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David, Ringman, John M., Warden, Donald, Roberson, Erik D., Wilcock, Gordon, Rogaeva, Ekaterina, Bruni, Amalia Cecilia, Rosen, Howard J., Gallo, Maura, Rosenberg, Roger N., Ben-Shlomo, Yoav, Sager, Mark A., Mecocci, Patrizia ORCID: 0000-0003-0729-5246, Saykin, Andrew J., Pastor, Pau ORCID: 0000-0002-7493-8777, Cuccaro, Michael L., Vance, Jeffery M., Schneider, Julie A., Schneider, Lori S., Slifer, Susan, Seeley, William W., Smith, Amanda G., Sonnen, Joshua A., Spina, Salvatore, Stern, Robert A., Swerdlow, Russell H., Tang, Mitchell, Tanzi, Rudolph E., Trojanowski, John Q., Troncoso, Juan C., Van Deerlin, Vivianna M., Van Eldik, Linda J., Vinters, Harry V., Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A., Wilhelmsen, Kirk C., Williamson, Jennifer, Wingo, Thomas S., Woltjer, Randall L., Wright, Clinton B., Yu, Chang-En, Yu, Lei, Saba, Yasaman, Pilotto, Alberto, Bullido, Maria J., Peters, Oliver, Crane, Paul K., Bennett, David, Bosco, Paola, Coto, Eliecer, Boccardi, Virginia, De Jager, Phil L., Lleo, Alberto, Warner, Nick, Lopez, Oscar L., Ingelsson, Martin, Deloukas, Panagiotis, Cruchaga, Carlos, Graff, Caroline, Gwilliam, Rhian, Fornage, Myriam, Goate, Alison M., Sanchez-Juan, Pascual, Kehoe, Patrick G., Amin, Najaf, Ertekin-Taner, Nilifur, Berr, Claudine ORCID: 0000-0001-5254-7655, Debette, Stphanie, Love, Seth, Launer, Lenore J., Younkin, Steven G., Dartigues, Jean-Francois, Corcoran, Chris, Ikram, M. Arfan, Dickson, Dennis W., Nicolas, Gael, Campion, Dominique, Tschanz, JoAnn, Schmidt, Helena, Hakonarson, Hakon, Clarimon, Jordi, 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 ORCID: 0000-0001-5696-0084, Mayeux, Richard, Escott-Price, Valentina ORCID: 0000-0003-1784-5483, Psaty, Bruce M., Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Wang, Li-San, Ruiz, Agustin, van Duijn, Cornelia M., Holmans, Peter A., Seshadri, Sudha ORCID: 0000-0001-6135-2622, Williams, Julie ORCID: 0000-0002-4069-0259, Amouyel, Phillippe, Schellenberg, Gerard D., Lambert, Jean-Charles and Pericak-Vance, Margaret A. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing. Nature Genet., 51 (3). S. 414 - 434. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1546-1718

Full text not available from this repository.

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 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 x 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
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Grenier-Boley, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Damotte, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Naj, Adam C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boland, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vronskaya, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Qu, LimingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Nacmias, BenedettaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Spalletta, GianfrancoUNSPECIFIEDorcid.org/0000-0002-7432-4249UNSPECIFIED
Raskind, MurrayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Wilcock, GordonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Bruni, Amalia CeciliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Ben-Shlomo, YoavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Tanzi, Rudolph E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trojanowski, John Q.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Troncoso, Juan C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Vonsattel, Jean PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weintraub, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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Wingo, Thomas S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woltjer, Randall L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, Clinton B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, Chang-EnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, LeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saba, YasamanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pilotto, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullido, Maria J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crane, Paul K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bennett, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bosco, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coto, EliecerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boccardi, VirginiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jager, Phil L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lleo, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warner, NickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopez, Oscar L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ingelsson, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deloukas, PanagiotisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruchaga, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graff, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gwilliam, RhianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fornage, MyriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goate, Alison M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanchez-Juan, PascualUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kehoe, Patrick G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amin, NajafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ertekin-Taner, NilifurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berr, ClaudineUNSPECIFIEDorcid.org/0000-0001-5254-7655UNSPECIFIED
Debette, StphanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Love, SethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Launer, Lenore J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Younkin, Steven G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dartigues, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corcoran, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ikram, M. ArfanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dickson, Dennis W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nicolas, GaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Campion, DominiqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tschanz, JoAnnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, HelenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hakonarson, HakonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clarimon, JordiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Munger, RonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ReinholdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrer, Lindsay A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Broeckhoven, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
O'Donovan, Michael C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
DeStefano, Anita L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, LesleyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haines, Jonathan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Owen, Michael J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gudnason, VilmundurUNSPECIFIEDorcid.org/0000-0001-5696-0084UNSPECIFIED
Mayeux, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Escott-Price, ValentinaUNSPECIFIEDorcid.org/0000-0003-1784-5483UNSPECIFIED
Psaty, Bruce M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
Wang, Li-SanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruiz, AgustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Duijn, Cornelia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holmans, Peter A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seshadri, SudhaUNSPECIFIEDorcid.org/0000-0001-6135-2622UNSPECIFIED
Williams, JulieUNSPECIFIEDorcid.org/0000-0002-4069-0259UNSPECIFIED
Amouyel, PhillippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schellenberg, Gerard D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lambert, Jean-CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pericak-Vance, Margaret A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-155699
DOI: 10.1038/s41588-019-0358-2
Journal or Publication Title: Nature Genet.
Volume: 51
Number: 3
Page Range: S. 414 - 434
Date: 2019
Publisher: NATURE PUBLISHING GROUP
Place of Publication: NEW YORK
ISSN: 1546-1718
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; DOMAIN-CONTAINING OXIDOREDUCTASE; ANGIOTENSIN-CONVERTING ENZYME; AMYLOID-BETA; TRANSCRIPTION FACTOR; GENOTYPE IMPUTATION; APOLIPOPROTEIN-E; COMMON VARIANTS; ONSET; MUTATIONSMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15569

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