Convergent genetic and expression data implicate immunity in Alzheimer's disease
Authors:   International Genomics of Alzheimer's Disease Consortium (IGAP), Jones Lesley , Lambert Jean‐Charles , Wang Li‐San , Choi Seung‐Hoan , Harold Denise , Vedernikov Alexey , Escott‐Price Valentina , Stone Timothy , Richards Alexander , Bellenguez Céline , 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‐Thérèse , 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 , Tárraga Lluís , Rubinsztein David C. , Eiriksdottir Gudny , Sleegers Kristel , Goate Alison M. , Fiévet 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 , Lleò Alberti , Bayer Anthony , Tsuang Debby W. , Yu Lei , Tsolaki Magda , Bossù Paola , Spalletta Gianfranco , Proitsi Petra , Collinge John , Sorbi Sandro , Sanchez Garcia Florentino , Fox Nick , Hardy John , Deniz Naranjo Maria Candida , Razquin Cristina , Bosco Paola , Clarke Robert , Brayne Carol , Galimberti Daniela , Mancuso Michelangelo ,   MRC CFAS, 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. , Nalls Michael A. , Ritchie Karen , Lunetta Kathryn L. , Kauwe John S.K. , Boerwinkle Eric , Riemenschneider Matthias , Boada Mercè , Hiltunen Mikko , Martin Eden R. , Pastor Pau , Schmidt Reinhold , Rujescu Dan , Dartigues Jean‐François , Mayeux Richard , Tzourio Christophe , Hofman Albert , Nöthen 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. 
Published: December 2014

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.