Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease
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Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease. / Le Guen, Yann; Belloy, Michael E.; Grenier-Boley, Benjamin; De Rojas, Itziar; Castillo-Morales, Atahualpa; Jansen, Iris; Nicolas, Aude; Bellenguez, Céline; Dalmasso, Carolina; Küçükali, Fahri; Eger, Sarah J.; Rasmussen, Katrine Laura; Thomassen, Jesper Qvist; Deleuze, Jean François; He, Zihuai; Napolioni, Valerio; Amouyel, Philippe; Jessen, Frank; Kehoe, Patrick G.; Van Duijn, Cornelia; Tsolaki, Magda; Sánchez-Juan, Pascual; Sleegers, Kristel; Ingelsson, Martin; Rossi, Giacomina; Hiltunen, Mikko; Sims, Rebecca; Van Der Flier, Wiesje M.; Ramirez, Alfredo; Andreassen, Ole A.; Frikke-Schmidt, Ruth; Williams, Julie; Ruiz, Agustín; Lambert, Jean Charles; Greicius, Michael D.; Arosio, Beatrice; Benussi, Luisa; Boland, Anne; Borroni, Barbara; Caffarra, Paolo; Daian, Delphine; Daniele, Antonio; Debette, Stéphanie; Dufouil, Carole; Düzel, Emrah; Galimberti, Daniela; Giedraitis, Vilmantas; Grimmer, Timo; Graff, Caroline; Grünblatt, Edna; Hanon, Olivier; Hausner, Lucrezia; Heilmann-Heimbach, Stefanie; Holstege, Henne; Hort, Jakub; Jürgen, Deckert; Kuulasmaa, Teemu; Van Der Lugt, Aad; Masullo, Carlo; Mecocci, Patrizia; Mehrabian, Shima; De Mendonça, Alexandre; Moebus, Susanne; Nacmias, Benedetta; Nicolas, Gael; Olaso, Robert; Papenberg, Goran; Parnetti, Lucilla; Pasquier, Florence; Peters, Oliver; Pijnenburg, Yolande A.L.; Popp, Julius; Rainero, Innocenzo; Ramakers, Inez; Riedel-Heller, Steffi; Scarmeas, Nikolaos; Scheltens, Philip; Scherbaum, Norbert; Schneider, Anja; Seripa, Davide; Soininen, Hilkka; Solfrizzi, Vincenzo; Spalletta, Gianfranco; Squassina, Alessio; Van Swieten, John; Tegos, Thomas J.; Tremolizzo, Lucio; Verhey, Frans; Vyhnalek, Martin; Wiltfang, Jens; Boada, Mercè; García-González, Pablo; Puerta, Raquel; Real, Luis M.; Álvarez, Victoria; Bullido, María J.; Clarimon, Jordi; García-Alberca, José María; Mir, Pablo; Moreno, Fermin; Pastor, Pau; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Pérez-Tur, Jordi; Rodríguez-Rodríguez, Eloy; Royo, Jose Luís; Sánchez-Valle, Raquel; Dichgans, Martin; Rujescu, Dan.
In: JAMA Neurology, Vol. 79, No. 7, 2022, p. 652-663.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Association of Rare APOE Missense Variants V236E and R251G with Risk of Alzheimer Disease
AU - Le Guen, Yann
AU - Belloy, Michael E.
AU - Grenier-Boley, Benjamin
AU - De Rojas, Itziar
AU - Castillo-Morales, Atahualpa
AU - Jansen, Iris
AU - Nicolas, Aude
AU - Bellenguez, Céline
AU - Dalmasso, Carolina
AU - Küçükali, Fahri
AU - Eger, Sarah J.
AU - Rasmussen, Katrine Laura
AU - Thomassen, Jesper Qvist
AU - Deleuze, Jean François
AU - He, Zihuai
AU - Napolioni, Valerio
AU - Amouyel, Philippe
AU - Jessen, Frank
AU - Kehoe, Patrick G.
AU - Van Duijn, Cornelia
AU - Tsolaki, Magda
AU - Sánchez-Juan, Pascual
AU - Sleegers, Kristel
AU - Ingelsson, Martin
AU - Rossi, Giacomina
AU - Hiltunen, Mikko
AU - Sims, Rebecca
AU - Van Der Flier, Wiesje M.
