New insights into the genetic etiology of Alzheimer’s disease and related dementias

EADB; GR@ACE; DEGESCO; EADI; GERAD; Demgene; FinnGen; ADGC; CHARGE

doi:10.1038/s41588-022-01024-z

New insights into the genetic etiology of Alzheimer’s disease and related dementias

EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE

Research output: Contribution to journal › Article › peer-review

297 Scopus citations

Abstract

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Original language	English
Pages (from-to)	412-436
Number of pages	25
Journal	Nature Genetics
Volume	54
Issue number	4
DOIs	https://doi.org/10.1038/s41588-022-01024-z
State	Published - Apr 1 2022

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10.1038/s41588-022-01024-z

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@article{f813632ed9d9469c93ead0385ac85f16,

title = "New insights into the genetic etiology of Alzheimer{\textquoteright}s disease and related dementias",

abstract = "Characterization of the genetic landscape of Alzheimer{\textquoteright}s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/{\textquoteleft}proxy{\textquoteright} AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.",

author = "EADB and GR@ACE and DEGESCO and EADI and GERAD and Demgene and FinnGen and ADGC and CHARGE and C{\'e}line Bellenguez and Fahri K{\"u}{\c c}{\"u}kali and Jansen, {Iris E.} and Luca Kleineidam and Sonia Moreno-Grau and Najaf Amin and Naj, {Adam C.} and Rafael Campos-Martin and Benjamin Grenier-Boley and Victor Andrade and Holmans, {Peter A.} and Anne Boland and Vincent Damotte and {van der Lee}, {Sven J.} and Costa, {Marcos R.} and Teemu Kuulasmaa and Qiong Yang and {de Rojas}, Itziar and Bis, {Joshua C.} and Amber Yaqub and Ivana Prokic and Julien Chapuis and Shahzad Ahmad and Vilmantas Giedraitis and Dag Aarsland and Pablo Garcia-Gonzalez and Carla Abdelnour and Emilio Alarc{\'o}n-Mart{\'i}n and Daniel Alcolea and Montserrat Alegret and Ignacio Alvarez and Victoria {\'A}lvarez and Armstrong, {Nicola J.} and Anthoula Tsolaki and Carmen Ant{\'u}nez and Ildebrando Appollonio and Marina Arcaro and Silvana Archetti and Pastor, {Alfonso Arias} and Beatrice Arosio and Lavinia Athanasiu and Henri Bailly and Nerisa Banaj and Miquel Baquero and Sandra Barral and Alexa Beiser and Pastor, {Ana Bel{\'e}n} and Below, {Jennifer E.} and Penelope Benchek and Luisa Benussi and Claudine Berr and C{\'e}line Besse and Valentina Bessi and Giuliano Binetti and Alessandra Bizarro and Rafael Blesa and Merc{\`e} Boada and Eric Boerwinkle and Barbara Borroni and Silvia Boschi and Paola Boss{\`u} and Geir Br{\aa}then and Jan Bressler and Catherine Bresner and Henry Brodaty and Brookes, {Keeley J.} and Brusco, {Luis Ignacio} and Dolores Buiza-Rueda and Katharina B{\^u}rger and Vanessa Burholt and Bush, {William S.} and Miguel Calero and Cantwell, {Laura B.