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

International Genomics of Alzheimer's Disease Consortium (IGAP)

doi:10.1016/j.jalz.2014.05.1757

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

International Genomics of Alzheimer's Disease Consortium (IGAP)

Neuroscience

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

120 Scopus citations

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 language	English (US)
Pages (from-to)	658-671
Number of pages	14
Journal	Alzheimer's and Dementia
Volume	11
Issue number	6
DOIs	https://doi.org/10.1016/j.jalz.2014.05.1757
State	Published - Jun 1 2015

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

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

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10.1016/j.jalz.2014.05.1757

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@article{7037698064644d76be1f171eaeb818e6,

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 × 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.",

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

author = "{International Genomics of Alzheimer's Disease Consortium (IGAP)} and Lesley Jones and Lambert, {Jean Charles} and Wang, {Li San} and Choi, {Seung Hoan} and Denise Harold and Alexey Vedernikov and Valentina Escott-Price and Timothy Stone and Alexander Richards and C{\'e}line Bellenguez and Ibrahim-Verbaas, {Carla A.} and Naj, {Adam C.} and Rebecca Sims and Amy Gerrish and Gyungah Jun and DeStefano, {Anita L.} and Bis, {Joshua C.} and Beecham, {Gary W.} and Benjamin Grenier-Boley and Giancarlo Russo and Thornton-Wells, {Tricia A.} and Nicola Jones and Smith, {Albert V.} and Vincent Chouraki and Charlene Thomas and Ikram, {M. Arfan} and Diana Zelenika and Vardarajan, {Badri N.} and Yoichiro Kamatani and Lin, {Chiao Feng} and Helena Schmidt and Kunkle, {Brian W.} and Dunstan, {Melanie L.} and Agustin Ruiz and Bihoreau, {Marie Th{\'e}r{\`e}se} and Christiane Reitz and Florence Pasquier and Paul Hollingworth and Olivier Hanon and Fitzpatrick, {Annette L.} and Buxbaum, {Joseph D.} and Dominique Campion and Crane, {Paul K.} and Tim Becker and Vilmundur Gudnason and Carlos Cruchaga and David Craig and Najaf Amin and Carrasquillo, {Minerva M.} and Younkin, {Steven G.}",

year = "2015",

month = jun,

day = "1",

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

language = "English (US)",

volume = "11",

pages = "658--671",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

number = "6",

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TY - JOUR

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

AU - International Genomics of Alzheimer's Disease Consortium (IGAP)

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 - 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 - Carrasquillo, Minerva M.

AU - Younkin, Steven G.

PY - 2015/6/1

Y1 - 2015/6/1

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.

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 × 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.

KW - ALIGATOR

KW - Alzheimer's disease

KW - Cholesterol metabolism

KW - Dementia

KW - Endocytosis

KW - Immune response

KW - Neurodegeneration

KW - Pathway analysis

KW - Ubiquitination

KW - Weighted gene co-expression network analysis

UR - http://www.scopus.com/inward/record.url?scp=84931560814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931560814&partnerID=8YFLogxK

U2 - 10.1016/j.jalz.2014.05.1757

DO - 10.1016/j.jalz.2014.05.1757

M3 - Article

C2 - 25533204

AN - SCOPUS:84931560814

SN - 1552-5260

VL - 11

SP - 658

EP - 671

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 6

ER -

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

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Keywords

ASJC Scopus subject areas

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