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

L. Jones; P.A. Holmans; M.L. Hamshere; D. Harold; V. Moskvina; D. Ivanov; A. Pocklington; R. Abraham; P. Hollingworth; R. Sims; A. Gerrish; J.S. Pahwa; N. Jones; A. Stretton; A.R. Morgan; S. Lovestone; J. Powell; P. Proitsi; M.K. Lupton; C. Brayne; D.C. Rubinsztein; M. Gill; B. Lawlor; A. Lynch; K. Morgan; K.S. Brown; Peter A. Passmore; David Craig; Bernadette McGuinness; Stephen Todd; C. Holmes; D. Mann; A.D. Smith; S. Love; P.G. Kehoe; S. Mead; N. Fox; M. Rossor; J. Collinge; W. Maier; F. Jessen; B. Schurmann; H. Van Den Bussche; I. Heuser; O. Peters; J. Kornhuber; J. Wiltfang; M. Dichgans; L. Frolich; H. Hampel; M. Hull; D. Rujescu; A.M. Goate; J.S.K. Kauwe; C. Cruchaga; P. Nowotny; J.C. Morris; K. Mayo; G. Livingston; N.J. Bass; H. Gurling; A. McQuillin; R. Gwilliam; P. Deloukas; A. Al-Chalabi; C.E. Shaw; A.B. Singleton; R. Guerreiro; T.W. Muhleisen; M.M. Nothen; S. Moebus; K.H. Jockel; N. Klopp; H.E. Wichmann; E. Ruther; M.M. Carrasquillo; V.S. Pankratz; S.G. Younkin; J. Hardy; M.C. O'Donovan; M.J. Owen; J. Williams

doi:10.1371/journal.pone.0013950

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

L. Jones, P.A. Holmans, M.L. Hamshere, D. Harold, V. Moskvina, D. Ivanov, A. Pocklington, R. Abraham, P. Hollingworth, R. Sims, A. Gerrish, J.S. Pahwa, N. Jones, A. Stretton, A.R. Morgan, S. Lovestone, J. Powell, P. Proitsi, M.K. Lupton, C. BrayneD.C. Rubinsztein, M. Gill, B. Lawlor, A. Lynch, K. Morgan, K.S. Brown, Peter A. Passmore, David Craig, Bernadette McGuinness, Stephen Todd, C. Holmes, D. Mann, A.D. Smith, S. Love, P.G. Kehoe, S. Mead, N. Fox, M. Rossor, J. Collinge, W. Maier, F. Jessen, B. Schurmann, H. Van Den Bussche, I. Heuser, O. Peters, J. Kornhuber, J. Wiltfang, M. Dichgans, L. Frolich, H. Hampel, M. Hull, D. Rujescu, A.M. Goate, J.S.K. Kauwe, C. Cruchaga, P. Nowotny, J.C. Morris, K. Mayo, G. Livingston, N.J. Bass, H. Gurling, A. McQuillin, R. Gwilliam, P. Deloukas, A. Al-Chalabi, C.E. Shaw, A.B. Singleton, R. Guerreiro, T.W. Muhleisen, M.M. Nothen, S. Moebus, K.H. Jockel, N. Klopp, H.E. Wichmann, E. Ruther, M.M. Carrasquillo, V.S. Pankratz, S.G. Younkin, J. Hardy, M.C. O'Donovan, M.J. Owen, J. Williams

School of Medicine, Dentistry and Biomedical Sciences

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
Article number	e13950
Journal	PLoS ONE
Volume	5
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0013950
Publication status	Published - 15 Nov 2010

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry,Genetics and Molecular Biology
General Medicine

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10.1371/journal.pone.0013950Licence: CC BY

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease
Copyright 2010 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 137 KBLicence: CC BY