} and Genevi{\`e}ve Chene and Jaeyoon Chung and Cuccaro, {Michael L.} and {\'A}ngel Carracedo and Roberta Cecchetti and Laura Cervera-Carles and Camille Charbonnier and Chen, {Hung Hsin} and Caterina Chillotti and Simona Ciccone and Claassen, {Jurgen A.H.R.} and Christopher Clark and Elisa Conti and Ana{\"i}s Corma-G{\'o}mez and Emanuele Costantini and Carlo Custodero and Delphine Daian and Dalmasso, {Maria Carolina} and Antonio Daniele and Efthimios Dardiotis and Dartigues, {Jean Fran{\c c}ois} and {de Deyn}, {Peter Paul} and {de Paiva Lopes}, Katia and {de Witte}, {Lot D.} and St{\'e}phanie Debette and J{\"u}rgen Deckert and {del Ser}, Teodoro and Nicola Denning and Anita DeStefano and Martin Dichgans and Janine Diehl-Schmid and M{\'o}nica Diez-Fairen and Rossi, {Paolo Dionigi} and Srdjan Djurovic and Emmanuelle Duron and Emrah D{\"u}zel and Carole Dufouil and Gudny Eiriksdottir and Sebastiaan Engelborghs and Valentina Escott-Price and Ana Espinosa and Michael Ewers and Faber, {Kelley M.} and Tagliavini Fabrizio and Nielsen, {Sune Fallgaard} and Fardo, {David W.} and Lucia Farotti and Chiara Fenoglio and Marta Fern{\'a}ndez-Fuertes and Raffaele Ferrari and Ferreira, {Catarina B.} and Evelyn Ferri and Bertrand Fin and Peter Fischer and Tormod Fladby and Klaus Flie{\ss}bach and Bernard Fongang and Myriam Fornage and Juan Fortea and Foroud, {Tatiana M.} and Silvia Fostinelli and Fox, {Nick C.} and Emlio Franco-Mac{\'i}as and Bullido, {Mar{\'i}a J.} and Ana Frank-Garc{\'i}a and Lutz Froelich and Brian Fulton-Howard and Daniela Galimberti and Garc{\'i}a-Alberca, {Jose Maria} and Pablo Garc{\'i}a-Gonz{\'a}lez and Sebastian Garcia-Madrona and Guillermo Garcia-Ribas and Roberta Ghidoni and Ina Giegling and Giaccone Giorgio and Goate, {Alison M.} and Oliver Goldhardt and Duber Gomez-Fonseca and Antonio Gonz{\'a}lez-P{\'e}rez and Caroline Graff and Giulia Grande and Emma Green and Timo Grimmer and Edna Gr{\"u}nblatt and Michelle Grunin and Vilmundur Gudnason and Tamar Guetta-Baranes and Annakaisa Haapasalo and Georgios Hadjigeorgiou and Haines, {Jonathan L.} and Hamilton-Nelson, {Kara L.} and Harald Hampel and Olivier Hanon and John Hardy and Hartmann, {Annette M.} and Lucrezia Hausner and Janet Harwood and Stefanie Heilmann-Heimbach and Seppo Helisalmi and Heneka, {Michael T.} and Isabel Hern{\'a}ndez and Herrmann, {Martin J.} and Per Hoffmann and Clive Holmes and Henne Holstege and Vilas, {Raquel Huerto} and Marc Hulsman and Jack Humphrey and Biessels, {Geert Jan} and Xueqiu Jian and Charlotte Johansson and Jun, {Gyungah R.} and Yuriko Kastumata and John Kauwe and Kehoe, {Patrick G.} and Lena Kilander and St{\aa}hlbom, {Anne Kinhult} and Miia Kivipelto and Anne Koivisto and Johannes Kornhuber and Kosmidis, {Mary H.} and Benitez, {Bruno A.} and Carlos Cruchaga and Victoria Fernandez-Hernandez and Oscar Harari and Laura Ibanez and Morris, {John C.}",

