Linkage disequilibrium score regression identifies genetic correlations between hepatocellular carcinoma and clinically relevant traits
Hepatocellular carcinoma (HCC) mortality is increasing globally, partly due to the growing prevalence of nonviral liver diseases. Genome-wide 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-development with hepatitis C virus-negative (HCV-negative) 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-negative 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-negative HCC and blood-based 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-negative HCC and diseases associated with metabolic dysfunction-associated 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-based biomarkers identified in this study for inferring HCC development among HCV-negative individuals.
Authors
- Jinyoung Byun (ORCID: https://orcid.org/0000-0001-8579-1435)
- Younghun Han (ORCID: https://orcid.org/0000-0001-5048-8479)
- Yun Shin Chun (ORCID: https://orcid.org/0000-0003-1384-8927)
- Amit G. Singal (ORCID: https://orcid.org/0000-0002-1172-3971)
- Robin Kate Kelley (ORCID: https://orcid.org/0000-0002-1984-2430)
- Catherine Zhu (ORCID: https://orcid.org/0000-0002-4939-515X)
- Rikita Hatia (ORCID: https://orcid.org/0000-0003-2591-5963)
- Sean Patrick Cleary (ORCID: https://orcid.org/0000-0002-5274-9983)
- R. Mark Ghobrial (ORCID: https://orcid.org/0000-0001-6077-9595)
- Roxana Bucur (ORCID: https://orcid.org/0009-0000-4108-8203)
- Christopher Ian Amos (ORCID: https://orcid.org/0000-0002-8540-7023)
- Alison Patricia Klein (ORCID: https://orcid.org/0000-0003-2737-8399)
- Katherine A. McGlynn (ORCID: https://orcid.org/0000-0003-2329-9933)
- Aaron P. Thrift (ORCID: https://orcid.org/0000-0002-0084-5308)
- Jennifer B. Permuth (ORCID: https://orcid.org/0000-0002-4726-9264)
- Mindie H. Nguyen (ORCID: https://orcid.org/0000-0002-6275-4989)
- Lewis R. Roberts (ORCID: https://orcid.org/0000-0001-7885-8574)
- Neehar D. Parikh (ORCID: https://orcid.org/0000-0002-5874-9933)
- Dimpy P. Shah (ORCID: https://orcid.org/0000-0001-9019-8310)
- Ping Chang (ORCID: https://orcid.org/0000-0002-5851-5934)
- Richard D. Kim (ORCID: https://orcid.org/0000-0002-8448-844X)
- Ahmed Omar Kaseb (ORCID: https://orcid.org/0000-0002-9491-0587)
- Jian Gu (ORCID: https://orcid.org/0000-0003-3499-0973)
- Vikram R. Shaw (ORCID: https://orcid.org/0000-0002-1172-5686)
- Paige M. Bracci (ORCID: https://orcid.org/0000-0001-9338-9307)
- Chad D. Huff (ORCID: https://orcid.org/0000-0002-1100-9364)
- Yuko Kono (ORCID: https://orcid.org/0000-0002-9357-4104)
- Anna S. Lok (ORCID: https://orcid.org/0000-0002-5811-6845)
- Prasun K. Jalal (ORCID: https://orcid.org/0000-0001-5353-2324)
- Jian‐Min Yuan (ORCID: https://orcid.org/0000-0002-4620-3108)
- Saira Aijaz Khaderi
- Donghui Li
- J. David Knox
- Asif Rashid
- Lu‐Yu Hwang
- Hui‐Chen Wu
- Hashem El‐Serag
- Manal M. Hassan (ORCID: https://orcid.org/0000-0002-8413-449X)
Institutions
- Mayo Clinic (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of San Diego (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of New Mexico (US)
- City University of New York (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- University of Michigan (US)
- WinnMed (US)
- Princess Margaret Cancer Centre (CA)
- Moffitt Cancer Center (US)
- University of California San Diego (US)
- Stanford Health Care (US)
- Methodist Hospital (US)
- Houston Institute for Clinical Research (US)
- UPMC Hillman Cancer Center (US)
- Stanford Medicine (US)
- National Cancer Institute (US)
- New Mexico Cancer Center (US)
- Pancreas Centre (Canada) (CA)
- Sidney Kimmel Comprehensive Cancer Center (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Mays Cancer Center at UT Health San Antonio (US)
- Division of Cancer Epidemiology and Genetics
- Columbia University (US)
- The University of Texas Southwestern Medical Center (US)
- The University of Texas Health Science Center at Houston (US)
- Stanford University (US)
Publication Details
- Journal
- International Journal of Cancer
- Published
- 2025-09-27
- DOI
- https://doi.org/10.1002/ijc.70136
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health