TY - JOUR
T1 - Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing
AU - Kunkle, Brian W.
AU - Grenier-Boley, Benjamin
AU - Sims, Rebecca
AU - Bis, Joshua C.
AU - Damotte, Vincent
AU - Naj, Adam C.
AU - Boland, Anne
AU - Vronskaya, Maria
AU - van der Lee, Sven J.
AU - Amlie-Wolf, Alexandre
AU - Bellenguez, Céline
AU - Frizatti, Aura
AU - Chouraki, Vincent
AU - Martin, Eden R.
AU - Sleegers, Kristel
AU - Badarinarayan, Nandini
AU - Jakobsdottir, Johanna
AU - Hamilton-Nelson, Kara L.
AU - Moreno-Grau, Sonia
AU - Olaso, Robert
AU - Raybould, Rachel
AU - Chen, Yuning
AU - Kuzma, Amanda B.
AU - Hiltunen, Mikko
AU - Morgan, Taniesha
AU - Ahmad, Shahzad
AU - Vardarajan, Badri N.
AU - Epelbaum, Jacques
AU - Hoffmann, Per
AU - Boada, Merce
AU - Beecham, Gary W.
AU - Garnier, Jean Guillaume
AU - Harold, Denise
AU - Fitzpatrick, Annette L.
AU - Valladares, Otto
AU - Moutet, Marie Laure
AU - Gerrish, Amy
AU - Smith, Albert V.
AU - Qu, Liming
AU - Bacq, Delphine
AU - Denning, Nicola
AU - Jian, Xueqiu
AU - Zhao, Yi
AU - Del Zompo, Maria
AU - Fox, Nick C.
AU - Choi, Seung Hoan
AU - Mateo, Ignacio
AU - Fardo, David W.
AU - Abner, Erin
AU - Van Eldik, Linda J.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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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U2 - 10.1038/s41588-019-0358-2
DO - 10.1038/s41588-019-0358-2
M3 - Article
C2 - 30820047
AN - SCOPUS:85063748662
SN - 1061-4036
VL - 51
SP - 414
EP - 430
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -