A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer Journal Article
| Authors: | López de Maturana, E.; Rodríguez, J. A.; Alonso, L.; Lao, O.; Molina-Montes, E.; Martín-Antoniano, I. A.; Gómez-Rubio, P.; Lawlor, R.; Carrato, A.; Hidalgo, M.; Iglesias, M.; Molero, X.; Löhr, M.; Michalski, C.; Perea, J.; O’Rorke, M.; Barberà, V. M.; Tardón, A.; Farré, A.; Muñoz-Bellvís, L.; Crnogorac-Jurcevic, T.; Domínguez-Muñoz, E.; Gress, T.; Greenhalf, W.; Sharp, L.; Arnes, L.; Cecchini, L.; Balsells, J.; Costello, E.; Ilzarbe, L.; Kleeff, J.; Kong, B.; Márquez, M.; Mora, J.; O’Driscoll, D.; Scarpa, A.; Ye, W.; Yu, J.; PanGenEU Investigators; García-Closas, M.; Kogevinas, M.; Rothman, N.; Silverman, D. T.; SBC/EPICURO Investigators; Albanes, D.; Arslan, A. A.; Beane-Freeman, L.; Bracci, P. M.; Brennan, P.; Bueno-de-Mesquita, B.; Buring, J.; Canzian, F.; Du, M.; Gallinger, S.; Gaziano, J. M.; Goodman, P. J.; Gunter, M.; LeMarchand, L.; Li, D.; Neale, R. E.; Peters, U.; Petersen, G. M.; Risch, H. A.; Sánchez, M. J.; Shu, X. O.; Thornquist, M. D.; Visvanathan, K.; Zheng, W.; Chanock, S. J.; Easton, D.; Wolpin, B. M.; Stolzenberg-Solomon, R. Z.; Klein, A. P.; Amundadottir, L. T.; Marti-Renom, M. A.; Real, F. X.; Malats, N. |
| Article Title: | A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer |
| 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. © 2021, The Author(s). |
| Keywords: | genetic susceptibility; 3d genomic structure; genome-wide association analysis; local indices of genome spatial autocorrelation; pancreatic cancer risk |
| Journal Title: | Genome Medicine |
| Volume: | 13 |
| ISSN: | 1756-994X |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2021-02-01 |
| Start Page: | 15 |
| Language: | English |
| DOI: | 10.1186/s13073-020-00816-4 |
| PUBMED: | 33517887 |
| PROVIDER: | scopus |
| PMCID: | PMC7849104 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2021 -- Source: Scopus |
