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

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

doi:https://doi.org/10.3389/fonc.2021.771312

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

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

Research output: Contribution to journal › Article › Academic › peer-review

8 Citations (Scopus)

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 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.

Original language	English
Article number	771312
Journal	Frontiers in Oncology
Volume	11
DOIs	https://doi.org/10.3389/fonc.2021.771312
Publication status	Published - 3 Dec 2021

Keywords

genetic polymorphisms
genome-wide association study
pancreatic cancer
recessive model
susceptibility

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https://doi.org/10.3389/fonc.2021.771312

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Lu, Y., Gentiluomo, M., Macauda, A., Gioffreda, D., Gazouli, M., Petrone, M. C., Kelemen, D., Ginocchi, L., Morelli, L., Papiris, K., Greenhalf, W., Izbicki, J. R., Kiudelis, V., Mohelníková-Duchoňová, B., Bueno-de-Mesquita, B., Vodicka, P., Brenner, H., Diener, M. K., Pezzilli, R., ... Canzian, F. (2021). Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk. Frontiers in Oncology, 11, Article 771312. https://doi.org/10.3389/fonc.2021.771312

@article{5907dec7a7df48039dc3a548065ef319,

title = "Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk",

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 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.",

keywords = "genetic polymorphisms, genome-wide association study, pancreatic cancer, recessive model, susceptibility",

author = "Ye Lu and Manuel Gentiluomo and Angelica Macauda and Domenica Gioffreda and Maria Gazouli and Petrone, {Maria C.} and Dezs{\H o} Kelemen and Laura Ginocchi and Luca Morelli and Konstantinos Papiris and William Greenhalf and Izbicki, {Jakob R.} and Vytautas Kiudelis and Beatrice Moheln{\'i}kov{\'a}-Ducho{\v n}ov{\'a} and Bas Bueno-de-Mesquita and Pavel Vodicka and Hermann Brenner and Diener, {Markus K.} and Raffaele Pezzilli and Audrius Ivanauskas and Roberto Salvia and Andrea Szentesi and Aoki, {Mateus N. brega} and N{\'e}meth, {Bal{\'a}zs C.} and Cosimo Sperti and Krzysztof Jamroziak and Roger Chammas and Martin Oliverius and Livia Archibugi and Stefano Ermini and Nov{\'a}k, {J. nos} and Juozas Kupcinskas and Ond{\v r}ej Strouhal and Pavel Sou{\v c}ek and Cavestro, {Giulia M.} and Milanetto, {Anna C.} and Giuseppe Vanella and Neoptolemos, {John P.} and Theodoropoulos, {George E.} and {van Laarhoven}, {Hanneke W. M.} and Andrea Mambrini and Stefania Moz and Zdenek Kala and Martin Love{\v c}ek and Daniela Basso and Uzunoglu, {Faik G.} and Thilo Hackert and Testoni, {Sabrina G. G.} and Viktor Hlav{\'a}{\v c} and Angelo Andriulli and Maurizio Lucchesi and Francesca Tavano and Silvia Carrara and Hegyi, {P. ter} and Arcidiacono, {Paolo G.} and Busch, {Olivier R.} and Lawlor, {Rita T.} and Marta Puzzono and Ugo Boggi and Feng Guo and Ewa Ma{\l}ecka-Panas and Gabriele Capurso and Stefano Landi and Renata Talar-Wojnarowska and Oliver Strobel and Xin Gao and Yogesh Vashist and Daniele Campa and Federico Canzian",

