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Convergent genetic and expression data implicate immunity in Alzheimer's disease
Authors :
Jones, Lesley Lambert, Jean-Charles Wang, Li-San Choi, Seung-Hoan Harold, Denise Vedernikov, Alexey Escott-Price, Valentina Stone, Timothy Richards, Alexander Bellenguez, Celine Ibrahim-Verbaas, Carla A. Naj, Adam C. Sims, Rebecca Gerrish, Amy Jun, Gyungah DeStefano, Anita L. Bis, Joshua C. Beecham, Gary W. Grenier-Boley, Benjamin Russo, Giancarlo Thornton-Wells, Tricia A. Jones, Nicola Smith, Albert V. Chouraki, Vincent Thomas, Charlene Ikram, M. Arfan Zelenika, Diana Vardarajan, Badri N. Kamatani, Yoichiro Lin, Chiao-Feng Schmidt, Helena Kunkle, Brian W. Dunstan, Melanie L. Ruiz, Agustin Bihoreau, Marie-Therese Reitz, Christiane Pasquier, Florence Hollingworth, Paul Hanon, Olivier Fitzpatrick, Annette L. Buxbaum, Joseph D. Campion, Dominique Crane, Paul K. Becker, Tim Gudnason, Vilmundur Cruchaga, Carlos Craig, David Amin, Najaf Berr, Claudine Lopez, Oscar L. De Jager, Philip L. Deramecourt, Vincent Johnston, Janet A. Evans, Denis Lovestone, Simon Letteneur, Luc Kornhuber, Johanes Tarraga, Lluis Rubinsztein, David C. Eiriksdottir, Gudny Sleegers, Kristel Goate, Alison M. Fievet, Nathalie Huentelman, Matthew J. Gill, Michael Emilsson, Valur Brown, Kristelle Kamboh, M. Ilyas Keller, Lina Barberger-Gateau, Pascale McGuinness, Bernadette Larson, Eric B. Myers, Amanda J. Dufouil, Carole Todd, Stephen Wallon, David Love, Seth Kehoe, Pat Rogaeva, Ekaterina Gallacher, John St George-Hyslop, Peter Clarimon, Jordi Lleo, Alberti Bayer, Anthony Tsuang, Debby W. Yu, Lei Tsolaki, Magda Bossu, Paola Spalletta, Gianfranco Proitsi, Petra Collinge, John Sorbi, Sandro Garcia, Fiorentino Sanchez Fox, Nick Hardy, John Deniz Naranjo, Maria Candida Razquin, Cristina Bosco, Paola Clarke, Robert Brayne, Carol Galimberti, Daniela Mancuso, Michelangelo Moebus, Susanne Mecocci, Patrizia del Zompo, Maria Maier, Wolfgang Hampel, Harald Pilotto, Alberto Bullido, Maria Panza, Francesco Caffarra, Paolo Nacmias, Benedetta Gilbert, John R. Mayhaus, Manuel Jessen, Frank Dichgans, Martin Lannfelt, Lars Hakonarson, Hakon Pichler, Sabrina Carrasquillo, Minerva M. Ingelsson, Martin Beekly, Duane Alavarez, Victoria Zou, Fanggeng Valladares, Otto Younkin, Steven G. Coto, Eliecer Hamilton-Nelson, Kara L. Mateo, Ignacio Owen, Michael J. Faber, Kelley M. Jonsson, Palmi V. Combarros, Onofre O'Donovan, Michael C. Cantwell, Laura B. Soininen, Hilkka Blacker, Deborah Mead, Simon Mosley, Thomas H. Bennett, David A. Harris, Tamara B. Fratiglioni, Laura Holmes, Clive de Bruijn, Renee F. A. G. Passmore, Peter Montine, Thomas J. Bettens, Karolien Rotter, Jerome I. Brice, Alexis Morgan, Kevin Foroud, Tatiana M. Kukull, Walter A. Hannequin, Didier Powell, John F. Nails, Michael A. Ritchie, Karen Lunetta, Kathryn L. Kauwe, John S. K. Boerwinkle, Eric Riemenschneider, Matthias Boada, Merce Hiltunen, Mikko Martin, Eden R. Pastor, Pau Schmidt, Reinhold Rujescu, Dan Dartigues, Jean-Francois Mayeux, Richard Tzourio, Christophe Hofman, Albert Noethen, Markus M. Graff, Caroline Psaty, Bruce M. Haines, Jonathan L. Lathrop, Mark Pericak-Vance, Margaret A. Launer, Lenore J. Farrer, Lindsay A. van Duijn, Cornelia M. Van Broeckhoven, Christine Ramirez, Alfredo Schellenberg, Gerard D. Seshadri, Sudha Amouyel, Philippe