Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
Aged
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ genetics
Case-Control Studies
Female
Genetic Loci
/ genetics
Genetic Predisposition to Disease
/ genetics
Genetic Testing
/ methods
Genome-Wide Association Study
/ methods
Haplotypes
/ genetics
Humans
Immunity
/ genetics
Lipid Metabolism
/ genetics
Lipids
/ genetics
Male
tau Proteins
/ genetics
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
12
03
2018
accepted:
22
01
2019
entrez:
2
3
2019
pubmed:
2
3
2019
medline:
25
4
2019
Statut:
ppublish
Résumé
Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10
Identifiants
pubmed: 30820047
doi: 10.1038/s41588-019-0358-2
pii: 10.1038/s41588-019-0358-2
pmc: PMC6463297
mid: NIHMS1021255
doi:
Substances chimiques
Amyloid beta-Peptides
0
Lipids
0
tau Proteins
0
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
414-430Subventions
Organisme : NIA NIH HHS
ID : P01 AG017586
Pays : United States
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Pays : United States
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Pays : United Kingdom
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Pays : United Kingdom
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Pays : United States
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Commentaires et corrections
Type : ErratumIn
Type : CommentIn
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