Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Valentina Escott-Price; Céline Bellenguez; Li San Wang; Seung Hoan Choi; Denise Harold; Lesley Jones; Peter Holmans; Amy Gerrish; Alexey Vedernikov; Alexander Richards; Anita L. DeStefano; Jean Charles Lambert; Carla A. Ibrahim-Verbaas; Adam C. Naj; Rebecca Sims; Gyungah Jun; Joshua C. Bis; Gary W. Beecham; Benjamin Grenier-Boley; Giancarlo Russo; Tricia A. Thornton-Wells; Nicola Denning; Albert V. Smith; Vincent Chouraki; Charlene Thomas; M. Arfan Ikram; Diana Zelenika; Badri N. Vardarajan; Yoichiro Kamatani; Chiao Feng Lin; Helena Schmidt; Brian Kunkle; Melanie L. Dunstan; Maria Vronskaya; Andrew D. Johnson; Agustin Ruiz; Marie Thérèse Bihoreau; Christiane Reitz; Florence Pasquier; Paul Hollingworth; Olivier Hanon; Annette L. Fitzpatrick; Joseph D. Buxbaum; Dominique Campion; Paul K. Crane; Clinton Baldwin 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 Letenneur; Isabel Hernández; David C. Rubinsztein; Gudny Eiriksdottir; Kristel Sleegers; Alison M. Goate; Nathalie Fiévet; Matthew J. Huentelman; Michael Gill; 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; Ekaterina Rogaeva; John Gallacher; Peter St George-Hyslop; Jordi Clarimon; Alberto Lleo; Anthony Bayer; Debby W. Tsuang; Lei Yu; Magda Tsolaki; Paola Bossù; Gianfranco Spalletta; Petra Proitsi; John Collinge; Sandro Sorbi; Florentino Sanchez Garcia; Nick C. Fox; John Hardy; Maria Candida Deniz Naranjo; Paolo Bosco; Robert Clarke; Carol Brayne; Daniela Galimberti; Elio Scarpini

doi:10.1371/journal.pone.0094661

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

Valentina Escott-Price, Céline Bellenguez, Li San Wang, Seung Hoan Choi, Denise Harold, Lesley Jones, Peter Holmans, Amy Gerrish, Alexey Vedernikov, Alexander Richards, Anita L. DeStefano, Jean Charles Lambert, Carla A. Ibrahim-Verbaas, Adam C. Naj, Rebecca Sims, Gyungah Jun, Joshua C. Bis, Gary W. Beecham, Benjamin Grenier-Boley, Giancarlo RussoTricia A. Thornton-Wells, Nicola Denning, Albert V. Smith, Vincent Chouraki, Charlene Thomas, M. Arfan Ikram, Diana Zelenika, Badri N. Vardarajan, Yoichiro Kamatani, Chiao Feng Lin, Helena Schmidt, Brian Kunkle, Melanie L. Dunstan, Maria Vronskaya, Andrew D. Johnson, Agustin Ruiz, Marie Thérèse Bihoreau, Christiane Reitz, Florence Pasquier, Paul Hollingworth, Olivier Hanon, Annette L. Fitzpatrick, Joseph D. Buxbaum, Dominique Campion, Paul K. Crane, Clinton Baldwin 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 Letenneur, Isabel Hernández, David C. Rubinsztein, Gudny Eiriksdottir, Kristel Sleegers, Alison M. Goate, Nathalie Fiévet, Matthew J. Huentelman, Michael Gill, 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, Ekaterina Rogaeva, John Gallacher, Peter St George-Hyslop, Jordi Clarimon, Alberto Lleo, Anthony Bayer, Debby W. Tsuang, Lei Yu, Magda Tsolaki, Paola Bossù, Gianfranco Spalletta, Petra Proitsi, John Collinge, Sandro Sorbi, Florentino Sanchez Garcia, Nick C. Fox, John Hardy, Maria Candida Deniz Naranjo, Paolo Bosco, Robert Clarke, Carol Brayne, Daniela Galimberti, Elio Scarpini

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

73 Citations (Scopus)

Abstract

Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

Original language	English
Article number	e94661
Journal	PLoS ONE
Volume	9
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0094661
Publication status	Published - 12 Jun 2014

