A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
Creators: name: López De Maturana, Evangelina
name: Rodríguez, Juan Antonio
name: Alonso, Lola
name: Lao, Oscar
name: Molina-Montes, Esther
name: Martín-Antoniano, Isabel Adoración
name: Gómez-Rubio, Paulina
name: Lawlor, Rita
name: Carrato, Alfredo
name: Hidalgo, Manuel
name: Iglesias, Mar
name: Molero, Xavier
name: Löhr, Matthias
name: Michalski, Christopher
name: Perea, José
name: O’Rorke, Michael
name: Barberà, Victor Manuel
name: Tardón, Adonina
name: Farré, Antoni
name: Muñoz-Bellvís, Luís
name: Crnogorac-Jurcevic, Tanja
name: Domínguez-Muñoz, Enrique
name: Gress, Thomas
name: Greenhalf, William
name: Sharp, Linda
name: Arnes, Luís
name: Cecchini, Lluís
name: Balsells, Joaquim
name: Costello, Eithne
name: Ilzarbe, Lucas
name: Kleeff, Jörg
name: Kong, Bo
name: Márquez, Mirari
name: Mora, Josefina
name: O’Driscoll, Damian
name: Scarpa, Aldo
name: Ye, Weimin
name: Yu, Jingru
name: García-Closas, Montserrat
name: Kogevinas, Manolis
name: Rothman, Nathaniel
name: Silverman, Debra T
name: Albanes, Demetrius
name: Arslan, Alan A
name: Beane-Freeman, Laura
name: Bracci, Paige M
name: Brennan, Paul
name: Bueno-De-Mesquita, Bas
name: Buring, Julie
name: Canzian, Federico
name: Du, Margaret
name: Gallinger, Steve
name: Gaziano, J Michael
name: Goodman, Phyllis J
name: Gunter, Marc
name: LeMarchand, Loic
name: Li, Donghui
name: Neale, Rachael E
name: Peters, Ulrika
name: Petersen, Gloria M
name: Risch, Harvey A
name: Sánchez, Maria José
name: Shu, Xiao-Ou
name: Thornquist, Mark D
name: Visvanathan, Kala
name: Zheng, Wei
name: Chanock, Stephen J
name: Easton, Douglas
name: Wolpin, Brian M
name: Stolzenberg-Solomon, Rachael Z
name: Klein, Alison P
name: Amundadottir, Laufey T
name: Marti-Renom, Marc A
name: Real, Francisco X
name: Malats, Núria
Publisher: name: Apollo - University of Cambridge Repository
Year: 2021
Subjects: Research
Pancreatic cancer risk
Genome-wide association analysis
Genetic susceptibility
3D genomic structure
Local indices of genome spatial autocorrelation

description: Funder: Fundación Científica Asociación Española Contra el Cáncer (ES)
description: Funder: Cancer Focus Northern Ireland and Department for Employment and Learning
description: Funder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA
description: 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.