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

Céline Bellenguez*, Fahri Küçükali, FinnGen, ADGC, CHARGE, EADB, GR@ACE, DEGESCO, 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

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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 languageEnglish
Pages (from-to)412-436
Number of pages25
JournalNature Genetics
Volume54
Issue number4
DOIs
Publication statusPublished - 4 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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