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 |
|---|---|
| Pages (from-to) | 658-671 |
| Number of pages | 14 |
| Journal | Alzheimer's and Dementia |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 1 2015 |
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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. / Jones, Lesley; Lambert, Jean Charles; Wang, Li San; Choi, Seung Hoan; Harold, Denise; Vedernikov, Alexey; Escott-Price, Valentina; Stone, Timothy; Richards, Alexander; Bellenguez, Céline; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Gerrish, Amy; Jun, Gyungah; DeStefano, Anita L.; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Jones, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao Feng; Schmidt, Helena; Kunkle, Brian W.; Dunstan, Melanie L.; Ruiz, Agustin; Bihoreau, Marie Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letteneur, Luc; Kornhuber, Johanes; Tárraga, Lluís; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Emilsson, Valur; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Kehoe, Pat; Rogaeva, Ekaterina; Gallacher, John; St George-Hyslop, Peter; Clarimon, Jordi; Lleò, Alberti; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Sanchez Garcia, Florentino; Fox, Nick; Hardy, John; Deniz Naranjo, Maria Candida; Razquin, Cristina; Bosco, Paola; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Moebus, Susanne; Mecocci, Patrizia; Del Zompo, Maria; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R.; Mayhaus, Manuel; Jessen, Frank; Dichgans, Martin; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alavarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; De Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Pastor, Pau; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Farrer, Lindsay A.; Van Duijn, Cornelia M.; Van Broeckhoven, Christine; Ramirez, Alfredo; Schellenberg, Gerard D.; Seshadri, Sudha; Amouyel, Philippe; Williams, Julie; Holmans, Peter A.; MRC CFAS, CFAS.
In: Alzheimer's and Dementia, Vol. 11, No. 6, 01.06.2015, p. 658-671.Research output: Contribution to journal › Article
}
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
AU - Galimberti, Daniela
AU - Mancuso, Michelangelo
AU - Moebus, Susanne
AU - Mecocci, Patrizia
AU - Del Zompo, Maria
AU - Maier, Wolfgang
AU - Hampel, Harald
AU - Pilotto, Alberto
AU - Bullido, Maria
AU - Panza, Francesco
AU - Caffarra, Paolo
AU - Nacmias, Benedetta
AU - Gilbert, John R.
AU - Mayhaus, Manuel
AU - Jessen, Frank
AU - Dichgans, Martin
AU - Lannfelt, Lars
AU - Hakonarson, Hakon
AU - Pichler, Sabrina
AU - Carrasquillo, Minerva M.
AU - Ingelsson, Martin
AU - Beekly, Duane
AU - Alavarez, Victoria
AU - Zou, Fanggeng
AU - Valladares, Otto
AU - Younkin, Steven G.
AU - Coto, Eliecer
AU - Hamilton-Nelson, Kara L.
AU - Mateo, Ignacio
AU - Owen, Michael J.
AU - Faber, Kelley M.
AU - Jonsson, Palmi V.
AU - Combarros, Onofre
AU - O'Donovan, Michael C.
AU - Cantwell, Laura B.
AU - Soininen, Hilkka
AU - Blacker, Deborah
AU - Mead, Simon
AU - Mosley, Thomas H.
AU - Bennett, David A.
AU - Harris, Tamara B.
AU - Fratiglioni, Laura
AU - Holmes, Clive
AU - De Bruijn, Renee F A G
AU - Passmore, Peter
AU - Montine, Thomas J.
AU - Bettens, Karolien
AU - Rotter, Jerome I.
AU - Brice, Alexis
AU - Morgan, Kevin
AU - Foroud, Tatiana M.
AU - Kukull, Walter A.
AU - Hannequin, Didier
AU - Powell, John F.
AU - Nalls, Michael A.
AU - Ritchie, Karen
AU - Lunetta, Kathryn L.
AU - Kauwe, John S K
AU - Boerwinkle, Eric
AU - Riemenschneider, Matthias
AU - Boada, Mercè
AU - Hiltunen, Mikko
AU - Martin, Eden R.
AU - Pastor, Pau
AU - Schmidt, Reinhold
AU - Rujescu, Dan
AU - Dartigues, Jean François
AU - Mayeux, Richard
AU - Tzourio, Christophe
AU - Hofman, Albert
AU - Nöthen, Markus M.
AU - Graff, Caroline
AU - Psaty, Bruce M.
AU - Haines, Jonathan L.
AU - Lathrop, Mark
AU - Pericak-Vance, Margaret A.
AU - Launer, Lenore J.
AU - Farrer, Lindsay A.
AU - Van Duijn, Cornelia M.
AU - Van Broeckhoven, Christine
AU - Ramirez, Alfredo
AU - Schellenberg, Gerard D.
AU - Seshadri, Sudha
AU - Amouyel, Philippe
AU - Williams, Julie
AU - Holmans, Peter A.
AU - MRC CFAS, CFAS
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
AN - SCOPUS:84931560814
VL - 11
SP - 658
EP - 671
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 6
ER -