A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
PanGenEU Investigators, Evangelina López de Maturana, SBC/EPICURO Investigators, Juan Antonio Rodríguez, Lola Alonso, Óscar Lao, Esther Molina‐Montes, Isabel Adoración Martín‐Antoniano, Paulina Gómez-Rubio, Rita T. Lawlor, Alfredo Carrato, Manuel Hidalgo, Mar Iglesias, Xavier Molero, Matthias Löhr, Christopher Michalski, José Perea, Michael O’Rorke, Víctor Manuel Barberá, Adonina Tardón, Antoni Farré, Luis Muñoz‐Bellvís, Tanja Crnogorac-Jurcevic, J. Enrique Domínguez‐Muñoz, Thomas M. Gress, William Greenhalf, Linda Sharp, Luís Arnes, Lluís Cecchini, J. Balsells, Eithne Costello, Lucas Ilzarbe, Jörg Kleeff, Bo Kong, Mirari Márquez, Josefina Móra, Damian O’Driscoll, Aldo Scarpa, Weimin Ye, Jingru Yu, Montserrat García‐Closas, Manolis Kogevinas, Nathaniel Rothman, Debra T. Silverman, Demetrius Albanes, Alan A. Arslan, Laura E. Beane Freeman, Paige M. Bracci, Paul Brennan, Bas Bueno‐de‐Mesquita, Julie E. Buring, Federico Canzian, Margaret Du, Steve Gallinger, J. Michael Gaziano, Phyllis J. Goodman, Marc J. Gunter, Loı̈c Le Marchand, Donghui Li, Rachael E Neale, Ulrika Peters, Gloria M. Petersen, Harvey A. Risch, María‐José Sánchez, Xiao‐Ou Shu, Mark Thornquist, Kala Visvanathan, Wei Zheng, Stephen J. Chanock, Douglas Easton, Brian M. Wolpin, Rachael Z. Stolzenberg‐Solomon, Alison P. Klein, Laufey T. Ámundadóttir, Marc A. Martı́-Renom, Francisco X. Real, Núria Malats
Abstract
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.