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

Lesley Jones, Jean Charles Lambert, Li San Wang, Seung Hoan Choi, Denise Harold, Alexey Vedernikov, Valentina Escott-Price, Timothy Stone, Alexander Richards, Céline Bellenguez, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Amy Gerrish, Gyungah Jun, Anita L. DeStefano, Joshua C. Bis, Gary W. Beecham, Benjamin Grenier-Boley, Giancarlo RussoTricia A. Thornton-Wells, Nicola Jones, Albert V. Smith, Vincent Chouraki, Charlene Thomas, M. Arfan Ikram, Diana Zelenika, Badri N. Vardarajan, Yoichiro Kamatani, Chiao Feng Lin, Helena Schmidt, Brian W. Kunkle, Melanie L. Dunstan, Agustin Ruiz, Marie Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L. Fitzpatrick, Joseph D. Buxbaum, Dominique Campion, Paul K. Crane, 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 Letteneur, Johanes Kornhuber, Lluís Tárraga, David C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M. Goate, Nathalie Fiévet, Matthew J. Huentelman, Michael Gill, Valur Emilsson, 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, 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

Research output: Contribution to journalArticleResearchpeer-review

114 Citations (Scopus)

Abstract

© 2015, Elsevier Inc. All rights reserved. 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.
Original languageEnglish
Pages (from-to)658-671
JournalAlzheimer's and Dementia
Volume11
Issue number6
DOIs
Publication statusPublished - 1 Jun 2015

Keywords

  • ALIGATOR
  • Alzheimer's disease
  • Cholesterol metabolism
  • Dementia
  • Endocytosis
  • Immune response
  • Neurodegeneration
  • Pathway analysis
  • Ubiquitination
  • Weighted gene co-expression network analysis

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