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; Carla A. Ibrahim-Verbaas; Adam C. Naj; Rebecca Sims; Amy Gerrish; David Craig; Janet A. Johnston; Bernadette McGuinness; Stephen Todd; Peter Passmore

doi:10.1016/j.jalz.2014.05.1757

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, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Amy Gerrish, David Craig, Janet A. Johnston, Bernadette McGuinness, Stephen Todd, Peter Passmore

Research output: Contribution to journal › Article › peer-review

123 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 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. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.

Original language	English
Pages (from-to)	658-671
Number of pages	14
Journal	Alzheimers & dementia
Volume	11
Issue number	6
DOIs	https://doi.org/10.1016/j.jalz.2014.05.1757
Publication status	Published - Jun 2015

Keywords

Alzheimer's disease
Dementia
Neurodegeneration
Immune response
Endocytosis
Cholesterol metabolism
Ubiquitination
Pathway analysis
ALIGATOR
Weighted gene co-expression network analysis
GENOME-WIDE ASSOCIATION
NETWORK ANALYSIS
UNITED-STATES
PREVALENCE
VARIANTS
POPULATION
BRAIN
LISTS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jalz.2014.05.1757

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Jones, L., Lambert, J-C., Wang, L-S., Choi, S-H., Harold, D., Vedernikov, A., Escott-Price, V., Stone, T., Richards, A., Ibrahim-Verbaas, C. A., Naj, A. C., Sims, R., Gerrish, A., Craig, D., Johnston, J. A., McGuinness, B., Todd, S., & Passmore, P. (2015). Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimers & dementia, 11(6), 658-671. https://doi.org/10.1016/j.jalz.2014.05.1757

@article{ccffe9754d8f4ad5809f74da005f5ffc,

title = "Convergent genetic and expression data implicate immunity in Alzheimer's disease",

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. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.",

keywords = "Alzheimer's disease, Dementia, Neurodegeneration, Immune response, Endocytosis, Cholesterol metabolism, Ubiquitination, Pathway analysis, ALIGATOR, Weighted gene co-expression network analysis, GENOME-WIDE ASSOCIATION, NETWORK ANALYSIS, UNITED-STATES, PREVALENCE, VARIANTS, POPULATION, BRAIN, LISTS",

author = "Lesley Jones and Jean-Charles Lambert and Li-San Wang and Seung-Hoan Choi and Denise Harold and Alexey Vedernikov and Valentina Escott-Price and Timothy Stone and Alexander Richards and Ibrahim-Verbaas, {Carla A.} and Naj, {Adam C.} and Rebecca Sims and Amy Gerrish and David Craig and Johnston, {Janet A.} and Bernadette McGuinness and Stephen Todd and Peter Passmore",

year = "2015",

month = jun,

doi = "10.1016/j.jalz.2014.05.1757",

language = "English",

volume = "11",

pages = "658--671",

journal = "Alzheimer's & Dementia: The Journal of the Alzheimer's Association",

issn = "1552-5260",

publisher = "Wiley-ISTE",

number = "6",

}

Jones, L, Lambert, J-C, Wang, L-S, Choi, S-H, Harold, D, Vedernikov, A, Escott-Price, V, Stone, T, Richards, A, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Gerrish, A, Craig, D, Johnston, JA, McGuinness, B, Todd, S & Passmore, P 2015, 'Convergent genetic and expression data implicate immunity in Alzheimer's disease', Alzheimers & dementia, vol. 11, no. 6, pp. 658-671. https://doi.org/10.1016/j.jalz.2014.05.1757

TY - JOUR

T1 - Convergent genetic and expression data implicate immunity in Alzheimer's disease

AU - Jones, Lesley

AU - Lambert, Jean-Charles

AU - Wang, Li-San

AU - Choi, Seung-Hoan

AU - Harold, Denise

AU - Vedernikov, Alexey

AU - Escott-Price, Valentina

AU - Stone, Timothy

AU - Richards, Alexander

AU - Ibrahim-Verbaas, Carla A.

AU - Naj, Adam C.

AU - Sims, Rebecca

AU - Gerrish, Amy

AU - Craig, David

AU - Johnston, Janet A.

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Passmore, Peter

PY - 2015/6

Y1 - 2015/6

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 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. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.

AB - 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. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.

KW - Alzheimer's disease

KW - Dementia

KW - Neurodegeneration

KW - Immune response

KW - Endocytosis

KW - Cholesterol metabolism

KW - Ubiquitination

KW - Pathway analysis

KW - ALIGATOR

KW - Weighted gene co-expression network analysis

KW - GENOME-WIDE ASSOCIATION

KW - NETWORK ANALYSIS

KW - UNITED-STATES

KW - PREVALENCE

KW - VARIANTS

KW - POPULATION

KW - BRAIN

KW - LISTS

U2 - 10.1016/j.jalz.2014.05.1757

DO - 10.1016/j.jalz.2014.05.1757

M3 - Article

VL - 11

SP - 658

EP - 671

JO - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

JF - Alzheimer's & Dementia: The Journal of the Alzheimer's Association

SN - 1552-5260

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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