Convergent genetic and expression data implicate immunity in Alzheimer's disease
Jones L., Lambert J., Wang L., Choi S., 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 C., Schmidt H., Kunkle BW., Dunstan ML., Ruiz A., Bihoreau M., 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., 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 JR., Mayhaus M., Jessen F., Dichgans M., Lannfelt L., Hakonarson H., Pichler S., Carrasquillo MM., Ingelsson M., Beekly D., Alavarez V., Zou F., Valladares O., Younkin SG., Coto E., Hamilton‐Nelson KL., Mateo I., Owen MJ., Faber KM., Jonsson PV., Combarros O., O'Donovan MC., Cantwell LB., Soininen H., Blacker D., Mead S., Mosley TH., Bennett DA., Harris TB., Fratiglioni L., Holmes C., de Bruijn RFAG., Passmore P., Montine TJ., Bettens K., Rotter JI., Brice A., Morgan K., Foroud TM., Kukull WA., Hannequin D., Powell JF., Nalls MA., Ritchie K., Lunetta KL., Kauwe JSK., Boerwinkle E., Riemenschneider M., Boada M., Hiltunen M., Martin ER., Pastor P., Schmidt R., Rujescu D., Dartigues J., Mayeux R., Tzourio C., Hofman A., Nöthen MM., Graff C., Psaty BM., Haines JL., Lathrop M., Pericak‐Vance MA., Launer LJ., Farrer LA., van Duijn CM., Van Broeckhoven C., Ramirez A., Schellenberg GD., Seshadri S., Amouyel P., Williams J., Holmans PA.
AbstractBackgroundLate‐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.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR 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).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.