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Genome\u2010wide association studies (GWAS) have identified genetic variants associated with HCC development. Leveraging GWAS summary statistics and linkage disequilibrium score regression (LDSR), we investigated disease co\u2010development with hepatitis C virus\u2010negative (HCV\u2010negative) HCC to provide unique insights into HCC etiology and prioritize relationships for further causal inquiry. We utilized the LDSR statistical framework to estimate the genetic correlation and heritability between HCV\u2010negative HCC with 901 epidemiologic, behavioral, and clinical traits from the United Kingdom Biobank (UKBB). First, we set the threshold for observed scale heritability of each trait at 0.02 to ensure reliable inferences with adequate study power. Next, we observed significant positive genetic correlations between HCV\u2010negative HCC and blood\u2010based biomarkers of liver injury (ALT, GGT) and allostatic load (including glycated hemoglobin, blood pressure, and total albumin). We also identified a positive genetic correlation between HCV\u2010negative HCC and diseases associated with metabolic dysfunction\u2010associated steatotic liver disease (MASLD), including diabetes, hypertension, chronic ischemic heart disease, and others. Taken together, our results help to identify polygenic and pleiotropic signals related to different phenotypic traits associated with HCC and support further exploration of the predictive power of blood\u2010based biomarkers identified in this study for inferring HCC development among HCV\u2010negative individuals.<\/jats:p>","DOI":"10.1002\/ijc.70136","type":"journal-article","created":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T07:03:36Z","timestamp":1758956616000},"page":"1193-1203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits"],"prefix":"10.1002","volume":"158","author":[{"given":"Younghun","family":"Han","sequence":"first","affiliation":[{"name":"Institute for Clinical and Translational Research Baylor College of Medicine  Houston Texas USA"},{"name":"Comprehensive Cancer Center University of New Mexico  Albuquerque New Mexico USA"},{"name":"Department of Medicine Baylor College of Medicine  Houston Texas USA"},{"name":"Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1172-5686","authenticated-orcid":false,"given":"Vikram R.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Research Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8579-1435","authenticated-orcid":false,"given":"Jinyoung","family":"Byun","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Research Baylor College of Medicine  Houston Texas USA"},{"name":"Comprehensive Cancer Center University of New Mexico  Albuquerque New Mexico USA"},{"name":"Department of Medicine Baylor College of Medicine  Houston Texas USA"},{"name":"Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0084-5308","authenticated-orcid":false,"given":"Aaron P.","family":"Thrift","sequence":"additional","affiliation":[{"name":"Department of Medicine Baylor College of Medicine  Houston Texas USA"},{"name":"Dan L Duncan Comprehensive Cancer Center Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Translational Research Baylor College of Medicine  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghui","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikita I.","family":"Hatia","sequence":"additional","affiliation":[{"name":"Department of Epidemiology The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin Kate","family":"Kelley","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean P.","family":"Cleary","sequence":"additional","affiliation":[{"name":"Division of Hepatobiliary &amp; 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