A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
Por:
de Maturana, E, Rodriguez, J, Alonso, L, Lao, O, Molina-Montes, E, Martin-Antoniano, I, Gomez-Rubio, P, Lawlor, R, Carrato, A, Hidalgo, M, Iglesias, M, Molero, X, Lohr, M, Michalski, C, Perea, J, O'Rorke, M, Barbera V, Tardon, A, Farre, A, Munoz-Bellvis, L, Crnogorac-Jurcevic, T, Dominguez-Munoz, E, Gress, T, Greenhalf, W, Sharp, L, Arnes, L, Cecchini, L, Balsells, J, Costello, E, Ilzarbe, L, Kleeff, J, Kong, B, Marquez, M, Mora, J, O'Driscoll, D, Scarpa, A, Ye, W, Yu, J, Garcia-Closas, M, Kogevinas, M, Rothman, N, Silverman, D, Albanes, D, Arslan, A, Beane-Freeman, L, Bracci, P, Brennan, P, Bueno-de-Mesquita, B, Buring, J, Canzian, F, Du, M, Gallinger, S, Gaziano, J, Goodman, P, Gunter, M, LeMarchand, L, Li, D, Neale, R, Peters, U, Petersen, G, Risch, H, Sanchez, M, Shu, X, Thornquist, M, Visvanathan, K, Zheng, W, Chanock, S, Easton, D, Wolpin, B, Stolzenberg-Solomon, R, Klein, A, Amundadottir, L, Marti-Renom, M, Real, F, Malats, N, PanGenEU Investigators and SBC EPICURO Investigators
Publicada:
1 feb 2021
Ahead of Print:
1 feb 2021
Resumen:
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.
Green Published, Green Submitted, gold
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