note = "Funding Information: We would like to thank Mrs. Angelika Stein for help with the lab work. The research used the genotyping data provided by the EPIC, we would like to thank the contributors from the UK and the Netherlands. The EPIC-Norfolk study (DOI 10.22025/ 2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors would also thank all the participants of the PanScan GWAS Study and Pancreatic Cancer Case Control Association Study, and dbGaP for providing cancer genotyping dataset. Funding Information: This work was supported by intramural funding of German Cancer Research Center (DKFZ); and by Fondazione Tizzi (www.fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it); the Economic Development and Innovation Operative Programme Grant (Grant number GINOP-2.3.2-15-2016-00048); the Human Resources Development Operational Programme Grant (Grant number EFOP 3.6.2?16?2017?0006); Associazione Italiana Ricerca Cancro (Grant number 5x1000, 12182, and IG 17177); Fondazione Italiana Malattie Pancreas ? Ministero Salute (Grant number FIMPCUP_J38D19000690001); Fondazione Cariverona: Oncology Biobank Project ?Antonio Schiavi? (Grant number 203885/2017); the Ministry of Health of the Czech Republic (Grant number NV19-03-00097, FNOL-00098892); student grant from Palacky University (Grant number IGA_LF_2020_005). The ESTHER study was funded by the Baden-W?rttemberg State Ministry of Science, Research and Arts (Stuttgart, Germany). Funding Information: This work was supported by intramural funding of German Cancer Research Center (DKFZ); and by Fondazione Tizzi (www. fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it); the Economic Development and Innovation Operative Programme Grant (Grant number GINOP-2.3.2-15-2016-00048); the Human Resources Development Operational Programme Grant (Grant number EFOP 3.6.2‐16‐2017‐0006); Associazione Italiana Ricerca Cancro (Grant number 5x1000, 12182, and IG 17177); Fondazione Italiana Malattie Pancreas – Ministero Salute (Grant number FIMPCUP_J38D19000690001); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (Grant number 203885/2017); the Ministry of Health of the Czech Republic (Grant number NV19-03-00097, FNOL-00098892); student grant from Palacky University (Grant number IGA_LF_2020_005). The ESTHER study was funded by the Baden-W{\"u}rttemberg State Ministry of Science, Research and Arts (Stuttgart, Germany). Publisher Copyright: Copyright {\textcopyright} 2021 Lu, Gentiluomo, Macauda, Gioffreda, Gazouli, Petrone, Kelemen, Ginocchi, Morelli, Papiris, Greenhalf, Izbicki, Kiudelis, Moheln{\'i}kov{\'a}-Ducho{\v n}ov{\'a}, Bueno-de-Mesquita, Vodicka, Brenner, Diener, Pezzilli, Ivanauskas, Salvia, Szentesi, Aoki, N{\'e}meth, Sperti, Jamroziak, Chammas, Oliverius, Archibugi, Ermini, Nov{\'a}k, Kupcinskas, Strouhal, Sou{\v c}ek, Cavestro, Milanetto, Vanella, Neoptolemos, Theodoropoulos, van Laarhoven, Mambrini, Moz, Kala, Love{\v c}ek, Basso, Uzunoglu, Hackert, Testoni, Hlav{\'a}{\v c}, Andriulli, Lucchesi, Tavano, Carrara, Hegyi, Arcidiacono, Busch, Lawlor, Puzzono, Boggi, Guo, Ma{\l}ecka-Panas, Capurso, Landi, Talar-Wojnarowska, Strobel, Gao, Vashist, Campa and Canzian.",

