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Genomic structural equation modeling was employed to identify a shared genetic factor (mvFibroPsych). Lead SNPs and associated genes were annotated using Functional Mapping and Annotation (FUMA), followed by gene-set and tissue enrichment analyses. The Latent Causal Variable (LCV) method was utilized to identify modifiable risk factors and phenotypes influenced by mvFibroPsych. Additionally, brain-wide and proteome-wide Mendelian randomization (MR) analyses were applied to explore brain regions and biomarkers associated with mvFibroPsych. Multi-layer molecular quantitative trait locus (QTL) analyses were conducted for mechanistic insights into mvFibroPsych.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Strong genetic correlations were observed among the four phenotypes (r\n                      <jats:sub>g<\/jats:sub>\n                      \u2009=\u20090.55\u20130.84), with excellent model fit for the common factor [comparative fit index (CFI) = 0.999, standardized root mean square residual (SRMR) = 0.015]. The mvFibroPsych GWAS identified 49 lead SNPs across 43 loci, including 32 novel loci. Gene prioritization revealed 342 protein-coding genes, and pathway analysis indicated enrichment in synaptic function pathway. LCV identified 133 phenotypes causally linked to mvFibroPsych. Brain-wide MR found fractional anisotropy in the splenium of the corpus callosum to be inversely associated with mvFibroPsych. Proteome-wide MR identified five proteins significantly associated with mvFibroPsych, while multi-layer brain QTL analysis prioritized CD40 as a potential target.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provides strong evidence for a shared genetic factor underlying fibromyalgia, insomnia, depression, and anxiety, linked to synaptic function, brain structure integrity, and neuroinflammatory pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pgen.1012034","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T18:52:24Z","timestamp":1769194344000},"page":"e1012034","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Shared latent genetic liability across fibromyalgia and psychiatric 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