Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

Lesley Jones; Peter A. Holmans; Marian L. Hamshere; Denise Harold; Valentina Moskvina; Dobril Ivanov; Andrew Pocklington; Richard Abraham; Paul Hollingworth; Rebecca Sims; Amy Gerrish; Jaspreet Singh Pahwa; Nicola Jones; Alexandra Stretton; Angharad R. Morgan; Simon Lovestone; John Powell; Petroula Proitsi; Michelle K. Lupton; Carol Brayne; David C. Rubinsztein; Michael Gill; Brian Lawlor; Aoibhinn Lynch; Kevin Morgan; Kristelle S. Brown; Peter A. Passmore; David Craig; Bernadette Mcguinness; Stephen Todd; Clive Holmes; David Mann; A. David Smith; Seth Love; Patrick G. Kehoe; Simon Mead; Nick Fox; Martin Rossor; John Collinge; Wolfgang Maier; Frank Jessen; Britta Schürmann; Hendrik van den Bussche; Isabella Heuser; Oliver Peters; Johannes Kornhuber; Jens Wiltfang; Martin Dichgans; Lutz Frölich; Hampel Harald; Michael Hüll; Dan Rujescu; Alison M. Goate; John S.K. Kauwe; Carlos Cruchaga; Petra Nowotny; John C. Morris; Kevin Mayo; Gill Livingston; Nicholas J. Bass; Hugh Gurling; Andrew Mcquillin; Rhian Gwilliam; Panos Deloukas; Ammar Al-Chalabi; Christopher E. Shaw; Andrew B. Singleton; Rita Guerreiro; Thomas W. Mühleisen; Markus M. Nöthen; Susanne Moebus; Karl Heinz Jöckel; Norman Klopp; H. Erich Wichmann; Eckhard Rüther; Minerva M. Carrasquillo; V. Shane Pankratz; Steven G. Younkin; John Hardy; Michael C. O'Donovan; Michael J. Owen; Julie Williams

doi:10.1371/journal.pone.0013950

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

Lesley Jones, Peter A. Holmans, Marian L. Hamshere, Denise Harold, Valentina Moskvina, Dobril Ivanov, Andrew Pocklington, Richard Abraham, Paul Hollingworth, Rebecca Sims, Amy Gerrish, Jaspreet Singh Pahwa, Nicola Jones, Alexandra Stretton, Angharad R. Morgan, Simon Lovestone, John Powell, Petroula Proitsi, Michelle K. Lupton, Carol BrayneDavid C. Rubinsztein, Michael Gill, Brian Lawlor, Aoibhinn Lynch, Kevin Morgan, Kristelle S. Brown, Peter A. Passmore, David Craig, Bernadette Mcguinness, Stephen Todd, Clive Holmes, David Mann, A. David Smith, Seth Love, Patrick G. Kehoe, Simon Mead, Nick Fox, Martin Rossor, John Collinge, Wolfgang Maier, Frank Jessen, Britta Schürmann, Hendrik van den Bussche, Isabella Heuser, Oliver Peters, Johannes Kornhuber, Jens Wiltfang, Martin Dichgans, Lutz Frölich, Hampel Harald, Michael Hüll, Dan Rujescu, Alison M. Goate, John S.K. Kauwe, Carlos Cruchaga, Petra Nowotny, John C. Morris, Kevin Mayo, Gill Livingston, Nicholas J. Bass, Hugh Gurling, Andrew Mcquillin, Rhian Gwilliam, Panos Deloukas, Ammar Al-Chalabi, Christopher E. Shaw, Andrew B. Singleton, Rita Guerreiro, Thomas W. Mühleisen, Markus M. Nöthen, Susanne Moebus, Karl Heinz Jöckel, Norman Klopp, H. Erich Wichmann, Eckhard Rüther, Minerva M. Carrasquillo, V. Shane Pankratz, Steven G. Younkin, John Hardy, Michael C. O'Donovan, Michael J. Owen, Julie Williams

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

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Abstract

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Original language	English (US)
Article number	e13950
Journal	PloS one
Volume	5
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0013950
State	Published - 2010

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Jones, L., Holmans, P. A., Hamshere, M. L., Harold, D., Moskvina, V., Ivanov, D., Pocklington, A., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Pahwa, J. S., Jones, N., Stretton, A., Morgan, A. R., Lovestone, S., Powell, J., Proitsi, P., Lupton, M. K., ... Williams, J. (2010). Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PloS one, 5(11), Article e13950. https://doi.org/10.1371/journal.pone.0013950

