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

Céline Bellenguez; Fahri Küçükali; FinnGen Consortium; ADGC; CHARGE Consortium; European Alzheimer & Dementia BioBank (EADB); The GR@ACE study group; DEGESCO consortium; the European AD Initiative (EADI); GERAD; Demgene; 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; Lot D. de Witte; Henne Holstege; Lenore Launer; Chien Yueh Lee; Merel Mol; Danielle Posthuma; Christiane Reitz; Gijsje J.L. Snijders; Andre Uitterlinden; Aad van der Lugt; Jeroen van Rooij; John van Swieten; M. Marín; Chien Yueh Lee; Hieab Adams; Monique Breteler; Hata Comic; Tavia Evans; Maria Knol; Debora Melo van Lent; Helena Schmidt; Alexander Teumer; Dina Vojinovic; Mohsen Ghanbari; M. Arfan Ikram; Kristel Sleegers; Cornelia M. van Duijn; Alfredo Ramirez; Jean Charles Lambert

doi:10.1038/s41588-022-01024-z

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

Céline Bellenguez^*, Fahri Küçükali, FinnGen Consortium, ADGC, CHARGE Consortium, European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, the European AD Initiative (EADI), GERAD, Demgene, Iris E. Jansen, Luca Kleineidam, Sonia Moreno-Grau, Najaf Amin, Adam C. Naj, Rafael Campos-Martin, Benjamin Grenier-Boley, Victor Andrade, Peter A. HolmansAnne 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, Lot D. de Witte, Henne Holstege, Lenore Launer, Chien Yueh Lee, Merel Mol, Danielle Posthuma, Christiane Reitz, Gijsje J.L. Snijders, Andre Uitterlinden, Aad van der Lugt, Jeroen van Rooij, John van Swieten, M. Marín, Chien Yueh Lee, Hieab Adams, Monique Breteler, Hata Comic, Tavia Evans, Maria Knol, Debora Melo van Lent, Helena Schmidt, Alexander Teumer, Dina Vojinovic, Mohsen Ghanbari, M. Arfan Ikram, Kristel Sleegers, Cornelia M. van Duijn, Alfredo Ramirez, Jean Charles Lambert

^*Corresponding author for this work

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

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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.

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
Publication status	Published - 1 Apr 2022

Bibliographical 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 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).

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New insights into the genetic etiology of Alzheimer’s disease and related dementiasFinal published version, 4.92 MBLicence: CC BY

Cite this

Bellenguez, C., Küçükali, F., FinnGen Consortium, ADGC, CHARGE Consortium, European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, the European AD Initiative (EADI), GERAD, Demgene, Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., ... Lambert, J. C. (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

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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 = "C{\'e}line Bellenguez and Fahri K{\"u}{\c c}{\"u}kali and {FinnGen Consortium} and ADGC and {CHARGE Consortium} and {European Alzheimer & Dementia BioBank (EADB)} and {The GR@ACE study group} and {DEGESCO consortium} and {the European AD Initiative (EADI)} and GERAD and Demgene 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 {de Witte}, {Lot D.} and Henne Holstege and Lenore Launer and Lee, {Chien Yueh} and Merel Mol and Danielle Posthuma and Christiane Reitz and Snijders, {Gijsje J.L.} and Andre Uitterlinden and {van der Lugt}, Aad and {van Rooij}, Jeroen and {van Swieten}, John and M. Mar{\'i}n and Lee, {Chien Yueh} and Hieab Adams and Monique Breteler and Hata Comic and Tavia Evans and Maria Knol and {van Lent}, {Debora Melo} and Helena Schmidt and Alexander Teumer and Dina Vojinovic and Mohsen Ghanbari and Ikram, {M. Arfan} and Kristel Sleegers and {van Duijn}, {Cornelia M.} and Alfredo Ramirez and Lambert, {Jean Charles}",

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).",

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month = apr,

day = "1",

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

language = "English",

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pages = "412--436",

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Bellenguez, C, Küçükali, F, FinnGen Consortium, ADGC, CHARGE Consortium, European Alzheimer & Dementia BioBank (EADB), The GR@ACE study group, DEGESCO consortium, the European AD Initiative (EADI), GERAD, Demgene, 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, de Witte, LD, Holstege, H, Launer, L, Lee, CY, Mol, M, Posthuma, D, Reitz, C, Snijders, GJL, Uitterlinden, A , van der Lugt, A , van Rooij, J , van Swieten, J, Marín, M, Lee, CY, Adams, H, Breteler, M, Comic, H, Evans, T, Knol, M, van Lent, DM, Schmidt, H, Teumer, A, Vojinovic, D, Ghanbari, M , Ikram, MA, Sleegers, K, van Duijn, CM, Ramirez, A & Lambert, JC 2022, 'New insights into the genetic etiology of Alzheimer’s disease and related dementias', Nature Genetics, vol. 54, no. 4, pp. 412-436. https://doi.org/10.1038/s41588-022-01024-z

TY - JOUR

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

AU - Bellenguez, Céline

AU - Küçükali, Fahri

AU - FinnGen Consortium

AU - ADGC

AU - CHARGE Consortium

AU - European Alzheimer & Dementia BioBank (EADB)

AU - The GR@ACE study group

AU - DEGESCO consortium

AU - the European AD Initiative (EADI)

AU - GERAD

AU - Demgene

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 - de Witte, Lot D.

AU - Holstege, Henne

AU - Launer, Lenore

AU - Lee, Chien Yueh

AU - Mol, Merel

AU - Posthuma, Danielle

AU - Reitz, Christiane

AU - Snijders, Gijsje J.L.

AU - Uitterlinden, Andre

AU - van der Lugt, Aad

AU - van Rooij, Jeroen

AU - van Swieten, John

AU - Marín, M.

AU - Lee, Chien Yueh

AU - Adams, Hieab

AU - Breteler, Monique

AU - Comic, Hata

AU - Evans, Tavia

AU - Knol, Maria

AU - van Lent, Debora Melo

AU - Schmidt, Helena

AU - Teumer, Alexander

AU - Vojinovic, Dina

AU - Ghanbari, Mohsen

AU - Ikram, M. Arfan

AU - Sleegers, Kristel

AU - van Duijn, Cornelia M.

AU - Ramirez, Alfredo

AU - Lambert, Jean Charles

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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