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Journal Articles Alzheimer's & Dementia : the Journal of the Alzheimer's Association Year : 2014

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Lesley Jones (1) , Jean‐charles Lambert (2, 3) , Li‐san Wang , Seung‐hoan Choi , Denise Harold (4, 5) , Alexey Vedernikov , Valentina Escott‐price , Timothy Stone , Alexander Richards (4) , Céline Bellenguez (2) , Carla A Ibrahim‐verbaas , Adam C Naj (6) , Rebecca Sims (5) , Amy Gerrish (5) , Gyungah Jun (7) , Anita L Destefano (7) , Joshua C Bis (8) , Gary W Beecham (9) , Benjamin Grenier‐boley (2) , Giancarlo Russo (5) , Tricia A Thornton‐wells , Nicola Jones (5) , Albert V Smith (10) , Vincent Chouraki (2) , Charlene Thomas (11) , M. Arfan Ikram (12, 13) , Diana Zelenika (14) , Badri N Vardarajan (15) , Yoichiro Kamatani (14, 16) , Chiao‐feng Lin , Helena Schmidt (17) , Brian W Kunkle (18) , Melanie L Dunstan , Agustin Ruiz , Marie‐thérèse Bihoreau , Christiane Reitz , Florence Pasquier , Paul Hollingworth , Olivier Hanon (19) , Annette L Fitzpatrick , Joseph D Buxbaum , Dominique Campion (20) , Paul K Crane , Tim Becker , Vilmundur Gudnason , Carlos Cruchaga , David Craig , Najaf Amin , Claudine Berr (21) , Oscar L Lopez , Philip L de Jager , Vincent Deramecourt (22) , Janet A Johnston , Denis Evans , Simon Lovestone , Luc Letteneur , Johanes Kornhuber , Lluís Tárraga , David C Rubinsztein , Gudny Eiriksdottir , Kristel Sleegers , Alison M Goate , Nathalie Fiévet (2) , Matthew J Huentelman , Michael Gill , Valur Emilsson , Kristelle Brown , M. Ilyas Kamboh , Lina Keller , Pascale Barberger‐gateau (23) , Bernadette Mcguinness , Eric B Larson , Amanda J Myers , Carole Dufouil (23) , Stephen Todd , David Wallon (20) , Seth Love , Pat Kehoe , Ekaterina Rogaeva , John Gallacher , Peter St George‐hyslop , Jordi Clarimon , Alberti Lleò , Anthony Bayer , Debby W Tsuang , Lei Yu , Magda Tsolaki , Paola Bossù , Gianfranco Spalletta , Petra Proitsi , John Collinge , Sandro Sorbi , Florentino Sanchez Garcia , Nick Fox , John Hardy , Maria Candida Deniz Naranjo , Cristina Razquin , Paola Bosco , Robert Clarke , Carol Brayne , Daniela Galimberti , Michelangelo Mancuso , Susanne Moebus , Patrizia Mecocci , Maria del Zompo , Wolfgang Maier , Harald Hampel (24) , Alberto Pilotto , Maria Bullido , Francesco Panza , Paolo Caffarra , Benedetta Nacmias , John R Gilbert , Manuel Mayhaus , Frank Jessen , Martin Dichgans , Lars Lannfelt , Hakon Hakonarson , Sabrina Pichler , Minerva M Carrasquillo , Martin Ingelsson , Duane Beekly , Victoria Alavarez , Fanggeng Zou , Otto Valladares , Steven G Younkin , Eliecer Coto , Kara L Hamilton‐nelson , 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 (25, 26) , Kevin Morgan , Tatiana M Foroud , Walter A Kukull , Didier Hannequin (20) , John F Powell , Michael A Nalls , Karen Ritchie (21) , Kathryn L Lunetta , John S K Kauwe , Eric Boerwinkle , Matthias Riemenschneider , Mercè Boada , Mikko Hiltunen , Eden R Martin , Pau Pastor , Reinhold Schmidt , Dan Rujescu , Jean‐françois Dartigues (23, 27) , Richard Mayeux , Christophe Tzourio , Albert Hofman , Markus M Nöthen , Caroline Graff , Bruce M Psaty , Jonathan L Haines , Mark Lathrop (14, 28) , Margaret A Pericak‐vance , Lenore J Launer , Lindsay A Farrer , Cornelia M van Duijn , Christine van Broeckhoven , Alfredo Ramirez , Gerard D Schellenberg , Sudha Seshadri , Philippe Amouyel (2, 3, 29) , Julie Williams (11) , Peter A Holmans
1 MRC Centre for Neuropsychiatric Genetics and Genomics
2 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
3 Institut Pasteur de Lille
4 Cardiff University
5 Bioinformatics
6 HUP - Hospital of the University of Pennsylvania
7 BU - Boston University [Boston]
8 Department of Medicine
9 John P. Hussman Institute for Human Genomics
