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

Kunkle, Brian W.; Grenier-Boley, Benjamin; Sims, Rebecca; Bis, Joshua C.; Naj, Adam C.; Boland, Anne; Vronskaya, Maria; van der Lee, Sven J; Amlie-Wolf, Alex; Bellenguez, Celine; Frizatti, Aura; Chouraki, Vincent; Schmidt, Helena; Hakonarson, Hakon; Munger, Ron; Schmidt, Reinhold; Farrer, Lindsay A.; Van Broeckhoven, Christine; O'Donovan, Michael C.; Destefano, Anita L.; Jones, Lesley; Haines, Jonathan L.; Deleuze, Jean-Francois; Owen, Michael J.; Gudnason, Vilmundur; Mayeux, Richard P.; Escott-Price, Valentina; Psaty, Bruce M.; Ruiz, Agustin; Ramirez, Alfredo; Wang, Li-San; van Duijn, Cornelia M.; Holmans, Peter A.; Seshadri, Sudha; Williams, Julie; Amouyel, Philippe; Schellenberg, Gerard D.; Lambert, Jean-Charles; Pericak-Vance, Margaret A.; Morgan, Kevin; Alzheimer's Disease Genetics Consortium (ADGC); European Alzheimer's Disease Initiative (EADI); Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE); Genetic and Environmental Risk in Alzheimer's Disease...

Authors

Brian W. Kunkle

Benjamin Grenier-Boley

Rebecca Sims

Joshua C. Bis

Adam C. Naj

Anne Boland

Maria Vronskaya

Sven J van der Lee

Alex Amlie-Wolf

Celine Bellenguez

Aura Frizatti

Vincent Chouraki

Helena Schmidt

Hakon Hakonarson

Ron Munger

Reinhold Schmidt

Lindsay A. Farrer

Christine Van Broeckhoven

Michael C. O'Donovan

Anita L. Destefano

Lesley Jones

Jonathan L. Haines

Jean-Francois Deleuze

Michael J. Owen

Vilmundur Gudnason

Richard P. Mayeux

Valentina Escott-Price

Bruce M. Psaty

Agustin Ruiz

Alfredo Ramirez

Li-San Wang

Cornelia M. van Duijn

Peter A. Holmans

Sudha Seshadri

Julie Williams

Philippe Amouyel

Gerard D. Schellenberg

Jean-Charles Lambert

Margaret A. Pericak-Vance

Kevin Morgan

Alzheimer's Disease Genetics Consortium (ADGC)

European Alzheimer's Disease Initiative (EADI)

Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE)

Genetic and Environmental Risk in Alzheimer's Disease Consortium (GERAD/PERADES)



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.

Citation

Kunkle, B. W., Grenier-Boley, B., Sims, R., Bis, J. C., Naj, A. C., Boland, A., …Genetic and Environmental Risk in 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. Nature Genetics, 51(3), 414-430. https://doi.org/10.1038/s41588-019-0358-2

Journal Article Type Article
Acceptance Date Jan 22, 2019
Online Publication Date Feb 28, 2019
Publication Date Feb 28, 2019
Deposit Date Nov 1, 2018
Publicly Available Date Mar 28, 2024
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 51
Issue 3
Pages 414-430
DOI https://doi.org/10.1038/s41588-019-0358-2
Public URL https://nottingham-repository.worktribe.com/output/1215926
Publisher URL https://www.nature.com/articles/s41588-019-0358-2

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