Jones, L, Holmans, PA, Hamshere, ML, Harold, D, Moskvina, V, Ivanov, D, Pocklington, A, Abraham, R, Hollingworth, P, Sims, R, Gerrish, A, Pahwa, JS, Jones, N, Stretton, A, Morgan, AR, Lovestone, S, Powell, J, Proitsi, P, Lupton, MK, Brayne, C, Rubinsztein, DC, Gill, M, Lawlor, B, Lynch, A, Morgan, K, Brown, KS, Passmore, PA, Craig, D, Mcguinness, B, Todd, S, Holmes, C, Mann, D, Smith, AD, Love, S, Kehoe, PG, Mead, S, Fox, N, Rossor, M, Collinge, J, Maier, W, Jessen, F, Schürmann, B, van den Bussche, H, Heuser, I, Peters, O, Kornhuber, J, Wiltfang, J, Dichgans, M, Frölich, L, Harald, H, Hüll, M, Rujescu, D, Goate, AM, Kauwe, JSK, Cruchaga, C, Nowotny, P, Morris, JC, Mayo, K, Livingston, G, Bass, NJ, Gurling, H, Mcquillin, A, Gwilliam, R, Deloukas, P, Al-Chalabi, A, Shaw, CE, Singleton, AB, Guerreiro, R, Mühleisen, TW, Nöthen, MM, Moebus, S, Jöckel, KH, Klopp, N, Wichmann, HE, Rüther, E, Carrasquillo, MM, Pankratz, VS, Younkin, SG, Hardy, J, O'Donovan, MC, Owen, MJ & Williams, J 2010, 'Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease', PloS one, vol. 5, no. 11, e13950. https://doi.org/10.1371/journal.pone.0013950

@article{13c420f8c34245cdb14316366fc006c5,

title = "Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease",

abstract = "Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.",

author = "Lesley Jones and Holmans, {Peter A.} and Hamshere, {Marian L.} and Denise Harold and Valentina Moskvina and Dobril Ivanov and Andrew Pocklington and Richard Abraham and Paul Hollingworth and Rebecca Sims and Amy Gerrish and Pahwa, {Jaspreet Singh} and Nicola Jones and Alexandra Stretton and Morgan, {Angharad R.} and Simon Lovestone and John Powell and Petroula Proitsi and Lupton, {Michelle K.} and Carol Brayne and Rubinsztein, {David C.} and Michael Gill and Brian Lawlor and Aoibhinn Lynch and Kevin Morgan and Brown, {Kristelle S.} and Passmore, {Peter A.} and David Craig and Bernadette Mcguinness and Stephen Todd and Clive Holmes and David Mann and Smith, {A. David} and Seth Love and Kehoe, {Patrick G.} and Simon Mead and Nick Fox and Martin Rossor and John Collinge and Wolfgang Maier and Frank Jessen and Britta Sch{\"u}rmann and {van den Bussche}, Hendrik and Isabella Heuser and Oliver Peters and Johannes Kornhuber and Jens Wiltfang and Martin Dichgans and Lutz Fr{\"o}lich and Hampel Harald and Michael H{\"u}ll and Dan Rujescu and Goate, {Alison M.} and Kauwe, {John S.K.} and Carlos Cruchaga and Petra Nowotny and Morris, {John C.} and Kevin Mayo and Gill Livingston and Bass, {Nicholas J.} and Hugh Gurling and Andrew Mcquillin and Rhian Gwilliam and Panos Deloukas and Ammar Al-Chalabi and Shaw, {Christopher E.} and Singleton, {Andrew B.} and Rita Guerreiro and M{\"u}hleisen, {Thomas W.} and N{\"o}then, {Markus M.} and Susanne Moebus and J{\"o}ckel, {Karl Heinz} and Norman Klopp and Wichmann, {H. Erich} and Eckhard R{\"u}ther and Carrasquillo, {Minerva M.} and Pankratz, {V. Shane} and Younkin, {Steven G.} and John Hardy and O'Donovan, {Michael C.} and Owen, {Michael J.} and Julie Williams",

note = "Funding Information: Profs Owen, J Williams and Dr Harold have a patent application in respect of genes identified in the GWAS Harold et al. Nature Genetics 2009;41(10):1088–93; this study provided data for this manuscript and was funded by the MRC and the Wellcome Trust. Dr Passmore has consulted for Pfizer and received compensation. Dr Hull has been funded by Wyeth and consulted for Pfizer, Wyeth and Merz; he has a patent pending for AD diagnostic tests. Dr Lynch has received travel expenses from Pfizer and Novartis. Prof Goate's work has been funded by NIH and AHAF. Prof Fox is a board member of the Alzheimer's Research Forum, has consulted for Abbott Laboratories and has received compensation for consulting for GE Healthcare. He has a patent for QA Box that did not arise from this work which contributes funds to his institution. Dr Morris is funded by NIA. Dr Livingston has received compensation from Lundbeck sa. Ms Stretton holds a CASE PhD studentship jointly funded by MRC and GSK. The remaining authors declare no potential conflict of interest. This does not alter the authors' adherence to all the PloS ONE policies on sharing data and materials. ",

year = "2010",

doi = "10.1371/journal.pone.0013950",

language = "English (US)",

volume = "5",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "11",

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TY - JOUR

T1 - Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

AU - Jones, Lesley

AU - Holmans, Peter A.

