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

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/‘pro...

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Published in:	Nature genetics Vol. 54; no. 4; pp. 412 - 436
Main Authors:	Holmans, Peter A., de Rojas, Itziar, Bis, Joshua C., Alarcón-Martín, Emilio, Alcolea, Daniel, Alegret, Montserrat, Alvarez, Ignacio, Álvarez, Victoria, Antúnez, Carmen, Arosio, Beatrice, Athanasiu, Lavinia, Banaj, Nerisa, Below, Jennifer E., Benussi, Luisa, Bossù, Paola, Burholt, Vanessa, Calero, Miguel, Cervera-Carles, Laura, Chen, Hung-Hsin, Custodero, Carlo, de Paiva Lopes, Katia, DeStefano, Anita, Dichgans, Martin, Diehl-Schmid, Janine, Duron, Emmanuelle, Dufouil, Carole, Espinosa, Ana, Nielsen, Sune Fallgaard, Fenoglio, Chiara, Ferrari, Raffaele, Fox, Nick C., Frank-García, Ana, Galimberti, Daniela, Grande, Giulia, Green, Emma, Grünblatt, Edna, Grunin, Michelle, Gudnason, Vilmundur, Hampel, Harald, Hausner, Lucrezia, Hulsman, Marc, Kivipelto, Miia, Kornhuber, Johannes, Kuzma, Amanda B., Launer, Lenore, Ma, Yiyi, Maier, Wolfgang, Montes, Angel Martín, Masullo, Carlo, Mendoza, Silvia, Moebus, Susanne, Morgan, Kevin, Muchnik, Carolina, Mukherjee, Shubhabrata, Nacmias, Benedetta, Ngandu, Tiia, Nicolas, Gael, Nordestgaard, Børge G., Ortega, Gemma, Paolo, Caffarra, Papenberg, Goran, Peloso, Gina, Pérez-Cordón, Alba, Pérez-Tur, Jordi, Pineda, Juan A., Pisanu, Claudia, Polak, Thomas, Quintela, Inés, Rábano, Alberto, Reinders, Marcel J. T., Riedel-Heller, Steffi, Rubino, Elisa, Rujescu, Dan, Sanabria, Ángela, Sánchez-Valle, Raquel, Satizabal, Claudia L., Scarpini, Elio, Scheltens, Philip, Schmid, Matthias, Schneider, Anja, Serrano, Manuel, Solomon, Alina, Song, Yeunjoo, Spalletta, Gianfranco, Squassina, Alessio, Stordal, Eystein, Tartan, Juan Pablo, Tárraga, Lluís, Thomas, Tegos, Tosto, Giuseppe, Wallon, David, Wang, Li-San, Weinhold, Leonie, Wiltfang, Jens, Zare, Habil, Farrer, Lindsay A., Psaty, Bruce M., Williams, Julie, Frikke-Schmidt, Ruth, Deleuze, Jean-François
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.04.2022 Nature Publishing Group
Subjects:	45/43 631/208/205/2138 692/699/375/365/1283 Age factors Agriculture Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease Amyloid Amyotrophic lateral sclerosis Animal Genetics and Genomics Apolipoprotein E Biobanks Biomedical and Life Sciences Biomedicine Brain Cancer Research Cognitive ability Cognitive Dysfunction - psychology Consortia Dementia Dementia disorders Etiology Gene expression Gene Function Genome-wide association studies Genome-Wide Association Study Genomes Genomics Health risk assessment Human Genetics Humans Life Sciences Loci Meta-analysis Microglia Neurodegenerative diseases Parkinson's disease Proteins Risk management Santé publique et épidémiologie Tau protein tau Proteins - genetics Tumor necrosis factor-α Ubiquitin
ISSN:	1061-4036, 1546-1718, 1546-1718
Online Access:	Get full text
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Summary:	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. Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-022-01024-z