10 Icelandic Heart Association
11 Institute of Psychological Medicine and Clinical Neurosciences
12 Erasmus MC - Erasmus University Medical Center [Rotterdam]
13 Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands
14 CNG - Centre National de Génotypage
15 Columbia University [New York]
16 RIKEN IMS - RIKEN Center for Integrative Medical Sciences [Yokohama]
17 Dpt of Pharmacology and Personalised Medicine [Maastricht]
18 John P. Hussman Institute for Human Genomics [Miami, FL, USA]
19 U894 - Centre de Psychiatrie et Neurosciences
20 Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques
21 Hôpital de la Colombière
22 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
23 Epidémiologie et Biostatistique [Bordeaux]
24 IM2A - Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre]
25 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
26 CHU Pitié-Salpêtrière [AP-HP]
27 CHU de Bordeaux Pellegrin [Bordeaux]
28 CEPH - Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris]
29 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
Li‐san Wang
  • Function : Author
Seung‐hoan Choi
  • Function : Author
Alexey Vedernikov
  • Function : Author
Valentina Escott‐price
  • Function : Author
Timothy Stone
  • Function : Author
Carla A Ibrahim‐verbaas
  • Function : Author
Rebecca Sims
  • Function : Author
Amy Gerrish
  • Function : Author
Giancarlo Russo
  • Function : Author
Tricia A Thornton‐wells
  • Function : Author
Nicola Jones
  • Function : Author
Chiao‐feng Lin
  • Function : Author
Melanie L Dunstan
  • Function : Author
Agustin Ruiz
  • Function : Author
Marie‐thérèse Bihoreau
  • Function : Author
Christiane Reitz
  • Function : Author
Florence Pasquier
  • Function : Author
Paul Hollingworth
  • Function : Author
Annette L Fitzpatrick
  • Function : Author
Joseph D Buxbaum
  • Function : Author
Paul K Crane
  • Function : Author
Tim Becker
  • Function : Author
Vilmundur Gudnason
  • Function : Author
Carlos Cruchaga
  • Function : Author
David Craig
  • Function : Author
Najaf Amin
  • Function : Author
Oscar L Lopez
  • Function : Author
Philip L de Jager
  • Function : Author
Janet A Johnston
  • Function : Author
Denis Evans
  • Function : Author
Simon Lovestone
  • Function : Author
Luc Letteneur
  • Function : Author
Johanes Kornhuber
  • Function : Author
Lluís Tárraga
  • Function : Author
David C Rubinsztein
  • Function : Author
Gudny Eiriksdottir
  • Function : Author
Kristel Sleegers
  • Function : Author
Alison M Goate
  • Function : Author
Matthew J Huentelman
  • Function : Author
Michael Gill
  • Function : Author
Valur Emilsson
  • Function : Author
Kristelle Brown
  • Function : Author
M. Ilyas Kamboh
  • Function : Author
Lina Keller
  • Function : Author
Bernadette Mcguinness
  • Function : Author
Eric B Larson
  • Function : Author
Amanda J Myers
  • Function : Author
Stephen Todd
  • Function : Author
Seth Love
  • Function : Author
Pat Kehoe
  • Function : Author
Ekaterina Rogaeva
  • Function : Author
John Gallacher
  • Function : Author
Peter St George‐hyslop
  • Function : Author
Jordi Clarimon
  • Function : Author
Alberti Lleò
  • Function : Author
Anthony Bayer
  • Function : Author
Debby W Tsuang
  • Function : Author
Lei Yu
  • Function : Author
Magda Tsolaki
  • Function : Author
Paola Bossù
  • Function : Author
Gianfranco Spalletta
  • Function : Author
Petra Proitsi
  • Function : Author
John Collinge
  • Function : Author
Sandro Sorbi
  • Function : Author
Florentino Sanchez Garcia
  • Function : Author
Nick Fox
  • Function : Author
John Hardy
  • Function : Author
Maria Candida Deniz Naranjo
  • Function : Author
Cristina Razquin
  • Function : Author
Paola Bosco
  • Function : Author
Robert Clarke
  • Function : Author
Carol Brayne
  • Function : Author
