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 Russo; Tricia 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

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, 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

Department of Medicine

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

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

Keywords

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

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., Bellenguez, C., Ibrahim-Verbaas, C. A., Naj, A. C., Sims, R., Gerrish, A., Jun, G., DeStefano, A. L., Bis, J. C., Beecham, G. W., Grenier-Boley, B., ... Brayne, C. (2015). Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimer's and Dementia, 11(6), 658-671. https://doi.org/10.1016/j.jalz.2014.05.1757

@article{f8852bcf89fb4962a27eaab4c9d88190,

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

abstract = "{\textcopyright} 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.",

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

author = "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 Claudine Berr and Lopez, {Oscar L.} and {De Jager}, {Philip L.} and Vincent Deramecourt and Johnston, {Janet A.} and Denis Evans and Simon Lovestone and Luc Letteneur and Johanes Kornhuber and Llu{\'i}s T{\'a}rraga and Rubinsztein, {David C.} and Gudny Eiriksdottir and Kristel Sleegers and Goate, {Alison M.} and Nathalie Fi{\'e}vet and Huentelman, {Matthew J.} and Michael Gill and Valur Emilsson and Kristelle Brown and Kamboh, {M. Ilyas} and Lina Keller and Pascale Barberger-Gateau and Bernadette McGuinness and Larson, {Eric B.} and Myers, {Amanda J.} and Carole Dufouil and Stephen Todd and David Wallon and Seth Love and Pat Kehoe and Ekaterina Rogaeva and John Gallacher and {St George-Hyslop}, Peter and Jordi Clarimon and Alberti Lle{\`o} and Anthony Bayer and Tsuang, {Debby W.} and Lei Yu and Magda Tsolaki and Paola Boss{\`u} and Gianfranco Spalletta and Petra Proitsi and John Collinge and Sandro Sorbi and {Sanchez Garcia}, Florentino and Nick Fox and John Hardy and {Deniz Naranjo}, {Maria Candida} and Cristina Razquin and Paola Bosco and Robert Clarke and Carol Brayne",

year = "2015",

month = jun,

day = "1",

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

language = "English",

volume = "11",

pages = "658--671",

number = "6",

}

Jones, L, Lambert, JC, Wang, LS, Choi, SH, Harold, D, Vedernikov, A, Escott-Price, V, Stone, T, Richards, A, Bellenguez, C, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Gerrish, A, Jun, G, DeStefano, AL, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Jones, N, Smith, AV, Chouraki, V, Thomas, C, Ikram, MA, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Schmidt, H, Kunkle, BW, Dunstan, ML, Ruiz, A, Bihoreau, MT, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Becker, T, Gudnason, V, Cruchaga, C, Craig, D, Amin, N, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letteneur, L, Kornhuber, J, Tárraga, L, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K, Goate, AM, Fiévet, N, Huentelman, MJ, Gill, M, Emilsson, V, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Kehoe, P, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleò, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Sanchez Garcia, F, Fox, N, Hardy, J, Deniz Naranjo, MC, Razquin, C, Bosco, P, Clarke, R & Brayne, C 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

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 - 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 - Lopez, Oscar L.

AU - De Jager, Philip L.

AU - Deramecourt, Vincent

AU - Johnston, Janet A.

AU - Evans, Denis

AU - Lovestone, Simon

AU - Letteneur, Luc

AU - Kornhuber, Johanes

AU - Tárraga, Lluís

AU - Rubinsztein, David C.

AU - Eiriksdottir, Gudny

AU - Sleegers, Kristel

AU - Goate, Alison M.

AU - Fiévet, Nathalie

AU - Huentelman, Matthew J.

AU - Gill, Michael

AU - Emilsson, Valur

AU - Brown, Kristelle

AU - Kamboh, M. Ilyas

AU - Keller, Lina

AU - Barberger-Gateau, Pascale

AU - McGuinness, Bernadette

AU - Larson, Eric B.

AU - Myers, Amanda J.

AU - Dufouil, Carole

AU - Todd, Stephen

AU - Wallon, David

AU - Love, Seth

AU - Kehoe, Pat

AU - Rogaeva, Ekaterina

AU - Gallacher, John

AU - St George-Hyslop, Peter

AU - Clarimon, Jordi

AU - Lleò, Alberti

AU - Bayer, Anthony

AU - Tsuang, Debby W.

AU - Yu, Lei

AU - Tsolaki, Magda

AU - Bossù, Paola

AU - Spalletta, Gianfranco

AU - Proitsi, Petra

AU - Collinge, John

AU - Sorbi, Sandro

AU - Sanchez Garcia, Florentino

AU - Fox, Nick

AU - Hardy, John

AU - Deniz Naranjo, Maria Candida

AU - Razquin, Cristina

AU - Bosco, Paola

AU - Clarke, Robert

AU - Brayne, Carol

PY - 2015/6/1

Y1 - 2015/6/1

N2 - © 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.

AB - © 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.

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

U2 - 10.1016/j.jalz.2014.05.1757

DO - 10.1016/j.jalz.2014.05.1757

M3 - Article

VL - 11

SP - 658

EP - 671

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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