A novel Alzheimer disease locus located near the gene encoding tau protein
Creators: name: Herold, Christine
name: Bird, Thomas D
name: Destefano, 
name: Hanon, 
name: Tárraga, 
name: Levey, Allan I
name: Vinters, Harry V
name: Frölich, Lutz
name: Rujescu, 
name: Reisberg, Barry
name: Martiniuk, Frank
name: Raskind, Murray
name: Clarke, 
name: Germanou, Antonia
name: Mosley, 
name: Mead, 
name: Miller, Carol A
name: Kehoe, Patrick G
name: Apostolova, Liana G
name: Roberson, Erik D
name: Hamilton, Ronald L
name: Welsh-Bohmer, Kathleen A
name: Reiman, 
name: Larson, 
name: Baldwin, Clinton T
name: Schneider, Julie A
name: Dunstan, 
name: Letenneur, 
name: Corneveaux, Jason
name: DeKosky, Steven T
name: Pickering-Brown, Stuart
name: Schellenberg, 
name: Owen, Michael J
name: Escott-Price, 
name: Rossor, Martin
name: Farrer, 
name: Nalls, 
name: Turton, James
name: Smith, Amanda G
name: Royall, Donald R
name: McQuillin, Andrew
name: Mukherjee, Shubhabrata
name: Vonsattel, Jean Paul
name: Dartigues, 
name: Wang, 
name: Seshadri, 
name: Leverenz, James B
name: Oldham, Harriet
name: Masliah, Eliezer
name: Glass, Jonathan D
name: Dick, Malcolm
name: Ben-Shlomo, Yoav
name: Yu, Lei
name: Kamboh, 
name: Faber, Kelley M
name: Ringman, John M
name: Russo, Giancarlo
name: Tanzi, Rudolph E
name: Schott, Jonathan M
name: Jöckel, Karl-Heinz
name: Crocco, Elizabeth A
name: Vronskaya, 
name: Tzourio, 
name: Lin, Chiao-Feng
name: Lord, Jenny
name: Lynch, Aoibhinn
name: Powell, 
name: Bigio, Eileen H
name: Buxbaum, 
name: Ma, Li
name: Ortega-Cubero, Sara
name: Riedel-Heller, Steffi
name: Emilsson, 
name: Barmada, Michjael M
name: Albin, Roger L
name: Gill, 
name: DeCarli, Charles
name: Wendland, 
name: Partch, Amanda
name: Collinge, John
name: Hooper, Nigel M
name: Cao, Chuanhai
name: Heuser, Isabella
name: Koo, Edward H
name: Adams, Perrie M
name: Miller, Joshua W
name: Miller, Bruce L
name: Murrell, Jill R
name: Stern, Robert A
name: Stretton, Alexandra
name: Wilhelmsen, 
name: Galasko, Douglas R
name: Moebus, Susanne
name: Kukull, 
name: Gkatzima, Olymbia
name: Hardy, John
name: Rosenberg, Roger N
name: Perry, William
name: McDavid, Andrew N
name: Schürmann, Britta
name: Albert, Marilyn S
name: Gwilliam, Rhian
name: Chui, Helena C
name: Tsolaki, Magda
name: Gilbert, John R
name: Brown, Kristelle
name: McCurry, Susan M
name: Lupton, Michelle
name: Farlow, Martin R
name: Mash, Deborah C
name: Carlson, Chris S
name: De Jager, 
name: Paulson, Henry L
name: Dichgans, Martin
name: Petersen, Ronald C
name: Hulette, Christine M
name: Head, Elizabeth
name: Hampel, 
name: Chouraki, 
name: Asthana, Sanjay
name: Lawlor, Brian
name: Schmidt, 
name: O'Bryant, Sid
name: Kauwe, John S. K.
name: Brayne, 
name: Raj, Ashok
name: Kim, Ronald
name: Burke, James R
name: Gudnason, 
name: Li, Ge
name: Williamson, Jennifer
name: Klopp, Norman
name: Warden, Donald
name: Gerrish, Amy
name: Denning, 
name: Love, 
name: Rotter, 
name: Cruchaga, Carlos
name: Ghetti, Bernardino
name: Chung, 
name: Ryan, Natalie
name: Parisi, Joseph E
name: Ferris, Steven
name: Nöthen, 
name: Psaty, 
name: Wright, Clinton B
name: Jin, Lee-Way
name: Ibrahim-Verbaas, 
name: Cairns, Nigel J
name: Thomas, Charlene
name: Naj, 
name: Barnes, Lisa L
name: Boada, 
name: Shaw, Christopher E
name: Arnold, Steven E
name: Blacker, Deborah
name: Van Broeckhoven, 
name: Heun, Reiner
name: Karydas, Anna
name: Hofman, 
name: Sano, Mary
name: Vardy, Emma
name: Pankratz, Vernon S
name: Graff-Radford, Neill R
name: Warren, Jason D
name: Gearing, Marla
name: Winslow, 
name: McKee, Ann C
name: Choi, 
name: Laza, 
name: Jonsson, 
name: Bisceglio, Gina
name: Kamatani, 
name: Seeley, William W
name: Al-Chalabi, Ammar
name: St George-Hyslop, 
name: Beekly, 
name: Sager, Mark A
name: Holmes, 
name: Reitz, Christiane
name: Huentelman, Matthew J
name: Bayer, Anthony
name: Lyketsos, Constantine G
name: Doody, Rachelle S
name: Mayo, Kevin
name: Eiriksdottir, 
name: Lacour, André
name: Van Eldik, Linda J
name: Fairchild, Thomas J
name: Launer, 
name: Makrina, Daniilidou
name: Jun, 
name: Tsuang, Debby W
name: LaFerla, Frank M
name: Maier, 
name: Yesim Demirci, 
name: Woltjer, Randall L
name: Amouyel, 
name: Mann, David
name: Honig, Lawrence S
name: Gurling, Hugh
