Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk
Authors: Lu Ye , Gentiluomo Manuel , Macauda Angelica , Gioffreda Domenica , Gazouli Maria , Petrone Maria C. , Kelemen Dezső , Ginocchi Laura , Morelli Luca , Papiris Konstantinos , Greenhalf William , Izbicki Jakob R. , Kiudelis Vytautas , Mohelníková-Duchoňová Beatrice , Bueno-de-Mesquita Bas , Vodicka Pavel , Brenner Hermann , Diener Markus K. , Pezzilli Raffaele , Ivanauskas Audrius , Salvia Roberto , Szentesi Andrea , Aoki Mateus Nóbrega , Németh Balázs C. , Sperti Cosimo , Jamroziak Krzysztof , Chammas Roger , Oliverius Martin , Archibugi Livia , Ermini Stefano , Novák János , Kupcinskas Juozas , Strouhal Ondřej , Souček Pavel , Cavestro Giulia M. , Milanetto Anna C. , Vanella Giuseppe , Neoptolemos John P. , Theodoropoulos George E. , van Laarhoven Hanneke W. M. , Mambrini Andrea , Moz Stefania , Kala Zdenek , Loveček Martin , Basso Daniela , Uzunoglu Faik G. , Hackert Thilo , Testoni Sabrina G. G. , Hlaváč Viktor , Andriulli Angelo , Lucchesi Maurizio , Tavano Francesca , Carrara Silvia , Hegyi Péter , Arcidiacono Paolo G. , Busch Olivier R. , Lawlor Rita T. , Puzzono Marta , Boggi Ugo , Guo Feng , Małecka-Panas Ewa , Capurso Gabriele , Landi Stefano , Talar-Wojnarowska Renata , Strobel Oliver , Gao Xin , Vashist Yogesh , Campa Daniele , Canzian Federico 
Published: December 2021

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&lt;10−5) compared with the additive effects (p&gt;10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p &lt; 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 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.