note = "Funding Information: We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille M{\'e}tropole Communaut{\'e} Urbaine and French government{\textquoteright}s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Note. Funding Information: We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille M{\'e}tropole Communaut{\'e} Urbaine and French government{\textquoteright}s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the . Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = apr,

day = "1",

doi = "10.1038/s41588-022-01024-z",

language = "English",

volume = "54",

pages = "412--436",

journal = "Nature Genetics",

issn = "1061-4036",

number = "4",

}

TY - JOUR

T1 - New insights into the genetic etiology of Alzheimer’s disease and related dementias

AU - EADB

AU - GR@ACE

AU - DEGESCO

AU - EADI

AU - GERAD

AU - Demgene

AU - FinnGen

AU - ADGC

AU - CHARGE

AU - Bellenguez, Céline

AU - Küçükali, Fahri

AU - Jansen, Iris E.

AU - Kleineidam, Luca

AU - Moreno-Grau, Sonia

AU - Amin, Najaf

AU - Naj, Adam C.

AU - Campos-Martin, Rafael

AU - Grenier-Boley, Benjamin

AU - Andrade, Victor

AU - Holmans, Peter A.

AU - Boland, Anne

AU - Damotte, Vincent

AU - van der Lee, Sven J.

AU - Costa, Marcos R.

AU - Kuulasmaa, Teemu

AU - Yang, Qiong

AU - de Rojas, Itziar

AU - Bis, Joshua C.

AU - Yaqub, Amber

AU - Prokic, Ivana

AU - Chapuis, Julien

AU - Ahmad, Shahzad

AU - Giedraitis, Vilmantas

AU - Aarsland, Dag

AU - Garcia-Gonzalez, Pablo

AU - Abdelnour, Carla

AU - Alarcón-Martín, Emilio

AU - Alcolea, Daniel

AU - Alegret, Montserrat

AU - Alvarez, Ignacio

AU - Álvarez, Victoria

AU - Armstrong, Nicola J.

AU - Tsolaki, Anthoula

AU - Antúnez, Carmen

AU - Appollonio, Ildebrando

AU - Arcaro, Marina

AU - Archetti, Silvana

AU - Pastor, Alfonso Arias

AU - Arosio, Beatrice

AU - Athanasiu, Lavinia

AU - Bailly, Henri

AU - Banaj, Nerisa

AU - Baquero, Miquel

AU - Barral, Sandra

AU - Beiser, Alexa

AU - Pastor, Ana Belén

AU - Below, Jennifer E.

AU - Benchek, Penelope

AU - Benussi, Luisa

AU - Berr, Claudine

AU - Besse, Céline

AU - Bessi, Valentina

AU - Binetti, Giuliano

AU - Bizarro, Alessandra

AU - Blesa, Rafael

AU - Boada, Mercè

AU - Boerwinkle, Eric

AU - Borroni, Barbara

AU - Boschi, Silvia

AU - Bossù, Paola

AU - Bråthen, Geir

AU - Bressler, Jan

AU - Bresner, Catherine

AU - Brodaty, Henry

AU - Brookes, Keeley J.

AU - Brusco, Luis Ignacio

AU - Buiza-Rueda, Dolores

AU - Bûrger, Katharina

AU - Burholt, Vanessa

AU - Bush, William S.

AU - Calero, Miguel

AU - Cantwell, Laura B.

AU - Chene, Geneviève

AU - Chung, Jaeyoon

AU - Cuccaro, Michael L.

AU - Carracedo, Ángel

AU - Cecchetti, Roberta

AU - Cervera-Carles, Laura

AU - Charbonnier, Camille

AU - Chen, Hung Hsin

AU - Chillotti, Caterina

AU - Ciccone, Simona

AU - Claassen, Jurgen A.H.R.

AU - Clark, Christopher

AU - Conti, Elisa

AU - Corma-Gómez, Anaïs

AU - Costantini, Emanuele

AU - Custodero, Carlo

AU - Daian, Delphine

AU - Dalmasso, Maria Carolina

AU - Daniele, Antonio

AU - Dardiotis, Efthimios

AU - Dartigues, Jean François

AU - de Deyn, Peter Paul

AU - de Paiva Lopes, Katia

AU - de Witte, Lot D.

AU - Debette, Stéphanie

AU - Deckert, Jürgen

AU - del Ser, Teodoro

AU - Denning, Nicola

AU - DeStefano, Anita

AU - Dichgans, Martin

AU - Diehl-Schmid, Janine

AU - Diez-Fairen, Mónica

AU - Rossi, Paolo Dionigi

AU - Djurovic, Srdjan

AU - Duron, Emmanuelle

AU - Düzel, Emrah

AU - Dufouil, Carole

AU - Eiriksdottir, Gudny

AU - Engelborghs, Sebastiaan

AU - Escott-Price, Valentina

AU - Espinosa, Ana

AU - Ewers, Michael

AU - Faber, Kelley M.

AU - Fabrizio, Tagliavini

AU - Nielsen, Sune Fallgaard

AU - Fardo, David W.

