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.
Convergent genetic and expression data implicate immunity in Alzheimer's disease / L. Jones, J. Lambert, L. Wang, S. Choi, D. Harold, A. Vedernikov, V. Escott Price, T. Stone, A. Richards, C. Bellenguez, C.A. Ibrahim Verbaas, A.C. Naj, R. Sims, A. Gerrish, G. Jun, A.L. Destefano, J.C. Bis, G.W. Beecham, B. Grenier Boley, G. Russo, T.A. Thornton Wells, N. Jones, A.V. Smith, V. Chouraki, C. Thomas, M.A. Ikram, D. Zelenika, B.N. Vardarajan, Y. Kamatani, C. Lin, H. Schmidt, B.W. Kunkle, M.L. Dunstan, A. Ruiz, M. Bihoreau, C. Reitz, F. Pasquier, P. Hollingworth, O. Hanon, A.L. Fitzpatrick, J.D. Buxbaum, D. Campion, P.K. Crane, T. Becker, V. Gudnason, C. Cruchaga, D. Craig, N. Amin, C. Berr, O.L. Lopez, P.L. De Jager, V. Deramecourt, J.A. Johnston, D. Evans, S. Lovestone, L. Letteneur, J. Kornhuber, L. Tárraga, D.C. Rubinsztein, G. Eiriksdottir, K. Sleegers, A.M. Goate, N. Fiévet, M.J. Huentelman, M. Gill, V. Emilsson, K. Brown, M.I. Kamboh, L. Keller, P. Barberger Gateau, B. Mcguinness, E.B. Larson, A.J. Myers, C. Dufouil, S. Todd, D. Wallon, S. Love, P. Kehoe, E. Rogaeva, J. Gallacher, P. St George Hyslop, J. Clarimon, A. Lleò, A. Bayer, D.W. Tsuang, L. Yu, M. Tsolaki, P. Bossù, G. Spalletta, P. Proitsi, J. Collinge, S. Sorbi, F. Sanchez Garcia, N. Fox, J. Hardy, M.C. Deniz Naranjo, C. Razquin, P. Bosco, R. Clarke, C. Brayne, D. Galimberti, M. Mancuso, S. Moebus, P. Mecocci, M. Del Zompo, W. Maier, H. Hampel, A. Pilotto, M. Bullido, F. Panza, P. Caffarra, B. Nacmias, J.R. Gilbert, M. Mayhaus, F. Jessen, M. Dichgans, L. Lannfelt, H. Hakonarson, S. Pichler, M.M. Carrasquillo, M. Ingelsson, D. Beekly, V. Alavarez, F. Zou, O. Valladares, S.G. Younkin, E. Coto, K.L. Hamilton Nelson, I. Mateo, M.J. Owen, K.M. Faber, P.V. Jonsson, O. Combarros, M.C. O'Donovan, L.B. Cantwell, H. Soininen, D. Blacker, S. Mead, T.H. Mosley, D.A. Bennett, T.B. Harris, L. Fratiglioni, C. Holmes, R.F.A.G. De Bruijn, P. Passmore, T.J. Montine, K. Bettens, J.I. Rotter, A. Brice, K. Morgan, T.M. Foroud, W.A. Kukull, D. Hannequin, J.F. Powell, M.A. Nalls, K. Ritchie, K.L. Lunetta, J.S.K. Kauwe, E. Boerwinkle, M. Riemenschneider, M. Boada, M. Hiltunen, E.R. Martin, P. Pastor, R. Schmidt, D. Rujescu, J. Dartigues, R. Mayeux, C. Tzourio, A. Hofman, M.M. Nöthen, C. Graff, B.M. Psaty, J.L. Haines, M. Lathrop, M.A. Pericak Vance, L.J. Launer, L.A. Farrer, C.M. Van Duijn, C. Van Broeckhoven, A. Ramirez, G.D. Schellenberg, S. Seshadri, P. Amouyel, J. Williams, P.A. Holmans, I. Genomics of Alzheimer’s Disease Consortium. - In: ALZHEIMER'S & DEMENTIA. - ISSN 1552-5260. - 11:6(2015 Jun), pp. 658-671. [10.1016/j.jalz.2014.05.1757]
Convergent genetic and expression data implicate immunity in Alzheimer's disease
P. Bosco;D. Galimberti;
2015
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.
| File | Dimensione | Formato | |
|---|---|---|---|
|
5. IGAP consortium including DG.pdf
accesso riservato
Tipologia:
Publisher's version/PDF
Dimensione
1.51 MB
Formato
Adobe PDF
|
1.51 MB | Adobe PDF | Visualizza/Apri Richiedi una copia |
|
nihms729581.pdf
accesso aperto
Tipologia:
Pre-print (manoscritto inviato all'editore)
Dimensione
731.93 kB
Formato
Adobe PDF
|
731.93 kB | Adobe PDF | Visualizza/Apri |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
