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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
Nature genetics, 2019-03, Vol.51 (3), p.414-430
2019

Details

Autor(en) / Beteiligte
Titel
Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
Ist Teil von
  • Nature genetics, 2019-03, Vol.51 (3), p.414-430
Ort / Verlag
United States: Nature Publishing Group
Erscheinungsjahr
2019
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
Sprache
Englisch
Identifikatoren
ISSN: 1061-4036, 1546-1718
eISSN: 1546-1718
DOI: 10.1038/s41588-019-0358-2
Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_140390500
Format
–
Schlagworte
ADAMTS-1 protein, Age, Aged, Alzheimer Disease - genetics, Alzheimer's disease, Alzheimers disease, Amyloid beta-Peptides - genetics, Amyloid precursor protein, Case-Control Studies, Consortia, Datasets, Dementia, Dementia disorders, Family medical history, Female, Gene loci, Gene mapping, Genes, Genetic analysis, Genetic Loci - genetics, Genetic Predisposition to Disease - genetics, Genetic Testing - methods, Genetic variance, Genetics, Genome-Wide Association Study - methods, Genomes, Genomics, Haplotypes - genetics, Health risks, Histocompatibility antigen HLA, Humans, Immunity, Immunity - genetics, Lipid metabolism, Lipid Metabolism - genetics, Lipids, Lipids - genetics, Male, Mapping, Medicin och hälsovetenskap, Meta-analysis, Metabolism, Neurodegenerative diseases, Ontology, Protein turnover, Proteins, Risk analysis, Risk factors, Secretase, Tau protein, tau Proteins - genetics, White blood cells

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