TY - JOUR
T1 - A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
AU - PanGenEU Investigators
AU - SBC/EPICURO Investigators
AU - López de Maturana, Evangelina
AU - Rodríguez, Juan Antonio
AU - Alonso, Lola
AU - Lao, Oscar
AU - Molina-Montes, Esther
AU - Martín-Antoniano, Isabel Adoración
AU - Gómez-Rubio, Paulina
AU - Lawlor, Rita
AU - Carrato, Alfredo
AU - Hidalgo, Manuel
AU - Iglesias, Mar
AU - Molero, Xavier
AU - Löhr, Matthias
AU - Michalski, Christopher
AU - Perea, José
AU - O’Rorke, Michael
AU - Barberà, Victor Manuel
AU - Tardón, Adonina
AU - Farré, Antoni
AU - Muñoz-Bellvís, Luís
AU - Crnogorac-Jurcevic, Tanja
AU - Domínguez-Muñoz, Enrique
AU - Gress, Thomas
AU - Greenhalf, William
AU - Sharp, Linda
AU - Arnes, Luís
AU - Cecchini, Lluís
AU - Balsells, Joaquim
AU - Costello, Eithne
AU - Ilzarbe, Lucas
AU - Kleeff, Jörg
AU - Kong, Bo
AU - Márquez, Mirari
AU - Mora, Josefina
AU - O’Driscoll, Damian
AU - Scarpa, Aldo
AU - Ye, Weimin
AU - Yu, Jingru
AU - García-Closas, Montserrat
AU - Kogevinas, Manolis
AU - Rothman, Nathaniel
AU - Silverman, Debra T.
AU - Albanes, Demetrius
AU - Arslan, Alan A.
AU - Beane-Freeman, Laura
AU - Bracci, Paige M.
AU - Brennan, Paul
AU - Bueno-de-Mesquita, Bas
AU - Visvanathan, Kala
AU - Klein, Alison P.
N1 - Funding Information:
The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (#PI061614, #PI11/01542, #PI0902102, #PI12/01635, #PI12/00815, #PI15/01573, #PI18/01347); Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/0036/0034, #RD12/0036/0050, #RD12/0036/0073); Spanish Ministerio de Ciencia, Innovación y Universidades (#BFU2017-85926-P); Fundación Científica de la AECC, Spain; European Cooperation in Science and Technology - COST Action #BM1204: EUPancreas. EU-6FP Integrated Project (#018771-MOLDIAG-PACA), EU-FP7-HEALTH (#259737-CANCERALIA, #256974-EPC-TM-Net), EU-FP7-ERC (#609989); Associazione Italiana Ricerca sul Cancro (#12182); Cancer Focus Northern Ireland and Department for Employment and Learning; and ALF (#SLL20130022), Sweden; Pancreatic Cancer Collective (PCC): Lustgarten Foundation & Stand-Up to Cancer (SU2C #6179); Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA; PANC4 GWAS RO1CA154823; NCI, US-NIH (#HHSN261200800001E).
Funding Information:
The authors are thankful to the patients, coordinators, field and administrative workers, and technicians of the European Study into Digestive Illnesses and Genetics (PanGenEU) and the Spanish Bladder Cancer (SBC/EPICURO) studies. We also thank Marta Rava former member of the GMEG-CNIO, Guillermo Pita and Anna González-Neira from CGEN-CNIO, and Joe Dennis and Laura Fachal from the University of Cambridge, for genotyping PanGenEU samples, performing variant calling and SNP imputation, and editing data. PanGenEU Study investigators (Additional file 1 : Annex 1) and SBC/EPICURO Investigators (Additional file 1 : Annex 2).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - 3D genomic structure
KW - Genetic susceptibility
KW - Genome-wide association analysis
KW - Local indices of genome spatial autocorrelation
KW - Pancreatic cancer risk
UR - http://www.scopus.com/inward/record.url?scp=85100156945&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85100156945&partnerID=8YFLogxK
U2 - 10.1186/s13073-020-00816-4
DO - 10.1186/s13073-020-00816-4
M3 - Article
C2 - 33517887
AN - SCOPUS:85100156945
VL - 13
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 15
ER -