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

Younghun Han; Jinyoung Byun; Caitlin J. VanLith; Matthew A. Cooley; Vikram R. Shaw; Rikita I. Hatia; Fowsiyo Y. Ahmed; Nasra H. Giama; Hawa M. Ali; Nellie A. Campbell; Mohamed Hassan; Jesper B. Andersen; Victor Ankoma-Sey; Jesus M. Banales; Luis Bujanda; Oliver F. Bathe; Tanios S. Bekaii-Saab; Mitesh J. Borad; Niklas K. Björkström; Carlos H.F. Chan; Sean P. Cleary; Martin Cornillet; Trine Folseraas; Peter R. Galle; Jeanine M. Genkinger; Robert J. MacInnis; Gregory J. Gores; Lipika Goyal; Richard S. Houlston; Sumera I. Ilyas; Milind Javle; Julia S. Johansen; Troels D. Christensen; Ashwin S. Kamath; Robin Kate Kelley; Shahid A. Khan; Richard D. Kim; Sandi A. Kwee; Angela Lamarca; Frank Lammert; Nicholas F. LaRusso; Stacie Lindsey; Rocio I.R. Macias; Harmeet Malhi; Tushar C. Patel; Jennifer B. Permuth; Helen L. Reeves; Stephen Rossi; William Sanchez; Rory L. Smoot; Anthony J. Swerdlow; Hop S. Tran Cao; Juan W. Valle; Arndt Weinmann; Julia Weinmann-Menke; Linda L. Wong; Xuehong Zhang; Vincent Zimmer; Andrew X. Zhu; Konstantinos N. Lazaridis; Brian D. Juran; Prasun Jalal; Jennifer J. Knox; Amy Hutchinson; Belynda Hicks; Jill E. Koshiol; Stephen J. Chanock; Manal M. Hassan; Christopher I. Amos; Katherine A. McGlynn; Lewis R. Roberts

doi:10.1097/HEP.0000000000001699

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

Younghun Han, Jinyoung Byun, Caitlin J. VanLith, Matthew A. Cooley, Vikram R. Shaw, Rikita I. Hatia, Fowsiyo Y. Ahmed, Nasra H. Giama, Hawa M. Ali, Nellie A. Campbell, Mohamed Hassan, Jesper B. Andersen, Victor Ankoma-Sey, Jesus M. Banales, Luis Bujanda, Oliver F. Bathe, Tanios S. Bekaii-Saab, Mitesh J. Borad, Niklas K. Björkström, Carlos H.F. ChanSean P. Cleary, Martin Cornillet, Trine Folseraas, Peter R. Galle, Jeanine M. Genkinger, Robert J. MacInnis, Gregory J. Gores, Lipika Goyal, Richard S. Houlston, Sumera I. Ilyas, Milind Javle, Julia S. Johansen, Troels D. Christensen, Ashwin S. Kamath, Robin Kate Kelley, Shahid A. Khan, Richard D. Kim, Sandi A. Kwee, Angela Lamarca, Frank Lammert, Nicholas F. LaRusso, Stacie Lindsey, Rocio I.R. Macias, Harmeet Malhi, Tushar C. Patel, Jennifer B. Permuth, Helen L. Reeves, Stephen Rossi, William Sanchez, Rory L. Smoot, Anthony J. Swerdlow, Hop S. Tran Cao, Juan W. Valle, Arndt Weinmann, Julia Weinmann-Menke, Linda L. Wong, Xuehong Zhang, Vincent Zimmer, Andrew X. Zhu, Konstantinos N. Lazaridis, Brian D. Juran, Prasun Jalal, Jennifer J. Knox, Amy Hutchinson, Belynda Hicks, Jill E. Koshiol, Stephen J. Chanock, Manal M. Hassan, Christopher I. Amos^*, Katherine A. McGlynn, Lewis R. Roberts^*

^*Corresponding author af dette arbejde

Afdeling for Kræftbehandling HGH

Abstract

Background & 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 & Results: – We conducted a GWAS of 2, 366 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 one new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and two 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 twelve 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.

