{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T16:05:28Z","timestamp":1792166728722,"version":"4.4.0"},"reference-count":67,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["T32 MH016880"],"award-info":[{"award-number":["T32 MH016880"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["R01 DA046064"],"award-info":[{"award-number":["R01 DA046064"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction"],"published-print":{"date-parts":[[2026,7]]},"abstract":"Abstract<\/jats:title>\n \n Background and aims<\/jats:title>\n Chronic pain and substance use disorders frequently co\u2010occur and may share general addiction\u2010related and substance\u2010specific genetic pathways. Additionally, substance consumption and problematic use may differ in their genetic associations with pain subtypes. We applied genomic structural equation modeling to assess shared genetic and neurological enrichment between general and musculoskeletal\u2010specific chronic pain to general addiction liability, substance use disorder\u2010specific risk and substance use.<\/jats:p>\n <\/jats:sec>\n \n Design<\/jats:title>\n Cross\u2010trait genomic structural equation modeling using genome\u2010wide association study (GWAS) summary statistics from large\u2010scale global consortia.<\/jats:p>\n <\/jats:sec>\n \n Setting<\/jats:title>\n Data were aggregated from international research collaborations and biobanks in the United States and Europe.<\/jats:p>\n <\/jats:sec>\n \n Participants<\/jats:title>\n \n Participants were individuals (\n n<\/jats:italic>\n \u2009=\u200963\u2009982 to 2\u2009428\u2009851) with European\u2010like ancestry from population\u2010based and clinical cohorts.\n <\/jats:p>\n <\/jats:sec>\n \n Measurements<\/jats:title>\n We analyzed a General Chronic Pain factor from 24 chronic pain GWASs and a Musculoskeletal\u2010specific Pain factor from 11 overlapping conditions. We constructed an Addiction factor from GWASs of alcohol, tobacco, cannabis and opioid use disorders, and partitioned out substance\u2010specific genetic risk. We used alcohol and smoking consumption GWASs to distinguish use from problematic use. We applied molecular neurological annotations to assess brain cell type enrichment in shared genetic effects.<\/jats:p>\n <\/jats:sec>\n \n Findings<\/jats:title>\n \n The Addiction factor was genetically correlated with General Chronic Pain [genetic correlation (\n r<\/jats:italic>\n g<\/jats:sub>\n )\n _<\/jats:sub>\n \u2009=\u20090.448, false discovery rate (FDR)\u2010corrected\n P<\/jats:italic>\n \u2009<\u20090.001, 95% confidence interval (95% CI)\u2009=\u20090.40, 0.49], but not with Musculoskeletal\u2010specific Pain (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u20090.001, FDR\u2010corrected\n P<\/jats:italic>\n \u2009=\u20090.998, 95% CI\u2009=\u2009\u22120.07 to 0.07). Controlling for Addiction, General Pain had substance\u2010specific associations: negative correlations with Problematic Alcohol Use (\n r<\/jats:italic>\n g<\/jats:sub>\n \u00a0=\u2009\u22120.155, FDR\u2010corrected\n P<\/jats:italic>\n \u2009=\u20090.049, 95% CI\u2009=\u2009\u22120.28 to \u22120.02) and Alcohol Frequency (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u2009\u22120.334, FDR\u2010corrected\n P<\/jats:italic>\n \u2009<\u20090.001, 95% CI\u2009=\u2009\u22120.46 to \u22120.21), and a positive correlation with Cigarette Frequency (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u20090.274, FDR\u2010corrected\n P<\/jats:italic>\n \u2009<\u20090.001, 95% CI\u2009=\u20090.21, 0.34). Musculoskeletal\u2010specific Pain positively associated with Tobacco Use Disorder (\n r<\/jats:italic>\n g<\/jats:sub>\n \u00a0=\u00a00.186, FDR\u2010corrected\n P<\/jats:italic>\n \u2009=\u20090.020, 95% CI\u2009=\u20090.05, 0.32) and Alcohol Frequency (\n r<\/jats:italic>\n g<\/jats:sub>\n \u2009=\u20090.161, FDR\u2010corrected\n P<\/jats:italic>\n \u2009=\u20090.049, 95% CI\u2009=\u20090.02, 0.30). General Pain related to Cannabis Use Disorder and Opioid Use Disorder entirely through the Addiction factor. Shared genetic components were enriched in excitatory and inhibitory neurons, glia and endothelial cells.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n General chronic pain appears to share substantial genetic overlap and neuronal enrichment with addiction risk and shows distinct associations with problematic alcohol use, alcohol consumption and cigarette use, reflecting both a broad transdiagnostic mechanism as well as substance\u2010specific paths. In contrast, musculoskeletal\u2010specific pain appears to be more narrowly linked to tobacco use disorder and alcohol use frequency, but not to general addiction liability.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/add.70387","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T04:52:40Z","timestamp":1773809560000},"page":"1683-1698","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic overlap of chronic pain, musculoskeletal\u2010specific pain, substance use disorders and substance use consumption: Common addiction and substance\u2010specific effects"],"prefix":"10.1111","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2290-7653","authenticated-orcid":false,"given":"Lydia","family":"Rader","sequence":"first","affiliation":[{"name":"Institute for Behavioral Genetics University of Colorado Boulder Boulder CO 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D.","family":"Wager","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences Dartmouth College Hanover NH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi P.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Institute for Behavioral Genetics University of Colorado Boulder Boulder CO USA"},{"name":"Department of Psychology & Neuroscience University of Colorado Boulder Boulder CO 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