Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

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Lu, Ye, Gentiluomo, Manuel, Macauda, Angelica, Gioffreda, Domenica, Gazouli, Maria, Petrone, Maria C, Kelemen, Dezso, Ginocchi, Laura, Morelli, Luca, Papiris, Konstantinos et al (show 59 more authors) , Greenhalf, William ORCID: 0000-0002-1865-3195, Izbicki, Jakob R, Kiudelis, Vytautas, Mohelnikova-Duchonova, Beatrice, Bueno-de-Mesquita, Bas, Vodicka, Pavel, Brenner, Hermann, Diener, Markus K, Pezzilli, Raffaele, Ivanauskas, Audrius, Salvia, Roberto, Szentesi, Andrea, Aoki, Mateus Nobrega, Nemeth, Balazs C, Sperti, Cosimo, Jamroziak, Krzysztof, Chammas, Roger, Oliverius, Martin, Archibugi, Livia, Ermini, Stefano, Novak, Janos, Kupcinskas, Juozas, Strouhal, Ondrej, Soucek, Pavel, Cavestro, Giulia M, Milanetto, Anna C, Vanella, Giuseppe, Neoptolemos, John P, Theodoropoulos, George E, van Laarhoven, Hanneke WM, Mambrini, Andrea, Moz, Stefania, Kala, Zdenek, Lovecek, Martin, Basso, Daniela, Uzunoglu, Faik G, Hackert, Thilo, Testoni, Sabrina GG, Hlavac, Viktor, Andriulli, Angelo, Lucchesi, Maurizio, Tavano, Francesca, Carrara, Silvia, Hegyi, Peter, Arcidiacono, Paolo G, Busch, Olivier R, Lawlor, Rita T, Puzzono, Marta, Boggi, Ugo, Guo, Feng, Malecka-Panas, Ewa, Capurso, Gabriele, Landi, Stefano, Talar-Wojnarowska, Renata, Strobel, Oliver, Gao, Xin, Vashist, Yogesh, Campa, Daniele and Canzian, Federico (2021) Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk. FRONTIERS IN ONCOLOGY, 11. 771312-.

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Abstract

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10^-5) compared with the additive effects (p>10^-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10^-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the <i>BCL2L11</i> and <i>BUB1</i> genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Item Type:	Article
Uncontrolled Keywords:	pancreatic cancer, susceptibility, genome-wide association study, recessive model, genetic polymorphisms
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	18 Apr 2023 08:39
Last Modified:	18 Apr 2023 08:39
DOI:	10.3389/fonc.2021.771312
Open Access URL:	https://doi.org/10.3389/fonc.2021.771312
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3169641