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

Céline Bellenguez; Fahri Küçükali; Iris E Jansen; Luca Kleineidam; Sonia Moreno-Grau; Najaf Amin; Adam C Naj; Rafael Campos-Martin; Benjamin Grenier-Boley; Victor Andrade; Peter A Holmans; Anne Boland; Vincent Damotte; Sven J van der Lee; Marcos R Costa; Teemu Kuulasmaa; Qiong Yang; Itziar de Rojas; Joshua C Bis; Amber Yaqub; Ivana Prokic; Julien Chapuis; Shahzad Ahmad; Vilmantas Giedraitis; Dag Aarsland; Pablo Garcia-Gonzalez; Carla Abdelnour; Emilio Alarcón-Martín; Daniel Alcolea; Montserrat Alegret; Ignacio Alvarez; Victoria Álvarez; Nicola J Armstrong; Anthoula Tsolaki; Carmen Antúnez; Ildebrando Appollonio; Marina Arcaro; Silvana Archetti; Alfonso Arias Pastor; Beatrice Arosio; Lavinia Athanasiu; Henri Bailly; Nerisa Banaj; Miquel Baquero; Sandra Barral; Sune Fallgaard Nielsen; Børge G Nordestgaard; Jesper Qvist Thomassen; Anne Tybjærg-Hansen; Ruth Frikke-Schmidt; EADB; GR@CE; 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

Céline Bellenguez, Fahri Küçükali, Iris E Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C Naj, Rafael Campos-Martin, Benjamin Grenier-Boley, Victor Andrade, Peter A Holmans, Anne Boland, Vincent Damotte, Sven J van der Lee, Marcos R Costa, Teemu Kuulasmaa, Qiong Yang, Itziar de Rojas, Joshua C Bis, Amber YaqubIvana Prokic, Julien Chapuis, Shahzad Ahmad, Vilmantas Giedraitis, Dag Aarsland, Pablo Garcia-Gonzalez, Carla Abdelnour, Emilio Alarcón-Martín, Daniel Alcolea, Montserrat Alegret, Ignacio Alvarez, Victoria Álvarez, Nicola J Armstrong, Anthoula Tsolaki, Carmen Antúnez, Ildebrando Appollonio, Marina Arcaro, Silvana Archetti, Alfonso Arias Pastor, Beatrice Arosio, Lavinia Athanasiu, Henri Bailly, Nerisa Banaj, Miquel Baquero, Sandra Barral, Sune Fallgaard Nielsen, Børge G Nordestgaard, Jesper Qvist Thomassen, Anne Tybjærg-Hansen, Ruth Frikke-Schmidt, EADB, GR@CE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE

Abstrakt

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.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	54
Udgave nummer	4
Sider (fra-til)	412-436
Antal sider	25
ISSN	1061-4036
DOI	https://doi.org/10.1038/s41588-022-01024-z
Status	Udgivet - apr. 2022

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Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., Holmans, P. A., Boland, A., Damotte, V., van der Lee, S. J., Costa, M. R., Kuulasmaa, T., Yang, Q., de Rojas, I., Bis, J. C., ... CHARGE (2022). New insights into the genetic etiology of Alzheimer's disease and related dementias. Nature Genetics, 54(4), 412-436. https://doi.org/10.1038/s41588-022-01024-z

Bellenguez, C, Küçükali, F, Jansen, IE, Kleineidam, L, Moreno-Grau, S, Amin, N, Naj, AC, Campos-Martin, R, Grenier-Boley, B, Andrade, V, Holmans, PA, Boland, A, Damotte, V, van der Lee, SJ, Costa, MR, Kuulasmaa, T, Yang, Q, de Rojas, I, Bis, JC, Yaqub, A, Prokic, I, Chapuis, J, Ahmad, S, Giedraitis, V, Aarsland, D, Garcia-Gonzalez, P, Abdelnour, C, Alarcón-Martín, E, Alcolea, D, Alegret, M, Alvarez, I, Álvarez, V, Armstrong, NJ, Tsolaki, A, Antúnez, C, Appollonio, I, Arcaro, M, Archetti, S, Pastor, AA, Arosio, B, Athanasiu, L, Bailly, H, Banaj, N, Baquero, M, Barral, S, Nielsen, SF , Nordestgaard, BG , Thomassen, JQ , Tybjærg-Hansen, A , Frikke-Schmidt, R, EADB, GR@CE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC & CHARGE 2022, 'New insights into the genetic etiology of Alzheimer's disease and related dementias', Nature Genetics, bind 54, nr. 4, s. 412-436. https://doi.org/10.1038/s41588-022-01024-z

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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.",

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author = "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 Nielsen, {Sune Fallgaard} and Nordestgaard, {B{\o}rge G} and Thomassen, {Jesper Qvist} and Anne Tybj{\ae}rg-Hansen and Ruth Frikke-Schmidt and EADB and GR@CE and DEGESCO and EADI and GERAD and Demgene and FinnGen and ADGC and CHARGE",

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

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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 - Nielsen, Sune Fallgaard

AU - Nordestgaard, Børge G

AU - Thomassen, Jesper Qvist

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AU - Frikke-Schmidt, Ruth

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AU - FinnGen

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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.

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KW - Cognitive Dysfunction/psychology

KW - Genome-Wide Association Study

KW - Humans

KW - tau Proteins/genetics

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U2 - 10.1038/s41588-022-01024-z

DO - 10.1038/s41588-022-01024-z

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SP - 412

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JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

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ER -

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

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