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

Jones, Lesley, Lambert, J-C., Wang, L-S., Choi, S-H., Harold, Denise, Vedernikov, Alexey, Escott-Price, Valentina, Stone, Timothy C., Richards, Alexander, Bellenguez, C., Ibrahim-Verbaas, C. A., Naj, A. C., Sims, Rebecca, Gerrish, Amy, Jun, G., DeStefano, A. L., Bis, J. C., Beecham, G. W., Grenier-Boley, B., Russo, G., Thornton-Wells, T. A., Denning, Nicola, Smith, A. V., Chouraki, V., Thomas, Charlene, Ikram, M. A., Zelenika, D., Vardarajan, B. N., Kamatani, Y., Lin, C-F., Schmidt, H., Kunkle, B. W., Dunstan, Melanie, Ruiz, A., Bihoreau, M-T., Reitz, C., Pasquier, F., Hollingworth, P., Hanon, O., Fitzpatrick, A. L., Buxbaum, J. D., Campion, D., Crane, P. K., Becker, T., Gudnason, V., Cruchaga, C., Craig, D., Amin, N., Berr, C., Lopez, O. L., De Jager, P. L., Deramecourt, V., Johnston, J. A., Evans, D., Lovestone, S., Letteneur, L., Kornhuber, J., Tarraga, L., Rubinsztein, D. C., Eiriksdottir, G., Sleegers, K., Goate, A. M., Fievet, N., Heuntelman, M. J., Gill, M., Emilsson, V., Brown, K., Kamboh, M. I., Keller, L., Barberger-Gateau, P., McGuinness, B., Larson, E. B., Myers, A. J., Dufoil, C., Todd, S., Wallon, D., Love, S., Kehoe, P., Rogaeva, E., Gallacher, J., St George-Hyslop, P., Clarimon, J., Lleo, A., Bayer, Antony, Tsuang, D. W., Yu, L., Tsolaki, M., Bossu, P., Spalletta, G., Proitsi, P., Collinge, J., Sorbi, S., Sanchez Garcia, F., Fox, N., Hardy, J., Deniz Naranjo, M. C., Razquin, C., Bosco, P., Clarke, R., Brayne, C., Galimberti, D., Mancuso, M., Moebus, S., Mecocci, P., del Zompo, M., Maier, W., Hampel, H., Pilotto, A., Bullido, M., Panza, F., Caffarra, P., Nacmias, B., Gilbert, J. R., Mayhaus, M., Jessen, F., Dichgans, M., Lannfelt, L., Hakonarson, H., Pichier, S., Carrasquillo, M. M., Ingelsson, M., Beekly, D., Alavarez, V., Zou, F., Valadares, O., Younkin, S. G., Coto, E., Hamilton-Nelson, K. L., Mateo, I., Owen, Michael John, Faber, K. M., Jonsson, P. V., Combarros, O., O'Donovan, Michael Conlon, Cantwell, L. B., Soininen, H., Blacker, D., Mead, S., Mosley Jr., T. H., Bennett, D. A., Harris, T. B., Fratiglioni, L., Holmes, C., de Bruijn, R. F. A. G., Passmore, P., Montine, T. J., Bettens, K., Rotter, J. I., Brice, A., Morgan, K., Faroud, T. M., Kukull, W. A., Hannequin, D., Powell, J. F., Nalls, M. A., Ritchie, K., Lunetta, K. L., Kauwe, J. S. K., Boenwinkle, E., Riemenschneider, M., Boada, M., Hiltunen, M., Martin, E. R., Pastor, P., Schmidt, R., Rujescu, D., Dartigues, J-F., Mayeaux, R., Tzourio, C., Hofman, A., Nothen, M. M., Graff, C., Psaty, B. W., Haines, J. L., Lathrop, M., Pericak-Vance, M. A., Launer, L. J., Farren, L. A., van Duijn, C. M., Van Broeckhoven, C., Ramirez, A., Schellenberg, G. D., Seshadri, S., Amouye, P., Williams, Julie and Holmans, Peter Alan 2015. Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimer's and Dementia 11 (6) , pp. 658-671. 10.1016/j.jalz.2014.05.1757

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Neuroscience and Mental Health Research Institute (NMHRI)
Medicine
Advanced Research Computing @ Cardiff (ARCCA)
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords: Alzheimer's disease; Dementia; Neurodegeneration; Immune response; Endocytosis; Cholesterol metabolism; Ubiquitination; Pathway analysis; ALIGATOR; Weighted gene co-expression network analysis
Publisher: Elsevier Masson
ISSN: 1552-5260
Last Modified: 19 Oct 2019 02:40
URI: http://orca.cf.ac.uk/id/eprint/74776

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