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, Daniela Galimberti, Michelangelo Mancuso, Susanne Moebus, Patrizia Mecocci, Maria Del Zompo, Wolfgang Maier, Harald Hampel, Alberto Pilotto, Maria Bullido, Francesco Panza, Paolo Caffarra, Benedetta Nacmias, John R. Gilbert, Manuel Mayhaus, Frank Jessen, Martin Dichgans, Lars Lannfelt, Hakon Hakonarson, Sabrina Pichler, Minerva M. Carrasquillo, Martin Ingelsson, Duane Beekly, Victoria Alavarez, Fanggeng Zou, Otto Valladares, Steven G. Younkin, Eliecer Coto, Kara L. Hamilton-Nelson, Ignacio Mateo, Michael J. Owen, Kelley M. Faber, Palmi V. Jonsson, Onofre Combarros, Michael C. O'Donovan, Laura B. Cantwell, Hilkka Soininen, Deborah Blacker, Simon Mead, Thomas H. Mosley, David A. Bennett, Tamara B. Harris, Laura Fratiglioni, Clive Holmes, Renee F A G De Bruijn, Peter Passmore, Thomas J. Montine, Karolien Bettens, Jerome I. Rotter, Alexis Brice, Kevin Morgan, Tatiana M. Foroud, Walter A. Kukull, Didier Hannequin, John F. Powell, Michael A. Nalls, Karen Ritchie, Kathryn L. Lunetta, John S K Kauwe, Eric Boerwinkle, Matthias Riemenschneider, Mercè Boada, Mikko Hiltunen, Eden R. Martin, Pau Pastor, Reinhold Schmidt, Dan Rujescu, Jean François Dartigues, Richard Mayeux, Christophe Tzourio, Albert Hofman, Markus M. Nöthen, Caroline Graff, Bruce M. Psaty, Jonathan L. Haines, Mark Lathrop, Margaret A. Pericak-Vance, Lenore J. Launer, Lindsay A. Farrer, Cornelia M. Van Duijn, Christine Van Broeckhoven, Alfredo Ramirez, Gerard D. Schellenberg, Sudha Seshadri, Philippe Amouyel, Julie Williams, Peter A. Holmans, CFAS MRC CFAS

Research output: Contribution to journalArticle

94 Citations (Scopus)

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 languageEnglish
Pages (from-to)658-671
Number of pages14
JournalAlzheimer's and Dementia
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

Fingerprint

Genomics
Endocytosis
Immunity
Alzheimer Disease
Cholesterol
Gene Expression
Inborn Genetic Diseases
Gene Regulatory Networks
Ubiquitination
Proteasome Endopeptidase Complex
Ubiquitin
Carrier Proteins
Genome
Brain
Genes
Therapeutics

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

Jones, L., Lambert, J. C., Wang, L. S., Choi, S. H., Harold, D., Vedernikov, A., ... MRC CFAS, CFAS. (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

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 journalArticle

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, 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, JF, 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 & MRC CFAS, CFAS 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
Jones L, Lambert JC, Wang LS, Choi SH, Harold D, Vedernikov A et al. Convergent genetic and expression data implicate immunity in Alzheimer's disease. Alzheimer's and Dementia. 2015 Jun 1;11(6):658-671. https://doi.org/10.1016/j.jalz.2014.05.1757
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. / Convergent genetic and expression data implicate immunity in Alzheimer's disease. In: Alzheimer's and Dementia. 2015 ; Vol. 11, No. 6. pp. 658-671.
@article{171e269740ce42c19d6d232abf711893,
title = "Convergent genetic and expression data implicate immunity in Alzheimer's disease",
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.",
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 and Daniela Galimberti and Michelangelo Mancuso and Susanne Moebus and Patrizia Mecocci and {Del Zompo}, Maria and Wolfgang Maier and Harald Hampel and Alberto Pilotto and Maria Bullido and Francesco Panza and Paolo Caffarra and Benedetta Nacmias and Gilbert, {John R.} and Manuel Mayhaus and Frank Jessen and Martin Dichgans and Lars Lannfelt and Hakon Hakonarson and Sabrina Pichler and Carrasquillo, {Minerva M.} and Martin Ingelsson and Duane Beekly and Victoria Alavarez and Fanggeng Zou and Otto Valladares and Younkin, {Steven G.} and Eliecer Coto and Hamilton-Nelson, {Kara L.} and Ignacio Mateo and Owen, {Michael J.} and Faber, {Kelley M.} and Jonsson, {Palmi V.} and Onofre Combarros and O'Donovan, {Michael C.} and Cantwell, {Laura B.} and Hilkka Soininen and Deborah Blacker and Simon Mead and Mosley, {Thomas H.} and Bennett, {David A.} and Harris, {Tamara B.} and Laura Fratiglioni and Clive Holmes and {De Bruijn}, {Renee F A G} and Peter Passmore and Montine, {Thomas J.} and Karolien Bettens and Rotter, {Jerome I.} and Alexis Brice and Kevin Morgan and Foroud, {Tatiana M.} and Kukull, {Walter A.} and Didier Hannequin and Powell, {John F.} and Nalls, {Michael A.} and Karen Ritchie and Lunetta, {Kathryn L.} and Kauwe, {John S K} and Eric Boerwinkle and Matthias Riemenschneider and Merc{\`e} Boada and Mikko Hiltunen and Martin, {Eden R.} and Pau Pastor and Reinhold Schmidt and Dan Rujescu and Dartigues, {Jean Fran{\cc}ois} and Richard Mayeux and Christophe Tzourio and Albert Hofman and N{\"o}then, {Markus M.} and Caroline Graff and Psaty, {Bruce M.} and Haines, {Jonathan L.} and Mark Lathrop and Pericak-Vance, {Margaret A.} and Launer, {Lenore J.} and Farrer, {Lindsay A.} and {Van Duijn}, {Cornelia M.} and {Van Broeckhoven}, Christine and Alfredo Ramirez and Schellenberg, {Gerard D.} and Sudha Seshadri and Philippe Amouyel and Julie Williams and Holmans, {Peter A.} and {MRC CFAS}, CFAS",
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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 -