Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses

Younghun Han^{1

2

3}, Jinyoung Byun^{1

2

3}, Caitlin J VanLith^{4

5

6}, Matthew A Cooley^{4

6}, Vikram R Shaw², Rikita I Hatia⁷, Fowsiyo Y Ahmed⁴, Nasra H Giama⁴, Hawa M Ali⁴, Nellie A Campbell⁴, Mohamed Hassan⁴, Jesper B Andersen⁸, Victor Ankoma-Sey⁹, Jesus M Banales^{10

11}, Luis Bujanda¹⁰, Oliver F Bathe¹², Tanios S Bekaii-Saab¹³, Mitesh J Borad¹³, Niklas K Björkström¹⁴, Carlos H F Chan¹⁵, Sean P Cleary¹⁶, Martin Cornillet¹⁴, Trine Folseraas¹⁷, Peter R Galle¹⁸, Jeanine M Genkinger^{19

20}, Robert J MacInnis^{21

22}, Gregory J Gores⁴, Lipika Goyal²³, Richard S Houlston²⁴, Sumera I Ilyas⁴, Milind Javle²⁵, Julia S Johansen²⁶, Troels D Christensen²⁶, Ashwin S Kamath²⁷, Robin Kate Kelley²⁸, Shahid A Khan²⁹, Richard D Kim³⁰, Sandi A Kwee³¹, Angela Lamarca^{32

33

34}, Frank Lammert³⁵, Nicholas F LaRusso⁴, Stacie Lindsey³⁶, Rocio I R Macias³⁷, Harmeet Malhi⁴, Tushar C Patel³⁸, Jennifer B Permuth^{29

39}, Helen L Reeves⁴⁰, Stephen Rossi⁴¹, William Sanchez⁴, Rory L Smoot⁴², Anthony J Swerdlow⁴³, Hop S Tran Cao⁴⁴, Juan W Valle^{36

34}, Arndt Weinmann¹⁸, Julia Weinmann-Menke¹⁸, Linda L Wong³¹, Xuehong Zhang^{45

46

47}, Vincent Zimmer⁴⁸, Andrew X Zhu^{49

50}, Konstantinos N Lazaridis⁴, Brian D Juran⁴, Prasun Jalal⁵¹, Jennifer J Knox⁵², Amy Hutchinson⁵³, Belynda Hicks⁵³, Jill E Koshiol⁵³, Stephen J Chanock⁵³, Manal M Hassan⁷, Christopher I Amos^{1

2

3}, Katherine A McGlynn⁵³, Lewis R Roberts⁴

Affiliations

¹ University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA.
² Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
⁴ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
⁵ Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, USA.
⁶ Mayo Clinic Graduate Program in Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, USA.
⁷ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁸ Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Liver Associates of Texas, Houston, Texas, USA.
¹⁰ Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain.
¹¹ Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
¹² Departments of Surgery and Oncology, University of Calgary; Arnie Charbonneau Cancer Institute, Calgary, Alberta, Canada.
¹³ Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, USA.
¹⁴ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
¹⁵ Division of Surgical Oncology, Department of Surgery, University of Iowa, Iowa City, Iowa, USA.
¹⁶ Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Transplantation Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital, Oslo, Norway.
¹⁸ Department of Internal Medicine I, University Medical Center of Mainz, Mainz, Germany.
¹⁹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
²⁰ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
²¹ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia.
²² Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.
²³ Department of Medicine, Stanford University, Palo Alto, California, USA.
²⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
²⁵ Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁶ Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark.
²⁷ Allina Health Cancer Institute, Minneapolis, Minnesota, USA.
²⁸ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
²⁹ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
³⁰ Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
³¹ University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
³² Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
³³ Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
³⁴ Division of Cancer Sciences, University of Manchester, Manchester, UK.
³⁵ Centre for Health Economics Research Hannover (CHERH), Hannover Medical School, Hannover, and Saarland University Medical Center, Homburg, Germany.
³⁶ Cholangiocarcinoma Foundation, Salt Lake City, Utah, USA.
³⁷ Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain.
³⁸ Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.
³⁹ Department of Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
⁴⁰ Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
⁴¹ PSC Partners Seeking a Cure, Greenwood Village, Colorado, USA.
⁴² Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA.
⁴³ Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁴⁴ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴⁵ Yale School of Nursing, Orange, Connecticut, USA.
⁴⁶ Department of Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
⁴⁷ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴⁸ Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
⁴⁹ Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁰ Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
⁵¹ Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA.
⁵² Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
⁵³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

PMID: 41627892
DOI: 10.1097/HEP.0000000000001699

Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses

Younghun Han et al. Hepatology. 2026.

. 2026 Feb 2.

doi: 10.1097/HEP.0000000000001699. Online ahead of print.