AU - Ramirez, Alfredo
AU - Andreassen, Ole A.
AU - Frikke-Schmidt, Ruth
AU - Williams, Julie
AU - Ruiz, Agustín
AU - Lambert, Jean Charles
AU - Greicius, Michael D.
AU - Arosio, Beatrice
AU - Benussi, Luisa
AU - Boland, Anne
AU - Borroni, Barbara
AU - Caffarra, Paolo
AU - Daian, Delphine
AU - Daniele, Antonio
AU - Debette, Stéphanie
AU - Dufouil, Carole
AU - Düzel, Emrah
AU - Galimberti, Daniela
AU - Giedraitis, Vilmantas
AU - Grimmer, Timo
AU - Graff, Caroline
AU - Grünblatt, Edna
AU - Hanon, Olivier
AU - Hausner, Lucrezia
AU - Heilmann-Heimbach, Stefanie
AU - Holstege, Henne
AU - Hort, Jakub
AU - Jürgen, Deckert
AU - Kuulasmaa, Teemu
AU - Van Der Lugt, Aad
AU - Masullo, Carlo
AU - Mecocci, Patrizia
AU - Mehrabian, Shima
AU - De Mendonça, Alexandre
AU - Moebus, Susanne
AU - Nacmias, Benedetta
AU - Nicolas, Gael
AU - Olaso, Robert
AU - Papenberg, Goran
AU - Parnetti, Lucilla
AU - Pasquier, Florence
AU - Peters, Oliver
AU - Pijnenburg, Yolande A.L.
AU - Popp, Julius
AU - Rainero, Innocenzo
AU - Ramakers, Inez
AU - Riedel-Heller, Steffi
AU - Scarmeas, Nikolaos
AU - Scheltens, Philip
AU - Scherbaum, Norbert
AU - Schneider, Anja
AU - Seripa, Davide
AU - Soininen, Hilkka
AU - Solfrizzi, Vincenzo
AU - Spalletta, Gianfranco
AU - Squassina, Alessio
AU - Van Swieten, John
AU - Tegos, Thomas J.
AU - Tremolizzo, Lucio
AU - Verhey, Frans
AU - Vyhnalek, Martin
AU - Wiltfang, Jens
AU - Boada, Mercè
AU - García-González, Pablo
AU - Puerta, Raquel
AU - Real, Luis M.
AU - Álvarez, Victoria
AU - Bullido, María J.
AU - Clarimon, Jordi
AU - García-Alberca, José María
AU - Mir, Pablo
AU - Moreno, Fermin
AU - Pastor, Pau
AU - Piñol-Ripoll, Gerard
AU - Molina-Porcel, Laura
AU - Pérez-Tur, Jordi
AU - Rodríguez-Rodríguez, Eloy
AU - Royo, Jose Luís
AU - Sánchez-Valle, Raquel
AU - Dichgans, Martin
AU - Rujescu, Dan
N1 - Publisher Copyright: © 2022 American Medical Association. All rights reserved.
PY - 2022
Y1 - 2022
N2 - Importance: 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 37409 nonunique participants of European or admixed European ancestry, with 11868 individuals with AD and 11934 controls passing analysis inclusion criteria. In stages 2 and 3, 475473 participants were considered across 8 cohorts, of which 84513 individuals with AD and proxy-AD and 328372 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, 76195 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 544384 participants were analyzed in the primary case-control analysis; 312476 (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..
AB - Importance: 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 37409 nonunique participants of European or admixed European ancestry, with 11868 individuals with AD and 11934 controls passing analysis inclusion criteria. In stages 2 and 3, 475473 participants were considered across 8 cohorts, of which 84513 individuals with AD and proxy-AD and 328372 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, 76195 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 544384 participants were analyzed in the primary case-control analysis; 312476 (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..
U2 - 10.1001/jamaneurol.2022.1166
DO - 10.1001/jamaneurol.2022.1166
M3 - Journal article
C2 - 35639372
AN - SCOPUS:85134221014
VL - 79
SP - 652
EP - 663
JO - JAMA Neurology
JF - JAMA Neurology
SN - 2168-6149
IS - 7
ER -
ID: 315036316