Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L. DeStefano, Jean-Charles Lambert, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Gyungah Jun, Joshua C. Bis, Gary W. Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A. Thornton-Wells, Nicola Denning, Albert V. Smith, Vincent Chouraki, Charlene Thomas, M. Arfan Ikram, Diana Zelenika, Badri N. Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L. Dunstan, Maria Vronskaya, Andrew D. Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L. Fitzpatrick, Joseph D. Buxbaum, Dominique Campion, Paul K. Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L. Lopez, Philip L. De Jager, Vincent Deramecourt, Janet A. Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M. Goate, Nathalie Fiévet, Matthew J. Huentelman, Michael Gill, Kristelle Brown, M. Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B. Larson, Amanda J. Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W. Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C. Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M. Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G. Younkin, Eliecer Coto, Kara L. Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J. Owen, Kelley M. Faber, Palmi V. Jonsson, Onofre Combarros, Michael C. O'Donovan, Laura B. Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H. Mosley, David A. Bennett, Tamara B. Harris, Laura Fratiglioni, Clive Holmes, Renee F. A. G. de Bruijn, Peter Passmore, Thomas J. Montine, Karolien Bettens, Jerome I. Rotter, Alexis Brice, Kevin Morgan, Tatiana M. Foroud, Walter A. Kukull, Didier Hannequin, John F. Powell, Michael A. Nalls, Karen Ritchie, Kathryn L. Lunetta, John S. K. Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R. Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus Maria Nöthen, Caroline Graff, Bruce M. Psaty, Jonathan L. Haines, Mark Lathrop, Margaret Ann Pericak-Vance, Lenore J. Launer, Christine Van Broeckhoven, Lindsay A. Farrer, Cornelia M. van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D. Schellenberg, Philippe Amouyel, Julie Williams

  • Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

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Author:Valentina Escott-Price, Céline Bellenguez, Li-San Wang, Seung-Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L. DeStefano, Jean-Charles Lambert, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Gyungah Jun, Joshua C. Bis, Gary W. Beecham, Benjamin Grenier-Boley, Giancarlo Russo, Tricia A. Thornton-Wells, Nicola Denning, Albert V. Smith, Vincent Chouraki, Charlene Thomas, M. Arfan Ikram, Diana Zelenika, Badri N. Vardarajan, Yoichiro Kamatani, Chiao-Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L. Dunstan, Maria Vronskaya, Andrew D. Johnson, Agustin Ruiz, Marie-Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L. Fitzpatrick, Joseph D. Buxbaum, Dominique Campion, Paul K. Crane, Clinton Baldwin, Tim Becker, Vilmundur Gudnason, Carlos Cruchaga, David Craig, Najaf Amin, Claudine Berr, Oscar L. Lopez, Philip L. De Jager, Vincent Deramecourt, Janet A. Johnston, Denis Evans, Simon Lovestone, Luc Letenneur, Isabel Hernández, David C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M. Goate, Nathalie Fiévet, Matthew J. Huentelman, Michael Gill, Kristelle Brown, M. Ilyas Kamboh, Lina Keller, Pascale Barberger-Gateau, Bernadette McGuinness, Eric B. Larson, Amanda J. Myers, Carole Dufouil, Stephen Todd, David Wallon, Seth Love, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W. Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C. Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini, Ubaldo Bonuccelli, Michelangelo Mancuso, Gabriele Siciliano, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Ana Frank-García, Francesco Panza, Vincenzo Solfrizzi, Paolo Caffarra, Benedetta Nacmias, William Perry, Manuel Mayhaus, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M. Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alvarez, Fanggeng Zou, Otto Valladares, Steven G. Younkin, Eliecer Coto, Kara L. Hamilton-Nelson, Wei Gu, Cristina Razquin, Pau Pastor, Ignacio Mateo, Michael J. Owen, Kelley M. Faber, Palmi V. Jonsson, Onofre Combarros, Michael C. O'Donovan, Laura B. Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H. Mosley, David A. Bennett, Tamara B. Harris, Laura Fratiglioni, Clive Holmes, Renee F. A. G. de Bruijn, Peter Passmore, Thomas J. Montine, Karolien Bettens, Jerome I. Rotter, Alexis Brice, Kevin Morgan, Tatiana M. Foroud, Walter A. Kukull, Didier Hannequin, John F. Powell, Michael A. Nalls, Karen Ritchie, Kathryn L. Lunetta, John S. K. Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R. Martin, Reinhold Schmidt, Dan Rujescu, Jean-François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus Maria Nöthen, Caroline Graff, Bruce M. Psaty, Jonathan L. Haines, Mark Lathrop, Margaret Ann Pericak-Vance, Lenore J. Launer, Christine Van Broeckhoven, Lindsay A. Farrer, Cornelia M. van Duijn, Alfredo Ramirez, Sudha Seshadri, Gerard D. Schellenberg, Philippe Amouyel, Julie Williams
URN:urn:nbn:de:hebis:30:3-342205
DOI:https://doi.org/10.1371/journal.pone.0094661
ISSN:1932-6203
Parent Title (English):PLoS One
Publisher:PLoS
Place of publication:Lawrence, Kan.
Document Type:Article
Language:English
Date of Publication (online):2014/06/12
Date of first Publication:2014/06/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/06/18
Volume:9
Issue:(6):e94661
Page Number:13
Note:
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
HeBIS-PPN:365578037
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0