Daniela Galimberti
  • Function : Author
Michelangelo Mancuso
  • Function : Author
Susanne Moebus
  • Function : Author
Patrizia Mecocci
  • Function : Author
Maria del Zompo
  • Function : Author
Wolfgang Maier
  • Function : Author
Alberto Pilotto
  • Function : Author
Maria Bullido
  • Function : Author
Francesco Panza
  • Function : Author
Paolo Caffarra
  • Function : Author
Benedetta Nacmias
  • Function : Author
John R Gilbert
  • Function : Author
Manuel Mayhaus
  • Function : Author
Frank Jessen
  • Function : Author
Martin Dichgans
  • Function : Author
Lars Lannfelt
  • Function : Author
Hakon Hakonarson
  • Function : Author
Sabrina Pichler
  • Function : Author
Minerva M Carrasquillo
  • Function : Author
Martin Ingelsson
  • Function : Author
Duane Beekly
  • Function : Author
Victoria Alavarez
  • Function : Author
Fanggeng Zou
  • Function : Author
Otto Valladares
  • Function : Author
Steven G Younkin
  • Function : Author
Eliecer Coto
  • Function : Author
Kara L Hamilton‐nelson
  • Function : Author
Ignacio Mateo
  • Function : Author
Michael J Owen
  • Function : Author
Kelley M Faber
  • Function : Author
Palmi V Jonsson
  • Function : Author
Onofre Combarros
  • Function : Author
Michael C O'Donovan
  • Function : Author
Laura B Cantwell
  • Function : Author
Hilkka Soininen
  • Function : Author
Deborah Blacker
  • Function : Author
Simon Mead
  • Function : Author
Thomas H Mosley
  • Function : Author
David A Bennett
  • Function : Author
Tamara B Harris
  • Function : Author
Laura Fratiglioni
  • Function : Author
Clive Holmes
  • Function : Author
Renee F a G de Bruijn
  • Function : Author
Peter Passmore
  • Function : Author
Thomas J Montine
  • Function : Author
Karolien Bettens
  • Function : Author
Jerome I Rotter
  • Function : Author
Kevin Morgan
  • Function : Author
Tatiana M Foroud
  • Function : Author
Walter A Kukull
  • Function : Author
John F Powell
  • Function : Author
Michael A Nalls
  • Function : Author
Kathryn L Lunetta
  • Function : Author
John S K Kauwe
  • Function : Author
Eric Boerwinkle
  • Function : Author
Matthias Riemenschneider
  • Function : Author
Mercè Boada
  • Function : Author
Mikko Hiltunen
  • Function : Author
Eden R Martin
  • Function : Author
Pau Pastor
  • Function : Author
Reinhold Schmidt
  • Function : Author
Dan Rujescu
  • Function : Author
Richard Mayeux
  • Function : Author
Christophe Tzourio
  • Function : Author
Albert Hofman
  • Function : Author
Markus M Nöthen
  • Function : Author
Caroline Graff
  • Function : Author
Bruce M Psaty
  • Function : Author
Jonathan L Haines
  • Function : Author
Margaret A Pericak‐vance
  • Function : Author
Lenore J Launer
  • Function : Author
Lindsay A Farrer
  • Function : Author
Cornelia M van Duijn
  • Function : Author
Christine van Broeckhoven
  • Function : Author
Alfredo Ramirez
  • Function : Author
Gerard D Schellenberg
  • Function : Author
Sudha Seshadri
  • Function : Author
Peter A Holmans
  • Function : Author

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 × 10 −12 after multiple testing correction for pathways), regulation of endocytosis ( P = 1.31 × 10 −11 ), cholesterol transport ( P = 2.96 × 10 −9 ), and proteasome‐ubiquitin activity ( P = 1.34 × 10 −6 ). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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cea-04587244 , version 1 (24-05-2024)

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Lesley Jones, Jean‐charles Lambert, Li‐san Wang, Seung‐hoan Choi, Denise Harold, et al.. Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimer's & Dementia : the Journal of the Alzheimer's Association, 2014, 11 (6), pp.658 - 671. ⟨10.1016/j.jalz.2014.05.1757⟩. ⟨cea-04587244⟩
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