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Escott-Price, V., Bellenguez, C., Wang, L. S., Choi, S. H., Harold, D., Jones, L., Holmans, P., Gerrish, A., Vedernikov, A., Richards, A., DeStefano, A. L., Lambert, J. C., Ibrahim-Verbaas, C. A., Naj, A. C., Sims, R., Jun, G., Bis, J. C., Beecham, G. W., Grenier-Boley, B., ... Scarpini, E. (2014). Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. PLoS ONE, 9(6), [e94661]. https://doi.org/10.1371/journal.pone.0094661

Escott-Price, Valentina ; Bellenguez, Céline ; Wang, Li San ; Choi, Seung Hoan ; Harold, Denise ; Jones, Lesley ; Holmans, Peter ; Gerrish, Amy ; Vedernikov, Alexey ; Richards, Alexander ; DeStefano, Anita L. ; Lambert, Jean Charles ; Ibrahim-Verbaas, Carla A. ; Naj, Adam C. ; Sims, Rebecca ; Jun, Gyungah ; Bis, Joshua C. ; Beecham, Gary W. ; Grenier-Boley, Benjamin ; Russo, Giancarlo ; Thornton-Wells, Tricia A. ; Denning, Nicola ; Smith, Albert V. ; Chouraki, Vincent ; Thomas, Charlene ; Arfan Ikram, M. ; Zelenika, Diana ; Vardarajan, Badri N. ; Kamatani, Yoichiro ; Lin, Chiao Feng ; Schmidt, Helena ; Kunkle, Brian ; Dunstan, Melanie L. ; Vronskaya, Maria ; Johnson, Andrew D. ; 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, Clinton Baldwin 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 ; Letenneur, Luc ; Hernández, Isabel ; Rubinsztein, David C. ; Eiriksdottir, Gudny ; Sleegers, Kristel ; Goate, Alison M. ; Fiévet, Nathalie ; Huentelman, Matthew J. ; Gill, Michael ; 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 ; Rogaeva, Ekaterina ; Gallacher, John ; St George-Hyslop, Peter ; Clarimon, Jordi ; Lleo, Alberto ; Bayer, Anthony ; Tsuang, Debby W. ; Yu, Lei ; Tsolaki, Magda ; Bossù, Paola ; Spalletta, Gianfranco ; Proitsi, Petra ; Collinge, John ; Sorbi, Sandro ; Sanchez Garcia, Florentino ; Fox, Nick C. ; Hardy, John ; Naranjo, Maria Candida Deniz ; Bosco, Paolo ; Clarke, Robert ; Brayne, Carol ; Galimberti, Daniela ; Scarpini, Elio. / Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. In: PLoS ONE. 2014 ; Vol. 9, No. 6.

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title = "Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease",

abstract = "Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.",

author = "Valentina Escott-Price and C{\'e}line Bellenguez and Wang, {Li San} and Choi, {Seung Hoan} and Denise Harold and Lesley Jones and Peter Holmans and Amy Gerrish and Alexey Vedernikov and Alexander Richards and DeStefano, {Anita L.} and Lambert, {Jean Charles} and Ibrahim-Verbaas, {Carla A.} and Naj, {Adam C.} and Rebecca Sims and Gyungah Jun and Bis, {Joshua C.} and Beecham, {Gary W.} and Benjamin Grenier-Boley and Giancarlo Russo and Thornton-Wells, {Tricia A.} and Nicola Denning and Smith, {Albert V.} and Vincent Chouraki and Charlene Thomas and {Arfan Ikram}, M. and Diana Zelenika and Vardarajan, {Badri N.} and Yoichiro Kamatani and Lin, {Chiao Feng} and Helena Schmidt and Brian Kunkle and Dunstan, {Melanie L.} and Maria Vronskaya and Johnson, {Andrew D.} 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 Becker, {Clinton Baldwin Tim} 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 Letenneur and Isabel Hern{\'a}ndez 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 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 Ekaterina Rogaeva and John Gallacher and {St George-Hyslop}, Peter and Jordi Clarimon and Alberto Lleo 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 Fox, {Nick C.} and John Hardy and Naranjo, {Maria Candida Deniz} and Paolo Bosco and Robert Clarke and Carol Brayne and Daniela Galimberti and Elio Scarpini",

