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...

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., Vronskaya, M., van der Lee, S. J., Amlie-Wolf, A., Bellenguez, C., Frizatti, A., Chouraki, V., Schmidt, H., Hakonarson, H., Munger, R., Schmidt, R., Farrer, L. A., Van Broeckhoven, C., O'Donovan, M. C., Destefano, A. L., …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: Aug 29, 2019
• 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
• Contract Date: Nov 1, 2018