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

Publication ,  Journal Article
Kunkle, BW; Grenier-Boley, B; Sims, R; Bis, JC; Damotte, V; Naj, AC; Boland, A; Vronskaya, M; van der Lee, SJ; Amlie-Wolf, A; Bellenguez, C ...
Published in: Nat Genet
March 2019

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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Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2019

Volume

51

Issue

3

Start / End Page

414 / 430

Location

United States

Related Subject Headings

  • tau Proteins
  • Male
  • Lipids
  • Lipid Metabolism
  • Immunity
  • Humans
  • Haplotypes
  • Genome-Wide Association Study
  • Genetic Testing
  • Genetic Predisposition to Disease
 

Citation

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Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., … Genetic and Environmental Risk in AD/Defining Genetic, Polygenic and Environmental Risk for Alzheimer’s Disease Consortium (GERAD/PERADES),. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet, 51(3), 414–430. https://doi.org/10.1038/s41588-019-0358-2
Kunkle, Brian W., Benjamin Grenier-Boley, Rebecca Sims, Joshua C. Bis, Vincent Damotte, Adam C. Naj, Anne Boland, et al. “Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.Nat Genet 51, no. 3 (March 2019): 414–30. https://doi.org/10.1038/s41588-019-0358-2.
Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019 Mar;51(3):414–30.
Kunkle, Brian W., et al. “Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.Nat Genet, vol. 51, no. 3, Mar. 2019, pp. 414–30. Pubmed, doi:10.1038/s41588-019-0358-2.
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Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019 Mar;51(3):414–430.

Published In

Nat Genet

DOI

EISSN

1546-1718

Publication Date

March 2019

Volume

51

Issue

3

Start / End Page

414 / 430

Location

United States

Related Subject Headings

  • tau Proteins
  • Male
  • Lipids
  • Lipid Metabolism
  • Immunity
  • Humans
  • Haplotypes
  • Genome-Wide Association Study
  • Genetic Testing
  • Genetic Predisposition to Disease