name: De Bruijn, 
name: Huebinger, Ryan M
name: Guerreiro, Rita
name: Hüll, Michael
name: Frosch, Matthew P
name: O'Donovan, 
name: Haines, 
name: Bellenguez, 
name: Pericak-Vance, 
name: Boxer, Adam
name: Mayhaus, Manuel
name: Lovestone, Simon
name: Fitzpatrick, 
name: Green, Robert C
name: Lathrop, 
name: Becker, 
name: Schmidt, 
name: Kunkle, 
name: McCormick, Wayne C
name: Kramer, Joel H
name: Wilcock, Gordon
name: Pasquier, 
name: Jessen, Frank
name: Weintraub, Sandra
name: Gu, Wei
name: Marson, Daniel C
name: Evans, 
name: Younkin, 
name: Amin, 
name: Troncoso, Juan C
name: Van Duijn, 
name: Gallacher, John
name: Campion, 
name: Proitsi, Petroula
name: Grenier-Boley, 
name: Saykin, Andrew J
name: Pichler, Sabrina
name: Lunetta, 
name: Fox, 
name: Craig, David
name: Carrasquillo, Minerva M
name: Boeve, Bradley F
name: Clark, David G
name: Poon, Wayne W
name: Todd, Stephen
name: Duara, Ranjan
name: Atwood, Craig S
name: Dufouil, 
name: Lopez, Oscar L
name: Olichney, John M
name: Warner, Nick
name: Wichmann, H.-Erich
name: Boland, 
name: Holmans, 
name: Bowen, James D
name: Singleton, Andrew B
name: Harrell, Lindy E
name: Peskind, Elaine
name: Bennett, 
name: Geschwind, Daniel H
name: Uphill, James
name: Thornton-Wells, Tricia A
name: Harold, 
name: Foroud, 
name: Zelenika, 
name: Crane, 
name: Trojanowski, John Q
name: Fisher, Elizabeth
name: Growdon, John H
name: Johnston, Janet A
name: Sims, 
name: Jakobsdóttir, 
name: Medway, Christopher
name: van den Bussche, Hendrik
name: Van Der Lee, 
name: Kornhuber, Johannes
name: Barber, 
name: Chapman, Jade
name: Jones, 
name: Ikram, 
name: Kölsch, Heike
name: Morgan, 
name: Wiltfang, Jens
name: Martin, 
name: Ramirez, 
name: Drichel, Dmitriy
name: Potter, Huntington
name: Hyman, Bradley T
name: Fievet, 
name: Smith, 
name: Valladares, 
name: Pierce, Aimee
name: Koutroumani, Maria
name: Deloukas, Panagiotis
name: Williams, 
name: Hamilton-Nelson, 
name: Jarvik, Gail P
name: Schneider, Lon S
name: Morgan, Angharad
name: Sonnen, Joshua A
name: Bass, Nicholas J
name: Yu, Chang-En
name: Beach, Thomas G
name: Jicha, Gregory A
name: Hakonarson, Hakon
name: Montine, 
name: Kaye, Jeffrey A
name: Wishnek, Sarah
name: Cribbs, David H
name: Pastor, 
name: Rosen, Howard J
name: Hoffmann, Per
name: Smith, A. David
name: Van Deerlin, Vivianna M
name: Hannequin, 
name: Carney, Regina M
name: Beecham, 
name: Goate, 
name: Spina, Salvatore
name: Mack, Wendy J
name: Mesulam, Marsel
name: Riemenschneider, Matthias
name: Reisch, Joan S
name: Berr, 
name: Ertekin-Taner, Nilufer
name: Deramecourt, 
name: Hollingworth, Paul
name: Avramidou, Despoina
name: Morris, John C
name: Wu, Chuang-Kuo
name: Passmore, 
name: Quinn, Joseph F
name: Feulner, Thomas
name: Carroll, Steven L
name: Rogaeva, Ekaterina
name: Cantwell, 
name: Bis, 
name: Dickson, Dennis W
name: Myers, Amanda J
name: Vardarajan, Badri N
name: Carasquillo, 
name: McGuinness, Bernadette
name: Kowall, Neil W
name: Rubinsztein, David C
name: Mayeux, 
name: Carlsson, Cynthia M
name: Livingston, Gill
name: Lieberman, Andrew P
name: Fallon, Kenneth B
name: Lambert, 
name: Lah, James J
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2016

description: APOE ε4, 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 ε4+ (10,352 cases and 9,207 controls) and APOE ε4− (7,184 cases and 26,968 controls) subgroups as well as in the total sample testing for interaction between a SNP and APOE ε4 status. Suggestive associations (P<1x10−4) in stage 1 were evaluated in an independent sample (stage 2) containing 4,203 subjects (APOE ε4+: 1,250 cases and 536 controls; APOE ε4-: 718 cases and 1,699 controls). Among APOE ε4− 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 datasets (best SNP, rs2732703, P=5·8x10−9). 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 ε4+ subjects (CR1 and CLU) or APOE ε4− 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=1·6x10−7) 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≤1.3x10−8), frontal cortex (P≤1.3x10−9), and temporal cortex (P≤1.2x10−11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2x10−6) and temporal cortex (P=2.6x10−6). 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 ε4 compared to 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.