AU - Hamshere, Marian L.

AU - Harold, Denise

AU - Moskvina, Valentina

AU - Ivanov, Dobril

AU - Pocklington, Andrew

AU - Abraham, Richard

AU - Hollingworth, Paul

AU - Sims, Rebecca

AU - Gerrish, Amy

AU - Pahwa, Jaspreet Singh

AU - Jones, Nicola

AU - Stretton, Alexandra

AU - Morgan, Angharad R.

AU - Lovestone, Simon

AU - Powell, John

AU - Proitsi, Petroula

AU - Lupton, Michelle K.

AU - Brayne, Carol

AU - Rubinsztein, David C.

AU - Gill, Michael

AU - Lawlor, Brian

AU - Lynch, Aoibhinn

AU - Morgan, Kevin

AU - Brown, Kristelle S.

AU - Passmore, Peter A.

AU - Craig, David

AU - Mcguinness, Bernadette

AU - Todd, Stephen

AU - Holmes, Clive

AU - Mann, David

AU - Smith, A. David

AU - Love, Seth

AU - Kehoe, Patrick G.

AU - Mead, Simon

AU - Fox, Nick

AU - Rossor, Martin

AU - Collinge, John

AU - Maier, Wolfgang

AU - Jessen, Frank

AU - Schürmann, Britta

AU - van den Bussche, Hendrik

AU - Heuser, Isabella

AU - Peters, Oliver

AU - Kornhuber, Johannes

AU - Wiltfang, Jens

AU - Dichgans, Martin

AU - Frölich, Lutz

AU - Harald, Hampel

AU - Hüll, Michael

AU - Rujescu, Dan

AU - Goate, Alison M.

AU - Kauwe, John S.K.

AU - Cruchaga, Carlos

AU - Nowotny, Petra

AU - Morris, John C.

AU - Mayo, Kevin

AU - Livingston, Gill

AU - Bass, Nicholas J.

AU - Gurling, Hugh

AU - Mcquillin, Andrew

AU - Gwilliam, Rhian

AU - Deloukas, Panos

AU - Al-Chalabi, Ammar

AU - Shaw, Christopher E.

AU - Singleton, Andrew B.

AU - Guerreiro, Rita

AU - Mühleisen, Thomas W.

AU - Nöthen, Markus M.

AU - Moebus, Susanne

AU - Jöckel, Karl Heinz

AU - Klopp, Norman

AU - Wichmann, H. Erich

AU - Rüther, Eckhard

AU - Carrasquillo, Minerva M.

AU - Pankratz, V. Shane

AU - Younkin, Steven G.

AU - Hardy, John

AU - O'Donovan, Michael C.

AU - Owen, Michael J.

AU - Williams, Julie

N1 - Funding Information: Profs Owen, J Williams and Dr Harold have a patent application in respect of genes identified in the GWAS Harold et al. Nature Genetics 2009;41(10):1088–93; this study provided data for this manuscript and was funded by the MRC and the Wellcome Trust. Dr Passmore has consulted for Pfizer and received compensation. Dr Hull has been funded by Wyeth and consulted for Pfizer, Wyeth and Merz; he has a patent pending for AD diagnostic tests. Dr Lynch has received travel expenses from Pfizer and Novartis. Prof Goate's work has been funded by NIH and AHAF. Prof Fox is a board member of the Alzheimer's Research Forum, has consulted for Abbott Laboratories and has received compensation for consulting for GE Healthcare. He has a patent for QA Box that did not arise from this work which contributes funds to his institution. Dr Morris is funded by NIA. Dr Livingston has received compensation from Lundbeck sa. Ms Stretton holds a CASE PhD studentship jointly funded by MRC and GSK. The remaining authors declare no potential conflict of interest. This does not alter the authors' adherence to all the PloS ONE policies on sharing data and materials.

PY - 2010

Y1 - 2010

N2 - Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

AB - Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

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U2 - 10.1371/journal.pone.0013950

DO - 10.1371/journal.pone.0013950

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VL - 5

JO - PloS one

JF - PloS one

IS - 11

M1 - e13950

ER -

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease

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