Sims, Rebecca, van der Lee, Sven J., Naj, Adam C., Bellenguez, Celine 
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T., Jr., Fairchild, Thomas J., Bossu, Paola, Lopez, Oscar L., Frosch, Matthew P., Sacchinelli, Eleonora, Ghetti, Bernardino, Yang, Qiong, Huebinger, Ryan M., Jessen, Frank, Li, Shuo, Kamboh, M. 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Dirk, Tschanz, Joann, Fitzpatrick, Annette L., Kukull, Walter A., Norton, Maria, Aspelund, Thor ORCID: 0000-0002-7998-5433, Larson, Eric B., Munger, Ron, Rotter, Jerome I., Lipton, Richard B., Bullido, Maria J., Hofman, Albert, Montine, Thomas J., Coto, Eliecer, Boerwinkle, Eric, Petersen, Ronald C., Alvarez, Victoria, Rivadeneira, Fernando ORCID: 0000-0001-9435-9441, Reiman, Eric M., Gallo, Maura, O'Donnell, Christopher J., Reisch, Joan S., Bruni, Amalia Cecilia, Royall, Donald R., Dichgans, Martin, Sano, Mary, Galimberti, Daniela ORCID: 0000-0002-9284-5953, St George-Hyslop, Peter ORCID: 0000-0003-0796-7209, Scarpini, Elio, Tsuang, Debby W., Mancuso, Michelangelo ORCID: 0000-0003-2738-8562, Bonuccelli, Ubaldo, Winslow, Ashley R., Daniele, Antonio, Wu, Chuang-Kuo, Peters, Oliver, Nacmias, Benedetta, Riemenschneider, Matthias, Heun, Reinhard, Brayne, Carol ORCID: 0000-0001-5307-663X, Rubinsztein, David C., Bras, Jose ORCID: 0000-0001-8186-0333, Guerreiro, Rita ORCID: 0000-0001-5879-3486, Al-Chalabi, Ammar, Shaw, Christopher E., Collinge, John, Mann, David, Tsolaki, Magda ORCID: 0000-0002-2072-8010, Clarimon, Jordi, Sussams, Rebecca, Lovestone, Simon, O'Donovan, Michael C., Owen, Michael J., Behrens, Timothy W., Mead, Simon ORCID: 0000-0002-4326-1468, Goate, Alison M., Uitterlinden, Andre G., Holmes, Clive ORCID: 0000-0003-1999-6912, Cruchaga, Carlos, Ingelsson, Martin, Bennett, David A., Powell, John, Golde, Todd E., Graff, Caroline, De Jager, Philip L., Morgan, Kevin ORCID: 0000-0002-8217-2396, Ertekin-Taner, Nilufer, Combarros, Onofre, Psaty, Bruce M., Passmore, Peter, Younkin, Steven G., Berr, Claudine, Gudnason, Vilmundur ORCID: 0000-0001-5696-0084, Rujescu, Dan, Dickson, Dennis W., Dartigues, Jean-Francois, DeStefano, Anita L., Ortega-Cubero, Sara, Hakonarson, Hakon, Campion, Dominique, Boada, Merce, Kauwe, John Keoni, Farrer, Lindsay A., Van Broeckhoven, Christine ORCID: 0000-0003-0183-7665, Ikram, M. Arfan, Jones, Lesley, Haines, Jonathan L., Tzourio, Christophe, Launer, Lenore J., Escott-Price, Valentina, Mayeux-, Richard, Deleuze, Jean-Francois, Amin, Najaf ORCID: 0000-0002-8944-1771, Holmans, Peter A., Pericak-Vance, Margaret A., Amouyel, Philippe ORCID: 0000-0001-9088-234X, van Duijn, Cornelia M., Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Wang, Li-San, Lambert, Jean-Charles, Seshadri, Sudha ORCID: 0000-0001-6135-2622, Williams, Julie ORCID: 0000-0002-4069-0259 and Schellenberg, Gerard D.
(2017).
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Nature Genet., 49 (9).
S. 1373 - 1388.
NEW YORK:
NATURE PUBLISHING GROUP.
ISSN 1546-1718
Full text not available from this repository.
