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dc.contributor.authorLópez de Maturana, Evangelinaen
dc.contributor.authorRodríguez, Juan Antonioen
dc.contributor.authorAlonso, Lolaen
dc.contributor.authorLao, Oscaren
dc.contributor.authorMolina-Montes, Estheren
dc.contributor.authorMartín-Antoniano, Isabel Adoraciónen
dc.contributor.authorGómez-Rubio, Paulinaen
dc.contributor.authorLawlor, Ritaen
dc.contributor.authorCarrato, Alfredoen
dc.contributor.authorHidalgo, Manuelen
dc.contributor.authorIglesias, Maren
dc.contributor.authorMolero, Xavieren
dc.contributor.authorLöhr, Matthiasen
dc.contributor.authorMichalski, Christopheren
dc.contributor.authorPerea, Joséen
dc.contributor.authorO'Rorke, Michaelen
dc.contributor.authorBarberà, Victor Manuelen
dc.contributor.authorTardón, Adoninaen
dc.contributor.authorFarré, Antonien
dc.contributor.authorMuñoz-Bellvís, Luísen
dc.contributor.authorCrnogorac-Jurcevic, Tanjaen
dc.contributor.authorDomínguez-Muñoz, Enriqueen
dc.contributor.authorGress, Thomasen
dc.contributor.authorGreenhalf, Williamen
dc.contributor.authorSharp, Lindaen
dc.contributor.authorArnes, Luísen
dc.contributor.authorCecchini, Lluísen
dc.contributor.authorBalsells, Joaquimen
dc.contributor.authorCostello, Eithneen
dc.contributor.authorIlzarbe, Lucasen
dc.contributor.authorKleeff, Jörgen
dc.contributor.authorKong, Boen
dc.contributor.authorMárquez, Mirarien
dc.contributor.authorMora, Josefinaen
dc.contributor.authorO'Driscoll, Damianen
dc.contributor.authorScarpa, Aldoen
dc.contributor.authorYe, Weiminen
dc.contributor.authorYu, Jingruen
dc.contributor.authorPanGenEU Investigators,en
dc.contributor.authorGarcía-Closas, Montserraten
dc.contributor.authorKogevinas, Manolisen
dc.contributor.authorRothman, Nathanielen
dc.contributor.authorSilverman, Debra Ten
dc.contributor.authorSBC/EPICURO Investigators,en
dc.contributor.authorAlbanes, Demetriusen
dc.contributor.authorArslan, Alan Aen
dc.contributor.authorBeane-Freeman, Lauraen
dc.contributor.authorBracci, Paige Men
dc.contributor.authorBrennan, Paulen
dc.contributor.authorBueno-de-Mesquita, Basen
dc.contributor.authorBuring, Julieen
dc.contributor.authorCanzian, Federicoen
dc.contributor.authorDu, Margareten
dc.contributor.authorGallinger, Steveen
dc.contributor.authorGaziano, J Michaelen
dc.contributor.authorGoodman, Phyllis Jen
dc.contributor.authorGunter, Marcen
dc.contributor.authorLeMarchand, Loicen
dc.contributor.authorLi, Donghuien
dc.contributor.authorNeale, Rachael Een
dc.contributor.authorPeters, Ulrikaen
dc.contributor.authorPetersen, Gloria Men
dc.contributor.authorRisch, Harvey Aen
dc.contributor.authorSánchez, Maria Joséen
dc.contributor.authorShu, Xiao-Ouen
dc.contributor.authorThornquist, Mark Den
dc.contributor.authorVisvanathan, Kalaen
dc.contributor.authorZheng, Weien
dc.contributor.authorChanock, Stephen Jen
dc.contributor.authorEaston, Douglasen
dc.contributor.authorWolpin, Brian Men
dc.contributor.authorStolzenberg-Solomon, Rachael Zen
dc.contributor.authorKlein, Alison Pen
dc.contributor.authorAmundadottir, Laufey Ten
dc.contributor.authorMarti-Renom, Marc Aen
dc.contributor.authorReal, Francisco Xen
dc.contributor.authorMalats, Núriaen
dc.date.accessioned2020-12-17T00:30:37Z
dc.date.available2020-12-17T00:30:37Z
dc.date.issued2021-02en
dc.identifier.issn1756-994X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/315182
dc.description.abstractBackground. 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 maps (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 3Dapproaches: 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.format.mediumElectronicen
dc.languageengen
dc.publisherBioMed Central
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectPanGenEU Investigatorsen
dc.subjectSBC/EPICURO Investigatorsen
dc.titleA multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2021en
prism.publicationNameGenome medicineen
prism.startingPage15
prism.volume13en
dc.identifier.doi10.17863/CAM.62290
dcterms.dateAccepted2020-12-03en
rioxxterms.versionofrecord10.1186/s13073-020-00816-4en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2021-02en
dc.contributor.orcidAlonso, Lola [0000-0002-3493-718X]
dc.contributor.orcidLöhr, Matthias [0000-0002-7647-198X]
dc.contributor.orcidTardón, Adonina [0000-0001-5150-1209]
dc.contributor.orcidArslan, Alan A [0000-0002-7775-8085]
dc.contributor.orcidEaston, Douglas [0000-0003-2444-3247]
dc.contributor.orcidMalats, Núria [0000-0003-2538-3784]
dc.identifier.eissn1756-994X
rioxxterms.typeJournal Article/Reviewen
cam.orpheus.counter6*
rioxxterms.freetoread.startdate2023-12-16


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