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Genetic meta-analysis of diagnosed Alzheimer's Disease identifies new risk loci and implicates Aβ, tau, immune and lipid processing.

Genetic meta-analysis of diagnosed Alzheimer's Disease identifies new risk loci and implicates Aβ, tau, immune and lipid processing.
Genetic meta-analysis of diagnosed Alzheimer's Disease identifies new risk loci and implicates Aβ, tau, immune and lipid processing.
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 × 10−7), 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.
1061-4036
414-430
Kunkle, Brian
b30dd816-4954-48df-8432-58e0c57b3542
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Sussams, Rebecca
7730c148-943d-4d97-b3c4-02e157bcc178
et al.
Kunkle, Brian
b30dd816-4954-48df-8432-58e0c57b3542
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Sussams, Rebecca
7730c148-943d-4d97-b3c4-02e157bcc178

Kunkle, Brian , et al. (2019) Genetic meta-analysis of diagnosed Alzheimer's Disease identifies new risk loci and implicates Aβ, tau, immune and lipid processing. Nature Genetics, 51 (3), 414-430. (doi:10.1038/s41588-019-0358-2).

Record type: Article

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 × 10−7), 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.

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More information

Accepted/In Press date: 22 January 2019
e-pub ahead of print date: 28 February 2019
Published date: 1 March 2019

Identifiers

Local EPrints ID: 430646
URI: http://eprints.soton.ac.uk/id/eprint/430646
ISSN: 1061-4036
PURE UUID: d5a1de62-32e4-48f9-a480-0b9def440660
ORCID for Clive Holmes: ORCID iD orcid.org/0000-0003-1999-6912

Catalogue record

Date deposited: 07 May 2019 16:30
Last modified: 26 Nov 2021 02:42

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Contributors

Author: Brian Kunkle
Author: Clive Holmes ORCID iD
Author: Rebecca Sussams
Corporate Author: et al.

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