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