Abstract
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
| Item Type: |
Journal Article
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| Creators: |
| Creators | Email | ORCID | ORCID Put Code |
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| Sims, Rebecca | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | van der Lee, Sven J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Naj, Adam C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Bellenguez, Celine | UNSPECIFIED | orcid.org/0000-0002-1240-7874 | UNSPECIFIED | | Badarinarayan, Nandini | UNSPECIFIED | orcid.org/0000-0002-6944-748X | UNSPECIFIED | | Jakobsdottir, Johanna | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Kunkle, Brian W. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Boland, Anne | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Raybould, Rachel | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Bis, Joshua C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Martin, Eden R. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Grenier-Boley, Benjamin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Heilmann-Heimbach, Stefanie | UNSPECIFIED | orcid.org/0000-0003-1057-465X | UNSPECIFIED | | Chouraki, Vincent | UNSPECIFIED | orcid.org/0000-0002-4698-1794 | UNSPECIFIED | | Kuzma, Amanda B. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Sleegers, Kristel | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Vronskaya, Maria | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Ruiz, Agustin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Graham, Robert R. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Olaso, Robert | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Hoffmann, Per | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Grove, Megan L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Vardarajan, Badri N. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Hiltunen, Mikko | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Noethen, Markus M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | White, Charles C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Hamilton-Nelson, Kara L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Epelbaum, Jacques | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Maier, Wolfgang | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Choi, Seung-Hoan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Beecham, Gary W. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Dulary, Cecile | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Herms, Stefan | UNSPECIFIED | orcid.org/0000-0002-2786-8200 | UNSPECIFIED | | Smith, Albert V. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Funk, Cory C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Derbois, Celine | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Forstner, Andreas J. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Ahmad, Shahzad | UNSPECIFIED | orcid.org/0000-0002-8658-3790 | UNSPECIFIED | | Li, Hongdong | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Bacq, Delphine | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Harold, Denise | UNSPECIFIED | orcid.org/0000-0001-5195-0143 | UNSPECIFIED | | Satizabal, Claudia L. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Valladares, Otto | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Squassina, Alessio | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Thomas, Rhodri | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Brody, Jennifer A. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Qu, Liming | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Sanchez-Juan, Pascual | UNSPECIFIED | orcid.org/0000-0002-6081-8037 | UNSPECIFIED | | Morgan, Taniesha | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Wolters, Frank J. | UNSPECIFIED | orcid.org/0000-0003-2226-4050 | UNSPECIFIED | | Zhao, Yi | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Sanchez Garcia, Florentino | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Denning, Nicola | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Fornage, Myriam | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Malamon, John | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Deniz Naranjo, Maria Candida | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Majounie, Elisa | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Mosley, Thomas H. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Dombroski, Beth | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Wallon, David | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Lupton, Michelle K. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Dupuis, Josee | UNSPECIFIED | orcid.org/0000-0003-2871-3603 | UNSPECIFIED | | Whitehead, Patrice | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Fratiglioni, Laura | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Medway, Christopher | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Jian, Xueqiu | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Mukherjee, Shubhabrata | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Keller, Lina | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Brown, Kristelle | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Lin, Honghuang | UNSPECIFIED | orcid.org/0000-0003-3043-3942 | UNSPECIFIED | | Cantwell, Laura B. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Panza, Francesco | UNSPECIFIED | orcid.org/0000-0002-7220-0656 | UNSPECIFIED | | McGuinness, Bernadette | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Moreno-Grau, Sonia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Burgess, Jeremy D. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Solfrizzi, Vincenzo | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Proitsi, Petra | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Adams, Hieab H. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Allen, Mariet | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Seripa, Davide | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Pastor, Pau | UNSPECIFIED | orcid.org/0000-0002-7493-8777 | UNSPECIFIED | | Cupples, L. Adrienne | UNSPECIFIED | orcid.org/0000-0003-0273-7965 | UNSPECIFIED | | Price, Nathan D. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Hannequin, Didier | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Frank-Garcia, Ana | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Levy, Daniel | UNSPECIFIED | orcid.org/0000-0003-1843-8724 | UNSPECIFIED | | Chakrabarty, Paramita | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Caffarra, Paolo | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Giegling, Ina | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Beiser, Alexa S. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Giedraitis, Vilmantas | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Hampel, Harald | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Garcia, Melissa E. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Wang, Xue | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Lannfelt, Lars | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Mecocci, Patrizia | UNSPECIFIED | orcid.org/0000-0003-0729-5246 | UNSPECIFIED | | Eiriksdottir, Gudny | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Crane, Paul K. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Pasquier, Florence | UNSPECIFIED | orcid.org/0000-0001-9880-9788 | UNSPECIFIED | | Boccardi, Virginia | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Henandez, Isabel | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Barber, Robert C. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Scherer, Martin | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Tarraga, Lluis | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Adams, Perrie M. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Leber, Markus | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Chen, Yuning | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Albert, Marilyn S. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Riedel-Heller, Steffi | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Emilsson, Valur | UNSPECIFIED | orcid.org/0000-0001-9982-0524 | UNSPECIFIED | | Beekly, Duane | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Braae, Anne | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Schmidt, Reinhold | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Blacker, Deborah | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Masullo, Carlo | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Schmidt, Helena | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Doody, Rachelle S. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED | | Spalletta, Gianfranco | UNSPECIFIED | orcid.org/0000-0002-7432-4249 | UNSPECIFIED | | Longstreth, W. 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|
| URN: |
urn:nbn:de:hbz:38-221016 |
| DOI: |
10.1038/ng.3916 |
| Journal or Publication Title: |
Nature Genet. |
| Volume: |
49 |
| Number: |
9 |
| Page Range: |
S. 1373 - 1388 |
| Date: |
2017 |
| Publisher: |
NATURE PUBLISHING GROUP |
| Place of Publication: |
NEW YORK |
| ISSN: |
1546-1718 |
| Language: |
English |
| Faculty: |
Unspecified |
| Divisions: |
Unspecified |
| Subjects: |
no entry |
| Uncontrolled Keywords: |
| Keywords | Language |
|---|
| GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; LOW-FREQUENCY; IDENTIFIES VARIANTS; COMMON VARIANTS; WAVE2 COMPLEX; LOCI; RISK; SUSCEPTIBILITY; METAANALYSIS | Multiple languages | | Genetics & Heredity | Multiple languages |
|
| Refereed: |
Yes |
| URI: |
http://kups.ub.uni-koeln.de/id/eprint/22101 |
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