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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-01

AUTHORS

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 Ikram, N 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, IGAP Consortium, 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, James T Becker, 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, Carlos Cruchaga, Philip L De Jager, 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, John Hardy, 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, John SK Kauwe, 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, Oscar L Lopez, 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, Rhoda Au, Philip A Wolf, Alexa Beiser, Claudia Satizabal, Andre G Uitterlinden, Fernando Rivadeneira, Peter J Koudstaal, William T Longstreth, Lewis H Kuller, Thomas Lumley, Kenneth Rice, Tamara B Harris, Michael Nalls, Josef J M Marksteiner, Peter Dal-Bianco, Anna Maria Töglhofer, Paul Freudenberger, Gerhard Ransmayr, Thomas Benke, Anna M Toeglhofer, Eric Boerwinkle, Jan Bressler, Myriam Fornage, Francisco J Morón, Isabel Hernández, Maitee Rosende Roca, Ana Mauleón, Montserrat Alegret, Reposo Ramírez-Lorca, Antonio González-Perez, Annick Alpérovitch, Victoria Alvarez, Pascale Barberger-Gateau, Karolien Bettens, Paola Bossù, Alexis Brice, Maria Bullido, Paolo Caffara, Jordi Clarimon, Onofre Combarros, Eliecer Coto, Maria del Zampo, Marc Delepine, Maria Candida Deniz Naranjo, Jacques Epelbaum, Laura Fratiglioni, Daniela Galimberti, Caroline Graff, Mikko Hiltunen, Martin Ingelsson, Lina Keller, Lars Lannfelt, Alberto Llèo, Michelangelo Mancuso, Ignacio Mateo, Patrizia Mecocci, Benedetta Nacmias, Francesco Panza, Alberto Pilotto, Florentino Sanchez Garcia, Elio Scarpini, Davide Seripa, Kristel Sleegers, Hlikka Soininen, Sandro Sorbi, Gianfranco Spalletta, David Wallon, 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, DClin Psy, 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, 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

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. More... »

PAGES

108

References to SciGraph publications

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  • Journal

    TITLE

    Molecular Psychiatry

    ISSUE

    1

    VOLUME

    21

    Author Affiliations

  • Boston University
  • Erasmus University Medical Center
  • Cardiff University
  • Pasteur Institute of Lille
  • Boston University School of Medicine
  • University of Pennsylvania
  • University of Miami
  • University of Washington
  • Trinity College Dublin
  • Icelandic Heart Association
  • Medical University of Graz
  • RIKEN
  • Centre National de Génotypage
  • University of Bonn
  • Indiana University – Purdue University Indianapolis
  • Centre Hospitalier Regional et Universitaire de Lille
  • Washington University in St. Louis
  • Hôpital Broca
  • University of North Texas Health Science Center
  • Frenchay Hospital
  • Rush University Medical Center
  • Délégation Languedoc-Roussillon
  • Aristotle University of Thessaloniki
  • Icahn School of Medicine at Mount Sinai
  • University of Pittsburgh
  • University College London
  • University of Bordeaux
  • University of Oxford
  • University of Mississippi Medical Center
  • University of Cambridge
  • German Center for Neurodegenerative Diseases
  • Broad Institute
  • University of Iceland
  • Centre Hospitalier Universitaire de Bordeaux
  • Ludwig Maximilian University of Munich
  • Instituto de Salud Carlos III
  • Group Health Cooperative
  • Harbor–UCLA Medical Center
  • National Institutes of Health
  • Translational Genomics Research Institute
  • National University Hospital of Iceland
  • University of Southampton
  • Queen's University Belfast
  • Pfizer (United States)
  • King's College London
  • Mayo Clinic
  • Brigham Young University
  • University of North Carolina at Chapel Hill
  • Martin Luther University Halle-Wittenberg
  • Case Western Reserve University
  • University of Antwerp
  • National Institute of Child Health and Human Development
  • Columbia University
  • McGill University and Génome Québec Innovation Centre
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/mp.2015.23

    DOI

    http://dx.doi.org/10.1038/mp.2015.23

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1037355133

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25778476


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