{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:10:37Z","timestamp":1790255437860,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,1]],"date-time":"2025-02-01T00:00:00Z","timestamp":1738368000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472478"],"award-info":[{"award-number":["82472478"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102317"],"award-info":[{"award-number":["82102317"]}],"id":[{"id":"10.13039\/501100001809","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":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sarcopenia severely affects the physical health of the elderly. Currently, there is no specific drug available for sarcopenia. This study aims to identify pathogenic proteins and druggable targets for sarcopenia through Mendelian randomization (MR)\u2013based analytical framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A sequential stepwise screening method that includes two\u2010sample MR, Steiger filtering test and colocalization (MRSC) was applied to identify causal proteins associated with sarcopenia\u2010related traits. In the MR analyses, 4372 circulating proteins with valid instrumental variables (IVs) from eight proteomic genome\u2010wide association studies were utilized as exposures, and nine sarcopenia\u2010related traits were utilized as outcomes. IVs were classified into cis\u2013protein quantitative trait loci (pQTLs) and trans\u2010pQTLs based on their positions. We conducted cis\u2010only MRSC analyses and cis\u2009+\u2009trans MRSC analyses using cis\u2010pQTLs and cis\u2009+\u2009trans pQTLs as IVs, respectively. Post\u2010MRSC analyses were conducted on the prioritized findings of MRSC, including annotation of protein\u2010altering variants (PAVs), assessment of overlap between pQTLs and expression quantitative trait loci (eQTLs), protein\u2013protein interaction (PPI) analysis, pathway enrichment analysis and annotation of drug targets. Utilizing data from the UK Biobank, we performed an observational study to explore the associations between baseline circulating protein levels and the longitudinal changes in nine sarcopenia\u2010related traits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 181 causal associations for 65 proteins were prioritized by the cis\u2010only MRSC analyses and 227 associations for 91 proteins were prioritized by the cis\u2009+\u2009trans MRSC analyses. Among the prioritized proteins, the majority of them employed non\u2010PAVs as IVs and most of their cis\u2010pQTLs overlapped with corresponding eQTLs and exhibited consistent directionality, with only one trans\u2010pQTL overlapping with an eQTL. The PPI network of cis\u2010only MRSC\u2010prioritized proteins (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20094.04\u2009\u00d7\u200910\n                      <jats:sup>\u22124<\/jats:sup>\n                      ) and cis\u2009+\u2009trans MRSC\u2010prioritized proteins (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20098.76\u2009\u00d7\u200910\n                      <jats:sup>\u22125<\/jats:sup>\n                      ) showed significantly more interactions than expected. Reactome, KEGG and GO pathway enrichment analyses for cis\u2010only MRSC\u2010prioritized proteins identified 52, 12 and 79 enriched pathways, respectively (adjusted\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). For proteins identified by cis\u2009+\u2009trans MRSC analyses, only 15 pathways were enriched through the GO pathway enrichment analyses. In the observational study, 197 circulating proteins were identified to be associated with one or more sarcopenia\u2010related traits (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05\/2923). Among them, the significant associations of CTSB (negative association) and ASGR1 (positive association) with sarcopenia\u2010related traits were observed to have consistent directional associations in both MR\u2010based studies and observational studies. Drug target annotations suggested that 52 MRSC\u2010prioritized proteins and 145 biomarkers are drug targets or druggable.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identified 89 potential pathogenic proteins and 197 candidate biomarkers for sarcopenia, providing valuable clues for the development of therapeutic drugs for sarcopenia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13720","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T02:18:51Z","timestamp":1739499531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Association Analysis of the Circulating Proteome With Sarcopenia\u2010Related Traits Reveals Potential Drug Targets for Sarcopenia"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8011-0493","authenticated-orcid":false,"given":"Simin","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Guangzhou First People's Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Clinical Research Centre, the Second Affiliated Hospital, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Guangzhou First People's Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Clinical Research Centre, the Second Affiliated Hospital, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xizeng","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Guangzhou First People's Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Clinical Research Centre, the Second Affiliated Hospital, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifeng","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Guangzhou First People's Hospital Guangzhou Medical University  Guangzhou China"},{"name":"Clinical Research Centre, the Second Affiliated Hospital, School of Medicine South China University of Technology  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wende","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Guangzhou First People's Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weipeng","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Guangzhou First People's Hospital Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Cen","sequence":"additional","affiliation":[{"name":"Clinical Research Centre, Zhujiang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaohua","family":"Zhu","sequence":"additional","affiliation":[{"name":"Clinical Research Centre, Zhujiang Hospital Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Population and Public Health Sciences, Keck School of Medicine University of Southern California  Los Angeles California 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