Title
Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
Document Type
Article
Publication Date
3-1-2019
Publication Title
Nature genetics
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
Clinical Institute
Neurosciences (Brain & Spine)
Department
Neurosciences
Recommended Citation
Kunkle, Brian W; Grenier-Boley, Benjamin; Sims, Rebecca; Bis, Joshua C; Damotte, Vincent; Naj, Adam C; Boland, Anne; Vronskaya, Maria; van der Lee, Sven J; Amlie-Wolf, Alexandre; Bellenguez, Céline; Frizatti, Aura; Chouraki, Vincent; Martin, Eden R; Sleegers, Kristel; Badarinarayan, Nandini; Jakobsdottir, Johanna; Hamilton-Nelson, Kara L; Moreno-Grau, Sonia; Olaso, Robert; Raybould, Rachel; Chen, Yuning; Kuzma, Amanda B; Hiltunen, Mikko; Morgan, Taniesha; Ahmad, Shahzad; Vardarajan, Badri N; Epelbaum, Jacques; Hoffmann, Per; Boada, Merce; Beecham, Gary W; Garnier, Jean-Guillaume; Harold, Denise; Fitzpatrick, Annette L; Valladares, Otto; Moutet, Marie-Laure; Gerrish, Amy; Smith, Albert V; Qu, Liming; Bacq, Delphine; Denning, Nicola; Jian, Xueqiu; Zhao, Yi; Del Zompo, Maria; Fox, Nick C; Choi, Seung-Hoan; Mateo, Ignacio; Hughes, Joseph T; Adams, Hieab H; Malamon, John; Sanchez-Garcia, Florentino; Patel, Yogen; Brody, Jennifer A; Dombroski, Beth A; Naranjo, Maria Candida Deniz; Daniilidou, Makrina; 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https://digitalcommons.providence.org/publications/1131