year = "2021",

month = dec,

day = "3",

doi = "https://doi.org/10.3389/fonc.2021.771312",

language = "English",

volume = "11",

journal = "Frontiers in Oncology",

issn = "2234-943X",

publisher = "Frontiers Media S.A.",

}

Lu, Y, Gentiluomo, M, Macauda, A, Gioffreda, D, Gazouli, M, Petrone, MC, Kelemen, D, Ginocchi, L, Morelli, L, Papiris, K, Greenhalf, W, Izbicki, JR, Kiudelis, V, Mohelníková-Duchoňová, B, Bueno-de-Mesquita, B, Vodicka, P, Brenner, H, Diener, MK, Pezzilli, R, Ivanauskas, A, Salvia, R, Szentesi, A, Aoki, MNB, Németh, BC, Sperti, C, Jamroziak, K, Chammas, R, Oliverius, M, Archibugi, L, Ermini, S, Novák, JN, Kupcinskas, J, Strouhal, O, Souček, P, Cavestro, GM, Milanetto, AC, Vanella, G, Neoptolemos, JP, Theodoropoulos, GE, van Laarhoven, HWM, Mambrini, A, Moz, S, Kala, Z, Loveček, M, Basso, D, Uzunoglu, FG, Hackert, T, Testoni, SGG, Hlaváč, V, Andriulli, A, Lucchesi, M, Tavano, F, Carrara, S, Hegyi, PT, Arcidiacono, PG, Busch, OR, Lawlor, RT, Puzzono, M, Boggi, U, Guo, F, Małecka-Panas, E, Capurso, G, Landi, S, Talar-Wojnarowska, R, Strobel, O, Gao, X, Vashist, Y, Campa, D & Canzian, F 2021, 'Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk', Frontiers in Oncology, vol. 11, 771312. https://doi.org/10.3389/fonc.2021.771312

TY - JOUR

T1 - Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

AU - Lu, Ye

AU - Gentiluomo, Manuel

AU - Macauda, Angelica

AU - Gioffreda, Domenica

AU - Gazouli, Maria

AU - Petrone, Maria C.

AU - Kelemen, Dezső

AU - Ginocchi, Laura

AU - Morelli, Luca

AU - Papiris, Konstantinos

AU - Greenhalf, William

AU - Izbicki, Jakob R.

AU - Kiudelis, Vytautas

AU - Mohelníková-Duchoňová, Beatrice

AU - Bueno-de-Mesquita, Bas

AU - Vodicka, Pavel

AU - Brenner, Hermann

AU - Diener, Markus K.

AU - Pezzilli, Raffaele

AU - Ivanauskas, Audrius

AU - Salvia, Roberto

AU - Szentesi, Andrea

AU - Aoki, Mateus N. brega

AU - Németh, Balázs C.

AU - Sperti, Cosimo

AU - Jamroziak, Krzysztof

AU - Chammas, Roger

AU - Oliverius, Martin

AU - Archibugi, Livia

AU - Ermini, Stefano

AU - Novák, J. nos

AU - Kupcinskas, Juozas

AU - Strouhal, Ondřej

AU - Souček, Pavel

AU - Cavestro, Giulia M.

AU - Milanetto, Anna C.

AU - Vanella, Giuseppe

AU - Neoptolemos, John P.

AU - Theodoropoulos, George E.

AU - van Laarhoven, Hanneke W. M.

AU - Mambrini, Andrea

AU - Moz, Stefania

AU - Kala, Zdenek

AU - Loveček, Martin

AU - Basso, Daniela

AU - Uzunoglu, Faik G.

AU - Hackert, Thilo

AU - Testoni, Sabrina G. G.

AU - Hlaváč, Viktor

AU - Andriulli, Angelo

AU - Lucchesi, Maurizio

AU - Tavano, Francesca

AU - Carrara, Silvia

AU - Hegyi, P. ter

AU - Arcidiacono, Paolo G.

AU - Busch, Olivier R.

AU - Lawlor, Rita T.