Originalsprog	Engelsk
Tidsskrift	Hepatology
Vol/bind	Publish Ahead of Print
ISSN	0270-9139
DOI	https://doi.org/10.1097/HEP.0000000000001699
Status	Udgivet - 2 feb. 2026

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Han, Y., Byun, J., VanLith, C. J., Cooley, M. A., Shaw, V. R., Hatia, R. I., Ahmed, F. Y., Giama, N. H., Ali, H. M., Campbell, N. A., Hassan, M., Andersen, J. B., Ankoma-Sey, V., Banales, J. M., Bujanda, L., Bathe, O. F., Bekaii-Saab, T. S., Borad, M. J., Björkström, N. K., ... Roberts, L. R. (2026). Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses. Hepatology, Publish Ahead of Print. https://doi.org/10.1097/HEP.0000000000001699

Han, Y, Byun, J, VanLith, CJ, Cooley, MA, Shaw, VR, Hatia, RI, Ahmed, FY, Giama, NH, Ali, HM, Campbell, NA, Hassan, M, Andersen, JB, Ankoma-Sey, V, Banales, JM, Bujanda, L, Bathe, OF, Bekaii-Saab, TS, Borad, MJ, Björkström, NK, Chan, CHF, Cleary, SP, Cornillet, M, Folseraas, T, Galle, PR, Genkinger, JM, MacInnis, RJ, Gores, GJ, Goyal, L, Houlston, RS, Ilyas, SI, Javle, M, Johansen, JS, Christensen, TD, Kamath, AS, Kelley, RK, Khan, SA, Kim, RD, Kwee, SA, Lamarca, A, Lammert, F, LaRusso, NF, Lindsey, S, Macias, RIR, Malhi, H, Patel, TC, Permuth, JB, Reeves, HL, Rossi, S, Sanchez, W, Smoot, RL, Swerdlow, AJ, Tran Cao, HS, Valle, JW, Weinmann, A, Weinmann-Menke, J, Wong, LL, Zhang, X, Zimmer, V, Zhu, AX, Lazaridis, KN, Juran, BD, Jalal, P, Knox, JJ, Hutchinson, A, Hicks, B, Koshiol, JE, Chanock, SJ, Hassan, MM, Amos, CI, McGlynn, KA & Roberts, LR 2026, 'Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses', Hepatology, bind Publish Ahead of Print. https://doi.org/10.1097/HEP.0000000000001699

@article{9e51fa325321453c8a0768544c6ad3fa,

title = "Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses",

abstract = "Background \& 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 \& Results: – We conducted a GWAS of 2, 366 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 one new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and two 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 twelve 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",

author = "Younghun Han and Jinyoung Byun and VanLith, \{Caitlin J.\} and Cooley, \{Matthew A.\} and Shaw, \{Vikram R.\} and Hatia, \{Rikita I.\} and Ahmed, \{Fowsiyo Y.\} and Giama, \{Nasra H.\} and Ali, \{Hawa M.\} and Campbell, \{Nellie A.\} and Mohamed Hassan and Andersen, \{Jesper B.\} and Victor Ankoma-Sey and Banales, \{Jesus M.\} and Luis Bujanda and Bathe, \{Oliver F.\} and Bekaii-Saab, \{Tanios S.\} and Borad, \{Mitesh J.\} and Bj{\"o}rkstr{\"o}m, \{Niklas K.\} and Chan, \{Carlos H.F.\} and Cleary, \{Sean P.\} and Martin Cornillet and Trine Folseraas and Galle, \{Peter R.\} and Genkinger, \{Jeanine M.\} and MacInnis, \{Robert J.\} and Gores, \{Gregory J.\} and Lipika Goyal and Houlston, \{Richard S.\} and Ilyas, \{Sumera I.\} and Milind Javle and Johansen, \{Julia S.\} and Christensen, \{Troels D.\} and Kamath, \{Ashwin S.\} and Kelley, \{Robin Kate\} and Khan, \{Shahid A.\} and Kim, \{Richard D.\} and Kwee, \{Sandi A.\} and Angela Lamarca and Frank Lammert and LaRusso, \{Nicholas F.\} and Stacie Lindsey and Macias, \{Rocio I.R.\} and Harmeet Malhi and Patel, \{Tushar C.\} and Permuth, \{Jennifer B.\} and Reeves, \{Helen L.\} and Stephen Rossi and William Sanchez and Smoot, \{Rory L.\} and Swerdlow, \{Anthony J.\} and \{Tran Cao\}, \{Hop S.\} and Valle, \{Juan W.\} and Arndt Weinmann and Julia Weinmann-Menke and Wong, \{Linda L.\} and Xuehong Zhang and Vincent Zimmer and Zhu, \{Andrew X.\} and Lazaridis, \{Konstantinos N.\} and Juran, \{Brian D.\} and Prasun Jalal and Knox, \{Jennifer J.\} and Amy Hutchinson and Belynda Hicks and Koshiol, \{Jill E.\} and Chanock, \{Stephen J.\} and Hassan, \{Manal M.\} and Amos, \{Christopher I.\} and McGlynn, \{Katherine A.\} and Roberts, \{Lewis R.\}",

