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dc.contributor.authorLópez de Maturana, Evangelina
dc.contributor.authorRodríguez, Juan Antonio
dc.contributor.authorAlonso, Lola
dc.contributor.authorLao, Oscar
dc.contributor.authorMolina-Montes, Esther
dc.contributor.authorMartín-Antoniano, Isabel Adoración
dc.contributor.authorGómez-Rubio, Paulina
dc.contributor.authorLawlor, Rita
dc.contributor.authorCarrato, Alfredo
dc.contributor.authorHidalgo, Manuel
dc.contributor.authorIglesias, Mar
dc.contributor.authorMolero, Xavier
dc.contributor.authorLöhr, Matthias
dc.contributor.authorMichalski, Christopher
dc.contributor.authorPerea, José
dc.contributor.authorO’Rorke, Michael
dc.contributor.authorBarberà, Victor Manuel
dc.contributor.authorTardón, Adonina
dc.contributor.authorFarré, Antoni
dc.contributor.authorMuñoz-Bellvís, Luís
dc.contributor.authorCrnogorac-Jurcevic, Tanja
dc.contributor.authorDomínguez-Muñoz, Enrique
dc.contributor.authorGress, Thomas
dc.contributor.authorGreenhalf, William
dc.contributor.authorSharp, Linda
dc.contributor.authorArnes, Luís
dc.contributor.authorCecchini, Lluís
dc.contributor.authorBalsells, Joaquim
dc.contributor.authorCostello, Eithne
dc.contributor.authorIlzarbe, Lucas
dc.contributor.authorKleeff, Jörg
dc.contributor.authorKong, Bo
dc.contributor.authorMárquez, Mirari
dc.contributor.authorMora, Josefina
dc.contributor.authorO’Driscoll, Damian
dc.contributor.authorScarpa, Aldo
dc.contributor.authorYe, Weimin
dc.contributor.authorYu, Jingru
dc.contributor.authorGarcía-Closas, Montserrat
dc.contributor.authorKogevinas, Manolis
dc.contributor.authorRothman, Nathaniel
dc.contributor.authorSilverman, Debra T
dc.contributor.authorAlbanes, Demetrius
dc.contributor.authorArslan, Alan A
dc.contributor.authorBeane-Freeman, Laura
dc.contributor.authorBracci, Paige M
dc.contributor.authorBrennan, Paul
dc.contributor.authorBueno-de-Mesquita, Bas
dc.contributor.authorBuring, Julie
dc.contributor.authorCanzian, Federico
dc.contributor.authorDu, Margaret
dc.contributor.authorGallinger, Steve
dc.contributor.authorGaziano, J Michael
dc.contributor.authorGoodman, Phyllis J
dc.contributor.authorGunter, Marc
dc.contributor.authorLeMarchand, Loic
dc.contributor.authorLi, Donghui
dc.contributor.authorNeale, Rachael E
dc.contributor.authorPeters, Ulrika
dc.contributor.authorPetersen, Gloria M
dc.contributor.authorRisch, Harvey A
dc.contributor.authorSánchez, Maria José
dc.contributor.authorShu, Xiao-Ou
dc.contributor.authorThornquist, Mark D
dc.contributor.authorVisvanathan, Kala
dc.contributor.authorZheng, Wei
dc.contributor.authorChanock, Stephen J
dc.contributor.authorEaston, Douglas
dc.contributor.authorWolpin, Brian M
dc.contributor.authorStolzenberg-Solomon, Rachael Z
dc.contributor.authorKlein, Alison P
dc.contributor.authorAmundadottir, Laufey T
dc.contributor.authorMarti-Renom, Marc A
dc.contributor.authorReal, Francisco X
dc.contributor.authorMalats, Núria
dc.date.accessioned2021-02-01T16:06:26Z
dc.date.available2021-02-01T16:06:26Z
dc.date.issued2021-02-01
dc.date.submitted2020-08-07
dc.identifier.others13073-020-00816-4
dc.identifier.other816
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/316927
dc.descriptionFunder: Fundación Científica Asociación Española Contra el Cáncer (ES)
dc.descriptionFunder: Cancer Focus Northern Ireland and Department for Employment and Learning
dc.descriptionFunder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA
dc.description.abstractAbstract: 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.
dc.languageen
dc.publisherBioMed Central
dc.rightsAttribution 4.0 International (CC BY 4.0)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectResearch
dc.subjectPancreatic cancer risk
dc.subjectGenome-wide association analysis
dc.subjectGenetic susceptibility
dc.subject3D genomic structure
dc.subjectLocal indices of genome spatial autocorrelation
dc.titleA multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
dc.typeArticle
dc.date.updated2021-02-01T16:06:26Z
prism.issueIdentifier1
prism.publicationNameGenome Medicine
prism.volume13
dc.identifier.doi10.17863/CAM.64040
dcterms.dateAccepted2020-12-03
rioxxterms.versionofrecord10.1186/s13073-020-00816-4
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMalats, Núria [0000-0003-2538-3784]
dc.identifier.eissn1756-994X
pubs.funder-project-idInstituto de Salud Carlos III ((#PI061614, #PI11/01542, #PI0902102, #PI12/01635, #PI12/00815, #PI15/01573, #PI18/01347, (#RD12/0036/0034, #RD12/0036/0050, #RD12/0036/0073)
pubs.funder-project-idEU H2020 COST (COST Action #BM1204)
pubs.funder-project-idEU-6FP Integrated Project (#018771-MOLDIAG-PACA)
pubs.funder-project-idEU-FP7-HEALTH (#259737-CANCERALIA)
pubs.funder-project-idEU-FP7-HEALTH (#256974-EPC-TM-Net)
pubs.funder-project-idAssociazione Angela Serra per la Ricerca sul Cancro (IT) (#12182)
pubs.funder-project-idALF (#SLL20130022)
pubs.funder-project-idLustgarten Foundation & Stand-Up to Cancer (SU2C #6179)


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)