Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

A novel Alzheimer disease locus located near the gene encoding tau protein

Jun, G, Ibrahim-Verbaas, C A, Vronskaya, M, Lambert, J-C, Chung, J, Naj, A C, Kunkle, B W, Wang, L-S, Bis, J C, Bellenguez, C, Harold, D, Lunetta, K L, Destefano, A L, Grenier-Boley, B, Sims, R, Beecham, G W, Smith, A V, Chouraki, V, Hamilton-Nelson, K L, Ikram, M A, Fievet, N, Denning, Nicola, Martin, E R, Schmidt, H, Kamatani, Y, Dunstan, Melanie, Valladares, O, Laza, A R, Zelenika, D, Ramirez, A, Foroud, T M, Choi, S-H, Boland, A, Becker, T, Kukull, W A, van der Lee, S J, Pasquier, F, Cruchaga, C, Beekly, D, Fitzpatrick, A L, Hanon, O, Gill, M, Barber, R, Gudnason, V, Campion, D, Love, S, Bennett, D A, Amin, N, Berr, C, Tsolaki, Magda, Buxbaum, J D, Lopez, O L, Deramecourt, V, Fox, N C, Cantwell, L B, Tárraga, L, Dufouil, C, Hardy, J, Crane, P K, Eiriksdottir, G, Hannequin, D, Clarke, R, Evans, D, Mosley, T H, Letenneur, L, Brayne, C, Maier, W, De Jager, P, Emilsson, V, Dartigues, J-F, Hampel, H, Kamboh, M I, de Bruijn, R F A G, Tzourio, C, Pastor, P, Larson, E B, Rotter, J I, O'Donovan, Michael Conlon, Montine, T J, Nalls, M A, Mead, S, Reiman, E M, Jonsson, P V, Holmes, C, St George-Hyslop, P H, Boada, M, Passmore, P, Wendland, J R, Schmidt, R, Morgan, K, Winslow, A R, Powell, J F, Carasquillo, M, Younkin, S G, Jakobsdóttir, J, Kauwe, J S K, Wilhelmsen, K C, Rujescu, D, Nöthen, M M, Hofman, A, Jones, Lesley, Adams, Perrie M, Albert, Marilyn S, Albin, Roger L, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Baldwin, Clinton T, Barmada, Michjael M, Barnes, Lisa L, Beach, Thomas G, Becker, James T, Bigio, Eileen H, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Burke, James R, Cairns, Nigel J, Cao, Chuanhai, Carlson, Chris S, Carlsson, Cynthia M, Carney, Regina M, Carrasquillo, Minerva M, Carroll, Steven L, Chui, Helena C, Clark, David G, Corneveaux, Jason, Cribbs, David H, Crocco, Elizabeth A, Cruchaga, Carlos, De Jager, Philip L, DeCarli, Charles, DeKosky, Steven T, Demirci, F Yesim, Dick, Malcolm, Dickson, Dennis W, Doody, Rachelle S, Duara, Ranjan, Ertekin-Taner, Nilufer, Faber, Kelley M, Fairchild, Thomas J, Fallon, Kenneth B, Farlow, Martin R, Ferris, Steven, Frosch, Matthew P, Galasko, Douglas R, Gearing, Marla, Geschwind, Daniel H, Ghetti, Bernardino, Gilbert, John R, Glass, Jonathan D, Graff-Radford, Neill R, Green, Robert C, Growdon, John H, Hakonarson, Hakon, Hamilton, Ronald L, Hardy, John, Harrell, Lindy E, Head, Elizabeth, Honig, Lawrence S, Huebinger, Ryan M, Huentelman, Matthew J, Hulette, Christine M, Hyman, Bradley T, Jarvik, Gail P, Jicha, Gregory A, Jin, Lee-Way, Karydas, Anna, Kauwe, John SK, Kaye, Jeffrey A, Kim, Ronald, Koo, Edward H, Kowall, Neil W, Kramer, Joel H, LaFerla, Frank M, Lah, James J, Leverenz, James B, Levey, Allan I, Li, Ge, Lieberman, Andrew P, Lin, Chiao-Feng, Lopez, Oscar L, Lyketsos, Constantine G, Mack, Wendy J, Marson, Daniel C, Martiniuk, Frank, Mash, Deborah C, Masliah, Eliezer, McCormick, Wayne C, McCurry, Susan M, McDavid, Andrew N, McKee, Ann C, Mesulam, Marsel, Miller, Bruce L, Miller, Carol A, Miller, Joshua W, Morris, John C, Mukherjee, Shubhabrata, Murrell, Jill R, Myers, Amanda J, O'Bryant, Sid, Olichney, John M, Pankratz, Vernon S, Parisi, Joseph E, Partch, Amanda, Paulson, Henry L, Perry, William, Peskind, Elaine, Petersen, Ronald C, Pierce, Aimee, Poon, Wayne W, Potter, Huntington, Quinn, Joseph F, Raj, Ashok, Raskind, Murray, Reisberg, Barry, Reisch, Joan S, Reitz, Christiane, Ringman, John M, Roberson, Erik D, Rogaeva, Ekaterina, Rosen, Howard J, Rosenberg, Roger N, Royall, Donald R, Sager, Mark A, Sano, Mary, Saykin, Andrew J, Schneider, Julie A, Schneider, Lon S, Seeley, William W, Smith, Amanda G, Sonnen, Joshua A, Spina, Salvatore, Stern, Robert A, Tanzi, Rudolph E, Thornton-Wells, Tricia A, Trojanowski, John Q, Troncoso, Juan C, Tsuang, Debby W, Van Deerlin, Vivianna