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Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease

dc.rights.licenseopenen_US
dc.contributor.authorLE GUEN, Yann
dc.contributor.authorBELLOY, Michael E.
dc.contributor.authorGRENIER-BOLEY, Benjamin
dc.contributor.authorDE ROJAS, Itziar
dc.contributor.authorCASTILLO-MORALES, Atahualpa
dc.contributor.authorJANSEN, Iris
dc.contributor.authorNICOLAS, Aude
dc.contributor.authorBELLENGUEZ, Celine
dc.contributor.authorDALMASSO, Carolina
dc.contributor.authorKUCUKALI, Fahri
dc.contributor.authorEGER, Sarah J.
dc.contributor.authorRASMUSSEN, Katrine Laura
dc.contributor.authorTHOMASSEN, Jesper Qvist
dc.contributor.authorDELEUZE, Jean-Francois
dc.contributor.authorHE, Zihuai
dc.contributor.authorNAPOLIONI, Valerio
dc.contributor.authorAMOUYEL, Philippe
dc.contributor.authorJESSEN, Frank
dc.contributor.authorKEHOE, Patrick G.
dc.contributor.authorVAN DUIJN, Cornelia
dc.contributor.authorTSOLAKI, Magda
dc.contributor.authorSANCHEZ-JUAN, Pascual
dc.contributor.authorSLEEGERS, Kristel
dc.contributor.authorINGELSSON, Martin
dc.contributor.authorROSSI, Giacomina
dc.contributor.authorHILTUNEN, Mikko
dc.contributor.authorSIMS, Rebecca
dc.contributor.authorVAN DER FLIER, Wiesje M.
dc.contributor.authorRAMIREZ, Alfredo
dc.contributor.authorANDREASSEN, Ole A.
dc.contributor.authorFRIKKE-SCHMIDT, Ruth
dc.contributor.authorWILLIAMS, Julie
dc.contributor.authorRUIZ, Agustin
dc.contributor.authorLAMBERT, Jean-Charles
dc.contributor.authorGREICIUS, Michael D.
dc.contributor.authorAROSIO, Beatrice
dc.contributor.authorBENUSSI, Luisa
dc.contributor.authorBOLAND, Anne
dc.contributor.authorBORRONI, Barbara
dc.contributor.authorCAFFARRA, Paolo
dc.contributor.authorDAIAN, Delphine
dc.contributor.authorDANIELE, Antonio
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDUFOUIL, Carole
dc.contributor.authorDUZEL, Emrah
dc.contributor.authorGALIMBERTI, Daniela
dc.contributor.authorGIEDRAITIS, Vilmantas
dc.contributor.authorGRIMMER, Timo
dc.contributor.authorGRAFF, Caroline
dc.contributor.authorGRUNBLATT, Edna
dc.contributor.authorHANON, Olivier
dc.contributor.authorHAUSNER, Lucrezia
dc.contributor.authorHEILMANN-HEIMBACH, Stefanie
dc.contributor.authorHOLSTEGE, Henne
dc.contributor.authorHORT, Jakub
dc.contributor.authorJURGEN, Deckert
dc.contributor.authorKUULASMAA, Teemu
dc.contributor.authorVAN DER LUGT, Aad
dc.contributor.authorMASULLO, Carlo
dc.contributor.authorMECOCCI, Patrizia
dc.contributor.authorMEHRABIAN, Shima
dc.contributor.authorDE MENDONCA, Alexandre
dc.contributor.authorMOEBUS, Susanne
dc.contributor.authorNACMIAS, Benedetta
dc.contributor.authorNICOLAS, Gael
dc.contributor.authorOLASO, Robert
dc.contributor.authorPAPENBERG, Goran
dc.contributor.authorPARNETTI, Lucilla
dc.contributor.authorPASQUIER, Florence
dc.contributor.authorPETERS, Oliver
dc.contributor.authorPIJNENBURG, Yolande A. L.
dc.contributor.authorPOPP, Julius
dc.contributor.authorRAINERO, Innocenzo
dc.contributor.authorRAMAKERS, Inez
dc.contributor.authorRIEDEL-HELLER, Steffi
dc.contributor.authorSCARMEAS, Nikolaos
dc.contributor.authorSCHELTENS, Philip
dc.contributor.authorSCHERBAUM, Norbert
dc.contributor.authorSCHNEIDER, Anja
dc.contributor.authorSERIPA, Davide
dc.contributor.authorSOININEN, Hilkka
dc.contributor.authorSOLFRIZZI, Vincenzo
dc.contributor.authorSPALLETTA, Gianfranco
dc.contributor.authorSQUASSINA, Alessio
dc.contributor.authorVAN SWIETEN, John
dc.contributor.authorTEGOS, Thomas J.
dc.contributor.authorTREMOLIZZO, Lucio
dc.contributor.authorVERHEY, Frans
dc.contributor.authorVYHNALEK, Martin
dc.contributor.authorWILTFANG, Jens
dc.contributor.authorBOADA, Merce
dc.contributor.authorGARCIA-GONZALEZ, Pablo
dc.contributor.authorPUERTA, Raquel
dc.contributor.authorREAL, Luis M.
dc.contributor.authorALVAREZ, Victoria
dc.contributor.authorBULLIDO, Maria J.
dc.contributor.authorCLARIMON, Jordi
dc.contributor.authorGARCIA-ALBERCA, Jose Maria
dc.contributor.authorMIR, Pablo
dc.contributor.authorMORENO, Fermin
dc.contributor.authorPASTOR, Pau
dc.contributor.authorPINOL-RIPOLL, Gerard
dc.contributor.authorMOLINA-PORCEL, Laura
dc.contributor.authorPEREZ-TUR, Jordi
dc.contributor.authorRODRIGUEZ-RODRIGUEZ, Eloy
dc.contributor.authorROYO, Jose Luis
dc.contributor.authorSANCHEZ-VALLE, Raquel
dc.contributor.authorDICHGANS, Martin
dc.contributor.authorRUJESCU, Dan
dc.date.accessioned2022-06-21T14:00:28Z
dc.date.available2022-06-21T14:00:28Z
dc.date.issued2022-05-31
dc.identifier.issn2168-6157 (Electronic) 2168-6149 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/140296
dc.description.abstractEnIMPORTANCE: The APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. OBJECTIVE: To determine whether rare missense variants on APOE are associated with AD risk. DESIGN, SETTING, AND PARTICIPANTS: Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. MAIN OUTCOMES AND MEASURES: In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. RESULTS: A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. CONCLUSIONS AND RELEVANCE: In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.
dc.language.isoENen_US
dc.title.enAssociation of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease
dc.typeArticle de revueen_US
dc.identifier.doi10.1001/jamaneurol.2022.1166en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed35639372en_US
bordeaux.journalJAMA neurologyen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamELEANOR_BPHen_US
bordeaux.teamPHARES_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03701054
hal.version1
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
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