AU - Puzzono, Marta

AU - Boggi, Ugo

AU - Guo, Feng

AU - Małecka-Panas, Ewa

AU - Capurso, Gabriele

AU - Landi, Stefano

AU - Talar-Wojnarowska, Renata

AU - Strobel, Oliver

AU - Gao, Xin

AU - Vashist, Yogesh

AU - Campa, Daniele

AU - Canzian, Federico

N1 - Funding Information: We would like to thank Mrs. Angelika Stein for help with the lab work. The research used the genotyping data provided by the EPIC, we would like to thank the contributors from the UK and the Netherlands. The EPIC-Norfolk study (DOI 10.22025/ 2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors would also thank all the participants of the PanScan GWAS Study and Pancreatic Cancer Case Control Association Study, and dbGaP for providing cancer genotyping dataset. Funding Information: This work was supported by intramural funding of German Cancer Research Center (DKFZ); and by Fondazione Tizzi (www.fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it); the Economic Development and Innovation Operative Programme Grant (Grant number GINOP-2.3.2-15-2016-00048); the Human Resources Development Operational Programme Grant (Grant number EFOP 3.6.2?16?2017?0006); Associazione Italiana Ricerca Cancro (Grant number 5x1000, 12182, and IG 17177); Fondazione Italiana Malattie Pancreas ? Ministero Salute (Grant number FIMPCUP_J38D19000690001); Fondazione Cariverona: Oncology Biobank Project ?Antonio Schiavi? (Grant number 203885/2017); the Ministry of Health of the Czech Republic (Grant number NV19-03-00097, FNOL-00098892); student grant from Palacky University (Grant number IGA_LF_2020_005). The ESTHER study was funded by the Baden-W?rttemberg State Ministry of Science, Research and Arts (Stuttgart, Germany). Funding Information: This work was supported by intramural funding of German Cancer Research Center (DKFZ); and by Fondazione Tizzi (www. fondazionetizzi.it); Fondazione Arpa (www.fondazionearpa.it); the Economic Development and Innovation Operative Programme Grant (Grant number GINOP-2.3.2-15-2016-00048); the Human Resources Development Operational Programme Grant (Grant number EFOP 3.6.2‐16‐2017‐0006); Associazione Italiana Ricerca Cancro (Grant number 5x1000, 12182, and IG 17177); Fondazione Italiana Malattie Pancreas – Ministero Salute (Grant number FIMPCUP_J38D19000690001); Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (Grant number 203885/2017); the Ministry of Health of the Czech Republic (Grant number NV19-03-00097, FNOL-00098892); student grant from Palacky University (Grant number IGA_LF_2020_005). The ESTHER study was funded by the Baden-Württemberg State Ministry of Science, Research and Arts (Stuttgart, Germany). Publisher Copyright: Copyright © 2021 Lu, Gentiluomo, Macauda, Gioffreda, Gazouli, Petrone, Kelemen, Ginocchi, Morelli, Papiris, Greenhalf, Izbicki, Kiudelis, Mohelníková-Duchoňová, Bueno-de-Mesquita, Vodicka, Brenner, Diener, Pezzilli, Ivanauskas, Salvia, Szentesi, Aoki, Németh, Sperti, Jamroziak, Chammas, Oliverius, Archibugi, Ermini, Novák, Kupcinskas, Strouhal, Souček, Cavestro, Milanetto, Vanella, Neoptolemos, Theodoropoulos, van Laarhoven, Mambrini, Moz, Kala, Loveček, Basso, Uzunoglu, Hackert, Testoni, Hlaváč, Andriulli, Lucchesi, Tavano, Carrara, Hegyi, Arcidiacono, Busch, Lawlor, Puzzono, Boggi, Guo, Małecka-Panas, Capurso, Landi, Talar-Wojnarowska, Strobel, Gao, Vashist, Campa and Canzian.

PY - 2021/12/3

Y1 - 2021/12/3

N2 - 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 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.

AB - 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 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.

KW - genetic polymorphisms

KW - genome-wide association study

KW - pancreatic cancer

KW - recessive model

KW - susceptibility

UR - http://www.scopus.com/inward/record.url?scp=85121395745&partnerID=8YFLogxK

U2 - https://doi.org/10.3389/fonc.2021.771312

DO - https://doi.org/10.3389/fonc.2021.771312

M3 - Article

C2 - 34926279

SN - 2234-943X

VL - 11

JO - Frontiers in Oncology

JF - Frontiers in Oncology

M1 - 771312

ER -

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

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Keywords

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