n ), higher grip strength (OR: 0.82, 95% CI: 0.75\u20130.90,\n P<\/jats:italic>\n \u00a0=\u00a02.1*10\n \u22125<\/jats:sup>\n ), and faster walking pace (beta: 0.03, 95% CI: 0.02\u20130.05,\n P<\/jats:italic>\n \u00a0=\u00a08.5*10\n \u22126<\/jats:sup>\n )], and\n MFGE8<\/jats:italic>\n [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06\u20130.11,\n P<\/jats:italic>\n \u00a0=\u00a06.1*10\n \u221213<\/jats:sup>\n ; blood pQTL, beta: 0.05, 95% CI: 0.03\u20130.07,\n P<\/jats:italic>\n \u00a0=\u00a03.8*10\n \u221209<\/jats:sup>\n )], as well as the down\u2010regulation of\n HLA\u2010DRA<\/jats:italic>\n [lower ALM (beta: \u20100.09, 95% CI: \u22120.11 to \u22120.08,\n P<\/jats:italic>\n \u00a0=\u00a05.4*10\n \u221236<\/jats:sup>\n ) and lower grip strength (OR: 1.13, 95% CI: 1.07\u20131.20,\n P<\/jats:italic>\n \u00a0=\u00a01.8*10\n \u22125<\/jats:sup>\n )] and\n COL15A1<\/jats:italic>\n [higher ALM (muscle eQTL, beta: \u20100.07, 95% CI: \u22120.10 to \u22120.04,\n P<\/jats:italic>\n \u00a0=\u00a03.4*10\n \u221207<\/jats:sup>\n ; blood pQTL, beta: \u20100.05, 95% CI: \u22120.06 to \u22120.03,\n P<\/jats:italic>\n \u00a0=\u00a01.6*10\n \u221207<\/jats:sup>\n )], decreased the risk of sarcopenia.\n AURKA<\/jats:italic>\n in blood (beta: \u20100.16, 95% CI: \u22120.22 to \u22120.09,\n P<\/jats:italic>\n \u00a0=\u00a02.1*10\n \u221206<\/jats:sup>\n ) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05,\n P<\/jats:italic>\n \u00a0=\u00a05.3*10\n \u221205<\/jats:sup>\n ) tissues showed an inverse relationship with sarcopenia risk. The Phe\u2010MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase\n \n clostridium histolyticum<\/jats:italic>\n <\/jats:styled-content>\n might be potential therapeutics for sarcopenia by activating\n HP<\/jats:italic>\n and inhibiting\n COL15A1<\/jats:italic>\n , respectively.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Our research indicated\n MAP 3K3<\/jats:italic>\n ,\n MFGE8<\/jats:italic>\n ,\n COL15A1<\/jats:italic>\n ,\n HP<\/jats:italic>\n , and\n HLA\u2010DRA<\/jats:italic>\n may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase\n \n clostridium histolyticum<\/jats:italic>\n <\/jats:styled-content>\n for sarcopenia requires further validation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/jcsm.13479","type":"journal-article","created":{"date-parts":[[2024,4,21]],"date-time":"2024-04-21T22:34:46Z","timestamp":1713738886000},"page":"1324-1334","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Systematic druggable genome\u2010wide Mendelian randomization identifies therapeutic targets for sarcopenia"],"prefix":"10.1002","volume":"15","author":[{"given":"Kang\u2010Fu","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Neurology, West China Hospital Sichuan University Chengdu China"},{"name":"Institute of Brain Science and Brain\u2010Inspired Technology, West China Hospital Sichuan University Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, West China Hospital Sichuan University Chengdu China"},{"name":"Institute of Brain Science 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