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oai:repisalud.isciii.es:20.500.12105/182182025-05-08T10:33:52Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud author López de Maturana, Evangelina author Rodríguez, Juan Antonio author Alonso, Lola author Lao, Oscar author Molina-Montes, Esther author Martín-Antoniano, Isabel Adoración author Gómez-Rubio, Paulina author Lawlor, Rita author Carrato, Alfredo author Hidalgo, Manuel author Iglesias, Mar author Molero, Xavier author Löhr, Matthias author Michalski, Christopher author Perea, José author O'Rorke, Michael author Barberà, Victor Manuel author Tardón, Adonina author Farré, Antoni author Muñoz-Bellvís, Luís author Crnogorac-Jurcevic, Tanja author Domínguez-Muñoz, Enrique author Gress, Thomas author Greenhalf, William author Sharp, Linda author Arnes, Luís author Cecchini, Lluís author Balsells, Joaquim author Costello, Eithne author Ilzarbe, Lucas author Kleeff, Jörg author Kong, Bo author Márquez, Mirari author Mora, Josefina author O'Driscoll, Damian author Scarpa, Aldo author Ye, Weimin author Yu, Jingru author García-Closas, Montserrat author Kogevinas, Manolis author Rothman, Nathaniel author Silverman, Debra T author Albanes, Demetrius author Arslan, Alan A author Beane-Freeman, Laura author Bracci, Paige M author Brennan, Paul author Bueno-de-Mesquita, Bas author Buring, Julie author Canzian, Federico author Du, Margaret author Gallinger, Steve author Gaziano, J Michael author Goodman, Phyllis J author Gunter, Marc author LeMarchand, Loic author Li, Donghui author Neale, Rachael E author Peters, Ulrika author Petersen, Gloria M author Risch, Harvey A author Sánchez, María-José author Shu, Xiao-Ou author Thornquist, Mark D author Visvanathan, Kala author Zheng, Wei author Chanock, Stephen J author Easton, Douglas author Wolpin, Brian M author Stolzenberg-Solomon, Rachael Z author Klein, Alison P author Amundadottir, Laufey T author Marti-Renom, Marc A author Real Arribas, Francisco author Malats, Nuria funder Instituto de Salud Carlos III funder Asociación Española Contra el Cáncer funder Unión Europea. European Cooperation in Science and Technology (COST) funder Unión Europea funder NIH - National Cancer Institute (NCI) (Estados Unidos) 2024-02-19T10:27:52Z 2024-02-19T10:27:52Z 2021-02-01 Genome Med . 2021 ;13(1):15 10.1186/s13073-020-00816-4 1756-994X Genome medicine 33517887 http://hdl.handle.net/20.500.12105/18218 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. eng A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer. research article 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 URL https://repisalud.isciii.es/bitstreams/1f7ec1c2-2a68-4a04-98f7-5c494f8b2ff0/download File MD5 fc28aba7d7390332421b98084dc6f497 6955351 application/pdf Amultilayeredpost-GWAS_2021.pdf URL https://repisalud.isciii.es/bitstreams/f50c6067-95a1-4938-b5a9-c7629b145b82/download File MD5 5d5df6a44b8903f6bfe2828718e23d3e 86315 text/plain Amultilayeredpost-GWAS_2021.pdf.txt