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Escott-Price, V, Bellenguez, C, Wang, LS, Choi, SH, Harold, D, Jones, L, Holmans, P, Gerrish, A, Vedernikov, A, Richards, A, DeStefano, AL, Lambert, JC, Ibrahim-Verbaas, CA, Naj, AC, Sims, R, Jun, G, Bis, JC, Beecham, GW, Grenier-Boley, B, Russo, G, Thornton-Wells, TA, Denning, N, Smith, AV, Chouraki, V, Thomas, C, Arfan Ikram, M, Zelenika, D, Vardarajan, BN, Kamatani, Y, Lin, CF, Schmidt, H, Kunkle, B, Dunstan, ML, Vronskaya, M, Johnson, AD, Ruiz, A, Bihoreau, MT, Reitz, C, Pasquier, F, Hollingworth, P, Hanon, O, Fitzpatrick, AL, Buxbaum, JD, Campion, D, Crane, PK, Becker, CBT, Gudnason, V, Cruchaga, C, Craig, D, Amin, N, Berr, C, Lopez, OL, De Jager, PL, Deramecourt, V, Johnston, JA, Evans, D, Lovestone, S, Letenneur, L, Hernández, I, Rubinsztein, DC, Eiriksdottir, G, Sleegers, K, Goate, AM, Fiévet, N, Huentelman, MJ, Gill, M, Brown, K, Kamboh, MI, Keller, L, Barberger-Gateau, P, McGuinness, B, Larson, EB, Myers, AJ, Dufouil, C, Todd, S, Wallon, D, Love, S, Rogaeva, E, Gallacher, J, St George-Hyslop, P, Clarimon, J, Lleo, A, Bayer, A, Tsuang, DW, Yu, L, Tsolaki, M, Bossù, P, Spalletta, G, Proitsi, P, Collinge, J, Sorbi, S, Sanchez Garcia, F, Fox, NC, Hardy, J, Naranjo, MCD, Bosco, P, Clarke, R, Brayne, C, Galimberti, D & Scarpini, E 2014, 'Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease', PLoS ONE, vol. 9, no. 6, e94661. https://doi.org/10.1371/journal.pone.0094661

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease. / Escott-Price, Valentina; Bellenguez, Céline; Wang, Li San; Choi, Seung Hoan; Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Denning, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Arfan Ikram, M.; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Vronskaya, Maria; Johnson, Andrew D.; 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, Clinton Baldwin 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; Letenneur, Luc; Hernández, Isabel; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; 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; Rogaeva, Ekaterina; Gallacher, John; St George-Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Sanchez Garcia, Florentino; Fox, Nick C.; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio.

In: PLoS ONE, Vol. 9, No. 6, e94661, 12.06.2014.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

AU - Escott-Price, Valentina

AU - Bellenguez, Céline

AU - Wang, Li San

AU - Choi, Seung Hoan

AU - Harold, Denise

AU - Jones, Lesley

AU - Holmans, Peter

AU - Gerrish, Amy

AU - Vedernikov, Alexey

AU - Richards, Alexander

AU - DeStefano, Anita L.

AU - Lambert, Jean Charles

AU - Ibrahim-Verbaas, Carla A.

AU - Naj, Adam C.

AU - Sims, Rebecca

AU - Jun, Gyungah

AU - Bis, Joshua C.

AU - Beecham, Gary W.

AU - Grenier-Boley, Benjamin

AU - Russo, Giancarlo

AU - Thornton-Wells, Tricia A.

AU - Denning, Nicola

AU - Smith, Albert V.

AU - Chouraki, Vincent

AU - Thomas, Charlene

AU - Arfan Ikram, M.

AU - Zelenika, Diana

AU - Vardarajan, Badri N.

AU - Kamatani, Yoichiro

AU - Lin, Chiao Feng

AU - Schmidt, Helena

AU - Kunkle, Brian

AU - Dunstan, Melanie L.

AU - Vronskaya, Maria

AU - Johnson, Andrew D.

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, Clinton Baldwin 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 - Letenneur, Luc

AU - Hernández, Isabel

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 - 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 - Rogaeva, Ekaterina

AU - Gallacher, John

AU - St George-Hyslop, Peter

AU - Clarimon, Jordi

AU - Lleo, Alberto

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 C.

AU - Hardy, John

AU - Naranjo, Maria Candida Deniz

AU - Bosco, Paolo

AU - Clarke, Robert

AU - Brayne, Carol

AU - Galimberti, Daniela

AU - Scarpini, Elio

PY - 2014/6/12

Y1 - 2014/6/12

N2 - Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

AB - Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

U2 - 10.1371/journal.pone.0094661

DO - 10.1371/journal.pone.0094661

M3 - Article

VL - 9

IS - 6

M1 - e94661

ER -

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

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