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

International Genomics of Alzheimer's Disease Consortium (IGAP)

Research output: Contribution to journalArticle

99 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)658-671
Number of pages14
JournalAlzheimer's and Dementia
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2015

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Genomics
Endocytosis
Immunity
Alzheimer Disease
Cholesterol
Gene Expression
Inborn Genetic Diseases
Gene Regulatory Networks
Ubiquitination
Proteasome Endopeptidase Complex
Ubiquitin
Carrier Proteins
Genome
Brain
Genes
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Epidemiology
  • Health Policy

Cite this

Convergent genetic and expression data implicate immunity in Alzheimer's disease. / International Genomics of Alzheimer's Disease Consortium (IGAP).

In: Alzheimer's and Dementia, Vol. 11, No. 6, 01.06.2015, p. 658-671.

Research output: Contribution to journalArticle

International Genomics of Alzheimer's Disease Consortium (IGAP) 2015, 'Convergent genetic and expression data implicate immunity in Alzheimer's disease', Alzheimer's and Dementia, vol. 11, no. 6, pp. 658-671. https://doi.org/10.1016/j.jalz.2014.05.1757
International Genomics of Alzheimer's Disease Consortium (IGAP). / Convergent genetic and expression data implicate immunity in Alzheimer's disease. In: Alzheimer's and Dementia. 2015 ; Vol. 11, No. 6. pp. 658-671.
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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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AU - International Genomics of Alzheimer's Disease Consortium (IGAP)

AU - Jones, Lesley

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AU - Choi, Seung Hoan

AU - Harold, Denise

AU - Vedernikov, Alexey

AU - Escott-Price, Valentina

AU - Stone, Timothy

AU - Richards, Alexander

AU - Bellenguez, Céline

AU - Ibrahim-Verbaas, Carla A.

AU - Naj, Adam C.

AU - Sims, Rebecca

AU - Gerrish, Amy

AU - Jun, Gyungah

AU - DeStefano, Anita L.

AU - Bis, Joshua C.

AU - Beecham, Gary W.

AU - Grenier-Boley, Benjamin

AU - Russo, Giancarlo

AU - Thornton-Wells, Tricia A.

AU - Jones, Nicola

AU - Smith, Albert V.

AU - Chouraki, Vincent

AU - Thomas, Charlene

AU - Ikram, M. Arfan

AU - Zelenika, Diana

AU - Vardarajan, Badri N.

AU - Kamatani, Yoichiro

AU - Lin, Chiao Feng

AU - Schmidt, Helena

AU - Kunkle, Brian W.

AU - Dunstan, Melanie L.

AU - Ruiz, Agustin

AU - Bihoreau, Marie Thérèse

AU - Reitz, Christiane

AU - Pasquier, Florence

AU - Hollingworth, Paul

AU - Hanon, Olivier

AU - Fitzpatrick, Annette L.

AU - Buxbaum, Joseph D.

AU - Campion, Dominique

AU - Crane, Paul K.

AU - Becker, Tim

AU - Gudnason, Vilmundur

AU - Cruchaga, Carlos

AU - Craig, David

AU - Amin, Najaf

AU - Berr, Claudine

AU - Foroud, Tatiana

PY - 2015/6/1

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N2 - 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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KW - Cholesterol metabolism

KW - Dementia

KW - Endocytosis

KW - Immune response

KW - Neurodegeneration

KW - Pathway analysis

KW - Ubiquitination

KW - Weighted gene co-expression network analysis

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