| Title: |
New insights into the genetic etiology of Alzheimer's disease and related dementias |
| Authors: |
EADB; GR ACE; DEGESCO; EADI; GERAD; Demgene; FinnGen; ADGC; CHARGE; Bellenguez, Celine; Kucukali, Fahri; Jansen, Iris E.; Koivisto, Anne; Lehtisalo, Jenni; Strandberg, Timo; Tuomilehto, Jaakko; Tienari, Pentti; Färkkilä, Martti; Pikkarainen, Sampsa; Kaprio, Jaakko |
| Contributors: |
University of Helsinki; Department of Neurosciences; HUS Internal Medicine and Rehabilitation; Timo Strandberg / Principal Investigator; Department of Medicine; Clinicum; HUS Neurocenter; Neurologian yksikkö; HUS Abdominal Center; Institute for Molecular Medicine Finland |
| Publisher Information: |
Nature Research |
| Publication Year: |
2022 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
GENOME-WIDE ASSOCIATION; NECROSIS-FACTOR-ALPHA; RISK LOCI; PREDICTION MODELS; AMYLOID-BETA; METAANALYSIS; VARIANTS; GENERATION; IMPUTATION; RESPONSES; Genetics; developmental biology; physiology |
| Description: |
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 epsilon 4 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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISBN: |
978-0-00-778079-2; 0-00-778079-6 |
| Relation: |
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 Metropole Communaute 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.; https://hdl.handle.net/10138/343325; 000778079600002 |
| Availability: |
https://hdl.handle.net/10138/343325 |
| Rights: |
info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.4B53FE79 |
| Database: |
BASE |