Article ; Online: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
2019 Volume 51, Issue 3, Page(s) 414–430
Abstract: 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 ... ...
| Abstract | 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 |
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| MeSH term(s) | 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 | ||||||||||
| Chemical Substances | Amyloid beta-Peptides ; Lipids ; tau Proteins | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2019-02-28 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Meta-Analysis ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 1108734-1 | ||||||||||
| ISSN | 1546-1718 ; 1061-4036 | ||||||||||
| ISSN (online) | 1546-1718 | ||||||||||
| ISSN | 1061-4036 | ||||||||||
| DOI | 10.1038/s41588-019-0358-2 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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