A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
| Autor: | López De Maturana, Evangelina, Rodríguez, Juan Antonio, Alonso, Lola, Lao, Oscar, Molina-Montes, Esther, Martín-Antoniano, Isabel Adoración, Gómez-Rubio, Paulina, Lawlor, Rita, Carrato, Alfredo, Hidalgo, Manuel, Iglesias, Mar, Molero, Xavier, Löhr, Matthias, Michalski, Christopher, Perea, José, O’Rorke, Michael, Barberà, Victor Manuel, Tardón, Adonina, Farré, Antoni, Muñoz-Bellvís, Luís, Crnogorac-Jurcevic, Tanja, Domínguez-Muñoz, Enrique, Gress, Thomas, Greenhalf, William, Sharp, Linda, Arnes, Luís, Cecchini, Lluís, Balsells, Joaquim, Costello, Eithne, Ilzarbe, Lucas, Kleeff, Jörg, Kong, Bo, Márquez, Mirari, Mora, Josefina, O’Driscoll, Damian, Scarpa, Aldo, Ye, Weimin, Yu, Jingru, García-Closas, Montserrat, Kogevinas, Manolis, Rothman, Nathaniel, Silverman, Debra T, Albanes, Demetrius, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Brennan, Paul, Bueno-De-Mesquita, Bas, Buring, Julie, Canzian, Federico, Du, Margaret, Gallinger, Steve, Gaziano, J Michael, Goodman, Phyllis J, Gunter, Marc, LeMarchand, Loic, Li, Donghui, Neale, Rachael E, Peters, Ulrika, Petersen, Gloria M, Risch, Harvey A, Sánchez, Maria José, Shu, Xiao-Ou, Thornquist, Mark D, Visvanathan, Kala, Zheng, Wei, Chanock, Stephen J, Easton, Douglas, Wolpin, Brian M, Stolzenberg-Solomon, Rachael Z, Klein, Alison P, Amundadottir, Laufey T, Marti-Renom, Marc A, Real, Francisco X, Malats, Núria |
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| Popis: | Funder: Fundación Científica Asociación Española Contra el Cáncer (ES) Funder: Cancer Focus Northern Ireland and Department for Employment and Learning Funder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases. |
| Databáze: | OpenAIRE |
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