Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk
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 addi...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/03eb0137b83d4b1689c42abdfe892baa |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:03eb0137b83d4b1689c42abdfe892baa |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:03eb0137b83d4b1689c42abdfe892baa2021-12-03T05:40:54ZIdentification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk2234-943X10.3389/fonc.2021.771312https://doaj.org/article/03eb0137b83d4b1689c42abdfe892baa2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.771312/fullhttps://doaj.org/toc/2234-943XAlthough 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.Ye LuYe LuManuel GentiluomoAngelica MacaudaDomenica GioffredaMaria GazouliMaria C. PetroneDezső KelemenLaura GinocchiLuca MorelliKonstantinos PapirisWilliam GreenhalfJakob R. IzbickiVytautas KiudelisBeatrice Mohelníková-DuchoňováBas Bueno-de-MesquitaPavel VodickaPavel VodickaPavel VodickaHermann BrennerHermann BrennerHermann BrennerMarkus K. DienerRaffaele PezzilliAudrius IvanauskasRoberto SalviaAndrea SzentesiAndrea SzentesiMateus Nóbrega AokiBalázs C. NémethCosimo SpertiKrzysztof JamroziakRoger ChammasRoger ChammasMartin OliveriusLivia ArchibugiLivia ArchibugiLivia ArchibugiStefano ErminiJános NovákJuozas KupcinskasOndřej StrouhalOndřej StrouhalPavel SoučekGiulia M. CavestroAnna C. MilanettoGiuseppe VanellaGiuseppe VanellaGiuseppe VanellaJohn P. NeoptolemosGeorge E. TheodoropoulosHanneke W. M. van LaarhovenAndrea MambriniStefania MozZdenek KalaMartin LovečekDaniela BassoFaik G. UzunogluThilo HackertSabrina G. G. TestoniViktor HlaváčAngelo AndriulliMaurizio LucchesiFrancesca TavanoSilvia CarraraPéter HegyiPéter HegyiPaolo G. ArcidiaconoOlivier R. BuschRita T. LawlorMarta PuzzonoUgo BoggiFeng GuoEwa Małecka-PanasGabriele CapursoGabriele CapursoGabriele CapursoStefano LandiRenata Talar-WojnarowskaOliver StrobelXin GaoYogesh VashistDaniele CampaFederico CanzianFrontiers Media S.A.articlepancreatic cancersusceptibilitygenome-wide association studyrecessive modelgenetic polymorphismsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
pancreatic cancer susceptibility genome-wide association study recessive model genetic polymorphisms Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
pancreatic cancer susceptibility genome-wide association study recessive model genetic polymorphisms Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Ye Lu 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 Pavel Vodicka Pavel Vodicka Hermann Brenner Hermann Brenner Hermann Brenner Markus K. Diener Raffaele Pezzilli Audrius Ivanauskas Roberto Salvia Andrea Szentesi Andrea Szentesi Mateus Nóbrega Aoki Balázs C. Németh Cosimo Sperti Krzysztof Jamroziak Roger Chammas Roger Chammas Martin Oliverius Livia Archibugi Livia Archibugi Livia Archibugi Stefano Ermini János Novák Juozas Kupcinskas Ondřej Strouhal Ondřej Strouhal Pavel Souček Giulia M. Cavestro Anna C. Milanetto Giuseppe Vanella Giuseppe Vanella 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 Péter Hegyi Péter Hegyi Paolo G. Arcidiacono Olivier R. Busch Rita T. Lawlor Marta Puzzono Ugo Boggi Feng Guo Ewa Małecka-Panas Gabriele Capurso Gabriele Capurso Gabriele Capurso Stefano Landi Renata Talar-Wojnarowska Oliver Strobel Xin Gao Yogesh Vashist Daniele Campa Federico Canzian Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk |
| description |
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. |
| format |
article |
| author |
Ye Lu 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 Pavel Vodicka Pavel Vodicka Hermann Brenner Hermann Brenner Hermann Brenner Markus K. Diener Raffaele Pezzilli Audrius Ivanauskas Roberto Salvia Andrea Szentesi Andrea Szentesi Mateus Nóbrega Aoki Balázs C. Németh Cosimo Sperti Krzysztof Jamroziak Roger Chammas Roger Chammas Martin Oliverius Livia Archibugi Livia Archibugi Livia Archibugi Stefano Ermini János Novák Juozas Kupcinskas Ondřej Strouhal Ondřej Strouhal Pavel Souček Giulia M. Cavestro Anna C. Milanetto Giuseppe Vanella Giuseppe Vanella 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 Péter Hegyi Péter Hegyi Paolo G. Arcidiacono Olivier R. Busch Rita T. Lawlor Marta Puzzono Ugo Boggi Feng Guo Ewa Małecka-Panas Gabriele Capurso Gabriele Capurso Gabriele Capurso Stefano Landi Renata Talar-Wojnarowska Oliver Strobel Xin Gao Yogesh Vashist Daniele Campa Federico Canzian |
| author_facet |
Ye Lu 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 Pavel Vodicka Pavel Vodicka Hermann Brenner Hermann Brenner Hermann Brenner Markus K. Diener Raffaele Pezzilli Audrius Ivanauskas Roberto Salvia Andrea Szentesi Andrea Szentesi Mateus Nóbrega Aoki Balázs C. Németh Cosimo Sperti Krzysztof Jamroziak Roger Chammas Roger Chammas Martin Oliverius Livia Archibugi Livia Archibugi Livia Archibugi Stefano Ermini János Novák Juozas Kupcinskas Ondřej Strouhal Ondřej Strouhal Pavel Souček Giulia M. Cavestro Anna C. Milanetto Giuseppe Vanella Giuseppe Vanella 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 Péter Hegyi Péter Hegyi Paolo G. Arcidiacono Olivier R. Busch Rita T. Lawlor Marta Puzzono Ugo Boggi Feng Guo Ewa Małecka-Panas Gabriele Capurso Gabriele Capurso Gabriele Capurso Stefano Landi Renata Talar-Wojnarowska Oliver Strobel Xin Gao Yogesh Vashist Daniele Campa Federico Canzian |
| author_sort |
Ye Lu |
| title |
Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk |
| title_short |
Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk |
| title_full |
Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk |
| title_fullStr |
Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk |
| title_full_unstemmed |
Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk |
| title_sort |
identification of recessively inherited genetic variants potentially linked to pancreatic cancer risk |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/03eb0137b83d4b1689c42abdfe892baa |
| work_keys_str_mv |