AU - Farotti, Lucia

AU - Fenoglio, Chiara

AU - Fernández-Fuertes, Marta

AU - Ferrari, Raffaele

AU - Ferreira, Catarina B.

AU - Ferri, Evelyn

AU - Fin, Bertrand

AU - Fischer, Peter

AU - Fladby, Tormod

AU - Fließbach, Klaus

AU - Fongang, Bernard

AU - Fornage, Myriam

AU - Fortea, Juan

AU - Foroud, Tatiana M.

AU - Fostinelli, Silvia

AU - Fox, Nick C.

AU - Franco-Macías, Emlio

AU - Bullido, María J.

AU - Frank-García, Ana

AU - Froelich, Lutz

AU - Fulton-Howard, Brian

AU - Galimberti, Daniela

AU - García-Alberca, Jose Maria

AU - García-González, Pablo

AU - Garcia-Madrona, Sebastian

AU - Garcia-Ribas, Guillermo

AU - Ghidoni, Roberta

AU - Giegling, Ina

AU - Giorgio, Giaccone

AU - Goate, Alison M.

AU - Goldhardt, Oliver

AU - Gomez-Fonseca, Duber

AU - González-Pérez, Antonio

AU - Graff, Caroline

AU - Grande, Giulia

AU - Green, Emma

AU - Grimmer, Timo

AU - Grünblatt, Edna

AU - Grunin, Michelle

AU - Gudnason, Vilmundur

AU - Guetta-Baranes, Tamar

AU - Haapasalo, Annakaisa

AU - Hadjigeorgiou, Georgios

AU - Haines, Jonathan L.

AU - Hamilton-Nelson, Kara L.

AU - Hampel, Harald

AU - Hanon, Olivier

AU - Hardy, John

AU - Hartmann, Annette M.

AU - Hausner, Lucrezia

AU - Harwood, Janet

AU - Heilmann-Heimbach, Stefanie

AU - Helisalmi, Seppo

AU - Heneka, Michael T.

AU - Hernández, Isabel

AU - Herrmann, Martin J.

AU - Hoffmann, Per

AU - Holmes, Clive

AU - Holstege, Henne

AU - Vilas, Raquel Huerto

AU - Hulsman, Marc

AU - Humphrey, Jack

AU - Biessels, Geert Jan

AU - Jian, Xueqiu

AU - Johansson, Charlotte

AU - Jun, Gyungah R.

AU - Kastumata, Yuriko

AU - Kauwe, John

AU - Kehoe, Patrick G.

AU - Kilander, Lena

AU - Ståhlbom, Anne Kinhult

AU - Kivipelto, Miia

AU - Koivisto, Anne

AU - Kornhuber, Johannes

AU - Kosmidis, Mary H.

AU - Benitez, Bruno A.

AU - Cruchaga, Carlos

AU - Fernandez-Hernandez, Victoria

AU - Harari, Oscar

AU - Ibanez, Laura

AU - Morris, John C.

N1 - Funding Information: We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the Supplementary Note. Funding Information: We thank the many study participants, researchers and staff for collecting and contributing to the data, the high-performance computing service at the University of Lille and the staff at CEA-CNRGH for their help with sample preparation and genotyping and excellent technical assistance. We thank Antonio Pardinas for his help. We thank the Netherlands Brain Bank. This research was conducted using the UKBB resource (application number 61054). This work was funded by a grant (EADB) from the EU Joint Programme – Neurodegenerative Disease Research. INSERM UMR1167 is also funded by the INSERM, Institut Pasteur de Lille, Lille Métropole Communauté Urbaine and French government’s LABEX DISTALZ program (development of innovative strategies for a transdisciplinary approach to AD). Full consortium acknowledgements and funding are in the . Publisher Copyright: © 2022, The Author(s).

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

AB - Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

UR - http://www.scopus.com/inward/record.url?scp=85128487295&partnerID=8YFLogxK

U2 - 10.1038/s41588-022-01024-z

DO - 10.1038/s41588-022-01024-z

M3 - Article

C2 - 35379992

AN - SCOPUS:85128487295

SN - 1061-4036

VL - 54

SP - 412

EP - 436

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

New insights into the genetic etiology of Alzheimer’s disease and related dementias

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