Authors

Affiliations

¹ University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA.
² Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas, USA.
³ Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.
⁴ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
⁵ Mayo Clinic Medical Scientist Training Program, Mayo Clinic College of Medicine and Science, Mayo Clinic, Rochester, Minnesota, USA.
⁶ Mayo Clinic Graduate Program in Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, USA.
⁷ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁸ Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹ Liver Associates of Texas, Houston, Texas, USA.
¹⁰ Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain.
¹¹ Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
¹² Departments of Surgery and Oncology, University of Calgary; Arnie Charbonneau Cancer Institute, Calgary, Alberta, Canada.
¹³ Division of Hematology and Medical Oncology, Mayo Clinic in Arizona, Phoenix, Arizona, USA.
¹⁴ Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
¹⁵ Division of Surgical Oncology, Department of Surgery, University of Iowa, Iowa City, Iowa, USA.
¹⁶ Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
¹⁷ Department of Transplantation Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital, Oslo, Norway.
¹⁸ Department of Internal Medicine I, University Medical Center of Mainz, Mainz, Germany.
¹⁹ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.
²⁰ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA.
²¹ Cancer Epidemiology Division, Cancer Council Victoria, East Melbourne, Victoria, Australia.
²² Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, Victoria, Australia.
²³ Department of Medicine, Stanford University, Palo Alto, California, USA.
²⁴ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
²⁵ Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²⁶ Department of Oncology, Copenhagen University Hospital-Herlev and Gentofte, Copenhagen, Denmark.
²⁷ Allina Health Cancer Institute, Minneapolis, Minnesota, USA.
²⁸ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USA.
²⁹ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
³⁰ Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
³¹ University of Hawai'i Cancer Center, Honolulu, Hawaii, USA.
³² Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
³³ Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
³⁴ Division of Cancer Sciences, University of Manchester, Manchester, UK.
³⁵ Centre for Health Economics Research Hannover (CHERH), Hannover Medical School, Hannover, and Saarland University Medical Center, Homburg, Germany.
³⁶ Cholangiocarcinoma Foundation, Salt Lake City, Utah, USA.
³⁷ Experimental Hepatology and Drug Targeting (HEVEPHARM), IBSAL, University of Salamanca, Salamanca, Spain.
³⁸ Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA.
³⁹ Department of Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
⁴⁰ Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
⁴¹ PSC Partners Seeking a Cure, Greenwood Village, Colorado, USA.
⁴² Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA.
⁴³ Division of Genetics and Epidemiology and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁴⁴ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴⁵ Yale School of Nursing, Orange, Connecticut, USA.
⁴⁶ Department of Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
⁴⁷ Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
⁴⁸ Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
⁴⁹ Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁰ Jiahui International Cancer Center, Jiahui Health, Shanghai, China.
⁵¹ Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA.
⁵² Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
⁵³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

PMID: 41627892
DOI: 10.1097/HEP.0000000000001699

Abstract

Background and aims: Cholangiocarcinoma (CCA) is a rare but aggressive malignancy with poorly understood genetic susceptibility. To date, genome-wide association studies (GWAS) investigating germline variants associated with CCA risk remain limited. We aimed to identify genetic risk loci for CCA and its clinical subtypes through comprehensive GWAS and post-GWAS analyses.

Approach and results: We conducted a GWAS of 2366 CCA cases and 11,750 controls of European ancestry. Genome-wide significant loci ( p <5×10 -8 ) were identified and further examined through fine-mapping, functional annotation, and HLA imputation. Subgroup analyses were conducted by CCA subtypes and primary sclerosing cholangitis (PSC) status. Cross-trait linkage disequilibrium score regression and Mendelian randomization were employed to investigate the shared genetic architecture and potential causal relationships with a diverse range of traits. We identified 1 new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and 2 variants associated with extrahepatic CCA: rs116224263 (OR=0.17) in LINC02506 at 4p15.1 and rs6914950 (OR=1.63) near HLA-DRB1/DQB1 . Stratified analyses revealed rs2395184 (OR=3.51) near HLA-DRA/DRB5 associated with PSC-related CCA, and rs142674434 (OR=2.98) in THSD7A at 7p21.3 associated with non-PSC-related CCA. HLA imputation uncovered new amino acid residues associated with disease risk. Cross-trait analyses identified shared genetic signals between CCA and anthropometric, lipidemic, lifestyle, and medical traits. Mendelian randomization supported putative causal associations for 12 traits with CCA or its subtypes.

Conclusions: Our large-scale GWAS highlights new genetic variants and HLA-linked mechanisms underlying CCA susceptibility. Integrating multi-step post-GWAS approaches enhances understanding of CCA pathogenesis and may facilitate the development of risk biomarkers for early detection and precision prevention strategies.

Keywords: cholangiocarcinoma; extrahepatic cholangiocarcinoma; genome-wide association study; intrahepatic cholangiocarcinoma; primary sclerosing cholangitis.

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References

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Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses

Affiliations

Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses

Authors

Affiliations

Abstract

References

LinkOut - more resources

Full Text Sources

Research Materials