AT yelu identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT yelu identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT manuelgentiluomo identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT angelicamacauda identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT domenicagioffreda identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT mariagazouli identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT mariacpetrone identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT dezsokelemen identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT lauraginocchi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT lucamorelli identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT konstantinospapiris identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT williamgreenhalf identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT jakobrizbicki identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT vytautaskiudelis identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT beatricemohelnikovaduchonova identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT basbuenodemesquita identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT pavelvodicka identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT pavelvodicka identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT pavelvodicka identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT hermannbrenner identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT hermannbrenner identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT hermannbrenner identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT markuskdiener identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT raffaelepezzilli identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT audriusivanauskas identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT robertosalvia identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT andreaszentesi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT andreaszentesi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT mateusnobregaaoki identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT balazscnemeth identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT cosimosperti identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT krzysztofjamroziak identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT rogerchammas identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT rogerchammas identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT martinoliverius identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT liviaarchibugi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT liviaarchibugi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT liviaarchibugi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT stefanoermini identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT janosnovak identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT juozaskupcinskas identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT ondrejstrouhal identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT ondrejstrouhal identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT pavelsoucek identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT giuliamcavestro identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT annacmilanetto identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT giuseppevanella identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT giuseppevanella identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT giuseppevanella identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT johnpneoptolemos identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT georgeetheodoropoulos identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT hannekewmvanlaarhoven identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT andreamambrini identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT stefaniamoz identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT zdenekkala identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT martinlovecek identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT danielabasso identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT faikguzunoglu identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT thilohackert identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT sabrinaggtestoni identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT viktorhlavac identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT angeloandriulli identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT mauriziolucchesi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT francescatavano identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT silviacarrara identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT peterhegyi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT peterhegyi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT paologarcidiacono identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT olivierrbusch identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT ritatlawlor identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT martapuzzono identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT ugoboggi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT fengguo identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT ewamałeckapanas identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT gabrielecapurso identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT gabrielecapurso identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT gabrielecapurso identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT stefanolandi identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT renatatalarwojnarowska identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT oliverstrobel identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT xingao identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT yogeshvashist identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT danielecampa identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk AT federicocanzian identificationofrecessivelyinheritedgeneticvariantspotentiallylinkedtopancreaticcancerrisk |
| _version_ |
1718373910898016256 |