{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T04:05:29Z","timestamp":1784261129434,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Traditional Chinese Medicine Heritage Inheritance \u201cNew 3 + 3\u201d Program","award":["2023-SZ-F-17"],"award-info":[{"award-number":["2023-SZ-F-17"]}]},{"name":"Capacity Enhancement Project of Xiyuan Hospital, China Academy of Chinese Medical Sciences","award":["XYZX0101-36"],"award-info":[{"award-number":["XYZX0101-36"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Depression-related liability is frequently accompanied by reduced physical function, yet the shared genetic architecture linking mood-related traits and physical-function decline remains incompletely characterized. Methods: We applied genomic structural equation modeling to European-ancestry GWAS summary statistics for five constituent phenotypes: depressive symptoms, depression diagnosis, grip strength, appendicular lean mass, and walking pace. A Depression\u2013Physical Function shared genetic factor was constructed as a cross-trait genetic covariance dimension and evaluated using LDSC-based validation and leave-one-trait-out sensitivity analyses. We then performed factor GWAS, FUMA locus annotation, Bayesian fine-mapping, MAGMA gene-based analysis, transcriptome-wide association analysis, pathway enrichment, CELLECT\/MAGMA cell-type specificity analysis, partitioned heritability analysis, and gsMap spatial transcriptomic mapping. Results: The shared factor showed good model fit and retained 755,397 quality-controlled variants for downstream analysis. The factor was positively genetically correlated with depression-related traits and negatively correlated with physical-function-related traits. FUMA identified 245 genome-wide significant SNPs, 44 lead SNPs, and 38 genomic risk loci, with 127 positional mapped genes. Fine-mapping prioritized one high-confidence locus. MAGMA identified 19 Bonferroni-significant genes and 326 FDR-significant genes, while TWAS identified 322 FDR-significant expression-associated genes. Integrating FUMA positional mapping, MAGMA gene-level association and TWAS expression-level association prioritized eight convergent genes: TMEM106B, CENPW, DRD2, LRFN5, NCAPG, DCAF16, SGIP1, and FAM120A. Functional enrichment highlighted postsynaptic structure, neuron spine, synaptic plasticity, and synapse organization. CELLECT\/MAGMA prioritized brain non-myeloid neurons and glial populations, with additional endocrine-metabolic and immune-hematopoietic signals. Spatial transcriptomic mapping localized top signals to brain and spinal cord regions in the embryonic neuro-muscle reference. Partitioned heritability analysis showed enrichment in conserved, intronic, promoter, and chromatin-related genomic annotations. Conclusions: These findings support a shared polygenic covariance dimension linking depression-related liability with reduced physical-function-related genetic propensity. Downstream analyses prioritized candidate loci, genes, and biological contexts, with enrichment patterns consistent with neuronal, synaptic, and regulatory genomic processes.<\/jats:p>","DOI":"10.3390\/genes17070813","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:12:38Z","timestamp":1784257958000},"page":"813","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multilayer Genomic Characterization of a Shared Genetic Factor Linking Depression-Related Liability and Reduced Physical Function"],"prefix":"10.3390","volume":"17","author":[{"given":"Wen","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiupeng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonggang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"c4467","DOI":"10.1136\/bmj.c4467","article-title":"Objectively measured physical capability levels and mortality: Systematic review and meta-analysis","volume":"341","author":"Cooper","year":"2010","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41572-023-00454-1","article-title":"Major depressive disorder","volume":"9","author":"Marx","year":"2023","journal-title":"Nat. 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