note = "Publisher Copyright: {\textcopyright} 2026",

year = "2026",

month = feb,

day = "2",

doi = "10.1097/HEP.0000000000001699",

language = "English",

volume = "Publish Ahead of Print",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

}

TY - JOUR

T1 - Uncovering the genetic landscape of cholangiocarcinoma and its subtypes via GWAS and integrative analyses

AU - Han, Younghun

AU - Byun, Jinyoung

AU - VanLith, Caitlin J.

AU - Cooley, Matthew A.

AU - Shaw, Vikram R.

AU - Hatia, Rikita I.

AU - Ahmed, Fowsiyo Y.

AU - Giama, Nasra H.

AU - Ali, Hawa M.

AU - Campbell, Nellie A.

AU - Hassan, Mohamed

AU - Andersen, Jesper B.

AU - Ankoma-Sey, Victor

AU - Banales, Jesus M.

AU - Bujanda, Luis

AU - Bathe, Oliver F.

AU - Bekaii-Saab, Tanios S.

AU - Borad, Mitesh J.

AU - Björkström, Niklas K.

AU - Chan, Carlos H.F.

AU - Cleary, Sean P.

AU - Cornillet, Martin

AU - Folseraas, Trine

AU - Galle, Peter R.

AU - Genkinger, Jeanine M.

AU - MacInnis, Robert J.

AU - Gores, Gregory J.

AU - Goyal, Lipika

AU - Houlston, Richard S.

AU - Ilyas, Sumera I.

AU - Javle, Milind

AU - Johansen, Julia S.

AU - Christensen, Troels D.

AU - Kamath, Ashwin S.

AU - Kelley, Robin Kate

AU - Khan, Shahid A.

AU - Kim, Richard D.

AU - Kwee, Sandi A.

AU - Lamarca, Angela

AU - Lammert, Frank

AU - LaRusso, Nicholas F.

AU - Lindsey, Stacie

AU - Macias, Rocio I.R.

AU - Malhi, Harmeet

AU - Patel, Tushar C.

AU - Permuth, Jennifer B.

AU - Reeves, Helen L.

AU - Rossi, Stephen

AU - Sanchez, William

AU - Smoot, Rory L.

AU - Swerdlow, Anthony J.

AU - Tran Cao, Hop S.

AU - Valle, Juan W.

AU - Weinmann, Arndt

AU - Weinmann-Menke, Julia

AU - Wong, Linda L.

AU - Zhang, Xuehong

AU - Zimmer, Vincent

AU - Zhu, Andrew X.

AU - Lazaridis, Konstantinos N.

AU - Juran, Brian D.

AU - Jalal, Prasun

AU - Knox, Jennifer J.

AU - Hutchinson, Amy

AU - Hicks, Belynda

AU - Koshiol, Jill E.

AU - Chanock, Stephen J.

AU - Hassan, Manal M.

AU - Amos, Christopher I.

AU - McGlynn, Katherine A.

AU - Roberts, Lewis R.

PY - 2026/2/2

Y1 - 2026/2/2

N2 - Background & 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 & Results: – We conducted a GWAS of 2, 366 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 one new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and two 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 twelve 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.

AB - Background & 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 & Results: – We conducted a GWAS of 2, 366 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 one new genome-wide significant variant, rs535777 (OR=1.44), near HLA-DRB1/DQA1 associated with CCA, and two 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 twelve 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.

KW - cholangiocarcinoma

KW - extrahepatic cholangiocarcinoma

KW - genome-wide association study

KW - intrahepatic cholangiocarcinoma

KW - primary sclerosing cholangitis

UR - https://www.scopus.com/pages/publications/105029791187

U2 - 10.1097/HEP.0000000000001699

DO - 10.1097/HEP.0000000000001699

M3 - Journal article

C2 - 41627892

AN - SCOPUS:105029791187

SN - 0270-9139

VL - Publish Ahead of Print

JO - Hepatology

JF - Hepatology

ER -

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

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