Alzheimer's disease; Gene expression; Genome wide association studies
Abstract :
[en] 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 A$\beta$ 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
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
Zompo, Maria Del
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
Eiriksdottir, Gudny
Mukherjee, Shubhabrata
Wallon, David
Uphill, James
Aspelund, Thor
Cantwell, Laura B.
Garzia, Fabienne
Galimberti, Daniela
Hofer, Edith
Butkiewicz, Mariusz
Fin, Bertrand
Scarpini, Elio
Sarnowski, Chloe
Bush, Will S.
Meslage, Stéphane
Kornhuber, Johannes
White, Charles C.
Song, Yuenjoo
Barber, Robert C.
Engelborghs, Sebastiaan
Sordon, Sabrina
Voijnovic, Dina
Adams, Perrie M.
Vandenberghe, Rik
Mayhaus, Manuel
Cupples, L. Adrienne
Albert, Marilyn S.
Deyn, Peter P. De
GU, Wei ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)