M, Van Eldik, Linda J, Vardarajan, Badri N, Vinters, Harry V, Vonsattel, Jean Paul, Weintraub, Sandra, Welsh-Bohmer, Kathleen A, Williamson, Jennifer, Wishnek, Sarah, Woltjer, Randall L, Wright, Clinton B, Wu, Chuang-Kuo, Yu, Chang-En, Yu, Lei, Au, Rhoda, Wolf, Philip A, Beiser, Alexa, Satizabal, Claudia, Uitterlinden, Andre G, Rivadeneira, Fernando, Koudstaal, Peter J, Longstreth Jr, William T, Becker, James T, Kuller, Lewis H, Lumley, Thomas, Rice, Kenneth, Harris, Tamara B, Nalls, Michael, Marksteiner, Josef J M, Dal-Bianco, Peter, Töglhofer, Anna Maria, Freudenberger, Paul, Ransmayr, Gerhard, Benke, Thomas, Toeglhofer, Anna M, Boerwinkle, Eric, Bressler, Jan, Fornage, Myriam, Morón, Francisco J, Hernández, Isabel, Roca, Maitee Rosende, Mauleón, Ana, Alegret, Montserrat, Ramírez-Lorca, Reposo, González-Perez, Antonio, Alpérovitch, Annick, Alvarez, Victoria, Barberger-Gateau, Pascale, Bettens, Karolien, Bossù, Paola, Brice, Alexis, Bullido, Maria, Caffara, Paolo, Clarimon, Jordi, Combarros, Onofre, Coto, Eliecer, Zampo, Maria del, Delepine, Marc, Deniz Naranjo, Maria Candida, Epelbaum, Jacques, Fratiglioni, Laura, Galimberti, Daniela, Graff, Caroline, Hiltunen, Mikko, Ingelsson, Martin, Keller, Lina, Lannfelt, Lars, Llèo, Alberto, Mancuso, Michelangelo, Mateo, Ignacio, Mecocci, Patrizia, Nacmias, Benedetta, Panza, Francesco, Pilotto, Alberto, Garcia, Florentino Sanchez, Scarpini, Elio, Seripa, Davide, Sleegers, Kristel, Soininen, Hlikka, Sorbi, Sandro, Spalletta, Gianfranco, Wallon, David, Thomas, Charlene, Gerrish, Amy, Chapman, Jade, Stretton, Alexandra, Morgan, Angharad, Oldham, Harriet, Owen, Michael John, Kehoe, Patrick G, Medway, Christopher, Brown, Kristelle, Lord, Jenny, Turton, James, Hooper, Nigel M, Vardy, Emma, Warren, Jason D, Schott, Jonathan M, Uphill, James, Hollingworth, Paul, Psy, DClin, Ryan, Natalie, Rossor, Martin, Collinge, John, Ben-Shlomo, Yoav, Makrina, Daniilidou, Gkatzima, Olymbia, Lupton, Michelle, Koutroumani, Maria, Avramidou, Despoina, Germanou, Antonia, Jessen, Frank, Riedel-Heller, Steffi, Dichgans, Martin, Heun, Reiner, Kölsch, Heike, Schürmann, Britta, Herold, Christine, Lacour, André, Drichel, Dmitriy, Hoffmann, Per, Kornhuber, Johannes, Gu, Wei, Feulner, Thomas, Mayhaus, Manuel, Pichler, Sabrina, Riemenschneider, Matthias, Bussche, Hendrik van den, Lawlor, Brian, Lynch, Aoibhinn, Mann, David, Smith, A David, Warden, Donald, Wilcock, Gordon, Heuser, Isabella, Wiltfang, Jens, Frölich, Lutz, Hüll, Michael, Mayo, Kevin, Livingston, Gill, Bass, Nicholas J, Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Al-Chalabi, Ammar, Shaw, Christopher E, Singleton, Andrew B, Guerreiro, Rita, Russo, Giancarlo, Jöckel, Karl-Heinz, Moebus, Susanne, Klopp, Norman, Wichmann, H-Erich, Dickson, Dennis W, Graff-Radford, Neill R, Ma, Li, Bisceglio, Gina, Fisher, Elizabeth, Warner, Nick, Pickering-Brown, Stuart, Craig, David, Johnston, Janet A, McGuinness, Bernadette, Todd, Stephen, Rubinsztein, David C, Lovestone, Simon, Bayer, Anthony, Gallacher, John, Proitsi, Petroula, Ortega-Cubero, Sara, Haines, J L, Psaty, B M, Van Broeckhoven, C, Holmans, P, Launer, L J, Mayeux, R, Lathrop, M, Goate, A M, Escott-Price, Valentina, Seshadri, S, Pericak-Vance, M A, Amouyel, P, Williams, J, van Duijn, C M, Schellenberg, G D and Farrer, L A 2015. A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular Psychiatry 21 , pp. 108-117. 10.1038/mp.2015.23

Full text not available from this repository.

Abstract

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10-8), frontal cortex (P⩽1.3 × 10-9) and temporal cortex (P⩽1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Publisher: Springer Nature
ISSN: 1359-4184
Date of Acceptance: 8 January 2015
Last Modified: 19 Oct 2019 02:41
URI: http://orca.cf.ac.uk/id/eprint/85008

Citation Data

Cited 48 times in Google Scholar. View in Google Scholar

Cited 65 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item