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

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

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

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 9207 controls) and APOE ε4- (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 ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 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 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 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=1·6 × 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 ε4 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.

Original languageEnglish (US)
Pages (from-to)108-117
Number of pages10
JournalMolecular Psychiatry
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    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., ... Ortega-Cubero, S. (2016). A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular Psychiatry, 21(1), 108-117. https://doi.org/10.1038/mp.2015.23