{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:43:40Z","timestamp":1791859420610,"version":"4.3.4"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Longevity and muscle strength are heritable traits, and age\u2010related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanisms underlying lifespan and sarcopenia remain unclear. This study aimed to identify genes associated with longevity and muscle weakness and to characterize their shared genetic architecture.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We integrated the largest genome\u2010wide association studies (GWAS) on longevity (age &gt;\u200990th:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200911\u2009262 cases; age &gt;\u200999th:\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093484 cases) and muscle weakness (European Working Group on Sarcopenia in Older People (EWGSOP):\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200948\u2009596 cases; Foundation for the National Institutes of Health (FNIH):\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920\u2009335 cases) with Genotype\u2010Tissue Expression (GTEx) v8 multi\u2010tissue expression quantitative trait locus (eQTL) data. Gene\u2013trait associations were evaluated using multi\u2010tissue and single\u2010tissue TWAS, and validated using Multi\u2010marker Analysis of GenoMic Annotation (MAGMA). Mendelian randomization (MR) and colocalization were applied to test causality and shared variants. Cross\u2010trait genetic correlation was estimated with LDSC, and pleiotropic loci were identified by pleiotropy analysis under the composite null hypothesis (PLACO) followed by Functional Mapping and Annotation (FUMA)\/MAGMA annotation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Across TWAS approaches, APOC1 and TOMM40 were identified as longevity\u2010associated genes, while DYM and TGFA were susceptibility genes for muscle weakness. In MR analysis, higher expression of APOC1 and TOMM40 increased the odds of longevity (OR &gt;\u20091,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), whereas higher expression of DYM and TGFA reduced the risk of muscle weakness (OR &lt;\u20091,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Colocalization supported shared causal variants for APOC1 (rs429358, PP.H4\u2009=\u20090.81) and TOMM40 (rs429358, PP.H4\u2009=\u20090.85) with longevity (age &gt;\u200990th survival percentile), and for DYM and TGFA with muscle weakness defined by both EWGSOP and FNIH (PP.H4\u2009&gt;\u20090.80). A significant negative genetic correlation was observed between longevity and muscle weakness (Rg &lt;\u20090,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Cross\u2010trait pleiotropy analysis identified several pleiotropic genes (PVRL2, PPP1R9A, SLC39A8 and the TOMM40\/APOE\/APOC1 gene cluster) that influence both longevity and muscle weakness.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified susceptibility genes for longevity (APOC1, TOMM40) and muscle weakness (DYM, TGFA) and uncovered shared pleiotropic loci linking aging and muscle decline. These findings improve the understanding of the genetic architecture underlying aging\u2010related phenotypes and provide potential molecular targets for promoting healthy aging and reducing late\u2010life disability.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70197","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T05:55:31Z","timestamp":1769493331000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identifying Susceptibility Genes and Shared Genetic Architecture for Longevity and Muscle Weakness"],"prefix":"10.1002","volume":"17","author":[{"given":"Yilong","family":"Lin","sequence":"first","affiliation":[{"name":"Depeartment of Breast Surgery, the First Affiliated Hospital of Xiamen University School of Medicine, Xiamen University  Xiamen China"},{"name":"School of Medicine Xiamen University  Xiamen 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