Williams, Julie Holmans, Peter A. Jones, Lesley Lambert, Jean-Charles Wang, Li-San Choi, Seung-Hoan Harold, Denise Vedernikov, Alexey Escott-Price, Valentina Stone, Timothy Richards, Alexander Bellenguez, Celine Ibrahim-Verbaas, Carla A. Naj, Adam C. Sims, Rebecca Gerrish, Amy Jun, Gyungah DeStefano, Anita L. Bis, Joshua C. Beecham, Gary W. Grenier-Boley, Benjamin Russo, Giancarlo Thornton-Wells, Tricia A. Jones, Nicola Smith, Albert V. Chouraki, Vincent Thomas, Charlene Ikram, M. Arfan Zelenika, Diana Vardarajan, Badri N. Kamatani, Yoichiro Lin, Chiao-Feng Schmidt, Helena Kunkle, Brian W. Dunstan, Melanie L. Ruiz, Agustin Bihoreau, Marie-Therese Reitz, Christiane Pasquier, Florence Hollingworth, Paul Hanon, Olivier Fitzpatrick, Annette L. Buxbaum, Joseph D. Campion, Dominique Crane, Paul K. Becker, Tim Gudnason, Vilmundur Cruchaga, Carlos Craig, David Amin, Najaf Berr, Claudine Lopez, Oscar L. De Jager, Philip L. Deramecourt, Vincent Johnston, Janet A. Evans, Denis Lovestone, Simon Letteneur, Luc Kornhuber, Johanes Tarraga, Lluis Rubinsztein, David C. Eiriksdottir, Gudny Sleegers, Kristel Goate, Alison M. Fievet, Nathalie Huentelman, Matthew J. Gill, Michael Emilsson, Valur Brown, Kristelle Kamboh, M. Ilyas Keller, Lina Barberger-Gateau, Pascale McGuinness, Bernadette Larson, Eric B. Myers, Amanda J. Dufouil, Carole Todd, Stephen Wallon, David Love, Seth Kehoe, Pat Rogaeva, Ekaterina Gallacher, John St George-Hyslop, Peter Clarimon, Jordi Lleo, Alberti Bayer, Anthony Tsuang, Debby W. Yu, Lei Tsolaki, Magda Bossu, Paola Spalletta, Gianfranco Proitsi, Petra Collinge, John Sorbi, Sandro Garcia, Fiorentino Sanchez Fox, Nick Hardy, John Deniz Naranjo, Maria Candida Razquin, Cristina Bosco, Paola Clarke, Robert Brayne, Carol Galimberti, Daniela Mancuso, Michelangelo Moebus, Susanne Mecocci, Patrizia del Zompo, Maria Maier, Wolfgang Hampel, Harald Pilotto, Alberto Bullido, Maria Panza, Francesco Caffarra, Paolo Nacmias, Benedetta Gilbert, John R. Mayhaus, Manuel Jessen, Frank Dichgans, Martin Lannfelt, Lars Hakonarson, Hakon Pichler, Sabrina Carrasquillo, Minerva M. Ingelsson, Martin Beekly, Duane Alavarez, Victoria Zou, Fanggeng Valladares, Otto Younkin, Steven G. Coto, Eliecer Hamilton-Nelson, Kara L. Mateo, Ignacio Owen, Michael J. Faber, Kelley M. Jonsson, Palmi V. Combarros, Onofre O'Donovan, Michael C. Cantwell, Laura B. Soininen, Hilkka Blacker, Deborah Mead, Simon Mosley, Thomas H. Bennett, David A. Harris, Tamara B. Fratiglioni, Laura Holmes, Clive de Bruijn, Renee F. A. G. Passmore, Peter Montine, Thomas J. Bettens, Karolien Rotter, Jerome I. Brice, Alexis Morgan, Kevin Foroud, Tatiana M. Kukull, Walter A. Hannequin, Didier Powell, John F. Nails, Michael A. Ritchie, Karen Lunetta, Kathryn L. Kauwe, John S. K. Boerwinkle, Eric Riemenschneider, Matthias Boada, Merce Hiltunen, Mikko Martin, Eden R. Pastor, Pau Schmidt, Reinhold Rujescu, Dan Dartigues, Jean-Francois Mayeux, Richard Tzourio, Christophe Hofman, Albert Noethen, Markus M. Graff, Caroline Psaty, Bruce M. Haines, Jonathan L. Lathrop, Mark Pericak-Vance, Margaret A. Launer, Lenore J. Farrer, Lindsay A. van Duijn, Cornelia M. Van Broeckhoven, Christine Ramirez, Alfredo Schellenberg, Gerard D. Seshadri, Sudha Amouyel, Philippe Williams, Julie Holmans, Peter A.
Publication Year :
2015
Abstract
Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.