Cite this

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

@article{cb9bc450144b43a5bdaa67b3cd07576e,

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

abstract = "BackgroundLate 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.MethodologyWe 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 FindingsWe 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.SignificanceProcesses 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 = "L. Jones and P.A. Holmans and M.L. Hamshere and D. Harold and V. Moskvina and D. Ivanov and A. Pocklington and R. Abraham and P. Hollingworth and R. Sims and A. Gerrish and J.S. Pahwa and N. Jones and A. Stretton and A.R. Morgan and S. Lovestone and J. Powell and P. Proitsi and M.K. Lupton and C. Brayne and D.C. Rubinsztein and M. Gill and B. Lawlor and A. Lynch and K. Morgan and K.S. Brown and Passmore, {Peter A.} and David Craig and Bernadette McGuinness and Stephen Todd and C. Holmes and D. Mann and A.D. Smith and S. Love and P.G. Kehoe and S. Mead and N. Fox and M. Rossor and J. Collinge and W. Maier and F. Jessen and B. Schurmann and {Van Den Bussche}, H. and I. Heuser and O. Peters and J. Kornhuber and J. Wiltfang and M. Dichgans and L. Frolich and H. Hampel and M. Hull and D. Rujescu and A.M. Goate and J.S.K. Kauwe and C. Cruchaga and P. Nowotny and J.C. Morris and K. Mayo and G. Livingston and N.J. Bass and H. Gurling and A. McQuillin and R. Gwilliam and P. Deloukas and A. Al-Chalabi and C.E. Shaw and A.B. Singleton and R. Guerreiro and T.W. Muhleisen and M.M. Nothen and S. Moebus and K.H. Jockel and N. Klopp and H.E. Wichmann and E. Ruther and M.M. Carrasquillo and V.S. Pankratz and S.G. Younkin and J. Hardy and M.C. O'Donovan and M.J. Owen and J. Williams",

year = "2010",

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day = "15",

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

language = "English",

volume = "5",

journal = "PLoS ONE",

issn = "1932-6203",

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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, Schurmann, B, Van Den Bussche, H, Heuser, I, Peters, O, Kornhuber, J, Wiltfang, J, Dichgans, M, Frolich, L, Hampel, H, Hull, 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, Muhleisen, TW, Nothen, MM, Moebus, S, Jockel, KH, Klopp, N, Wichmann, HE, Ruther, 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

TY - JOUR

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

AU - Jones, L.

AU - Holmans, P.A.

AU - Hamshere, M.L.

AU - Harold, D.

AU - Moskvina, V.

AU - Ivanov, D.

AU - Pocklington, A.

AU - Abraham, R.

AU - Hollingworth, P.

AU - Sims, R.

AU - Gerrish, A.

AU - Pahwa, J.S.

AU - Jones, N.

AU - Stretton, A.

AU - Morgan, A.R.

AU - Lovestone, S.

AU - Powell, J.

AU - Proitsi, P.

AU - Lupton, M.K.

AU - Brayne, C.

AU - Rubinsztein, D.C.

AU - Gill, M.

AU - Lawlor, B.

AU - Lynch, A.

AU - Morgan, K.

AU - Brown, K.S.

AU - Passmore, Peter A.

AU - Craig, David

AU - McGuinness, Bernadette

AU - Todd, Stephen

AU - Holmes, C.

AU - Mann, D.

AU - Smith, A.D.

AU - Love, S.

AU - Kehoe, P.G.

AU - Mead, S.

AU - Fox, N.

AU - Rossor, M.

AU - Collinge, J.

AU - Maier, W.

AU - Jessen, F.

AU - Schurmann, B.

AU - Van Den Bussche, H.

AU - Heuser, I.

AU - Peters, O.

AU - Kornhuber, J.

AU - Wiltfang, J.

AU - Dichgans, M.

AU - Frolich, L.

AU - Hampel, H.

AU - Hull, M.

AU - Rujescu, D.

AU - Goate, A.M.

AU - Kauwe, J.S.K.

AU - Cruchaga, C.

AU - Nowotny, P.

AU - Morris, J.C.

AU - Mayo, K.

AU - Livingston, G.

AU - Bass, N.J.

AU - Gurling, H.

AU - McQuillin, A.

AU - Gwilliam, R.

AU - Deloukas, P.

AU - Al-Chalabi, A.

AU - Shaw, C.E.

AU - Singleton, A.B.

AU - Guerreiro, R.

AU - Muhleisen, T.W.

AU - Nothen, M.M.

AU - Moebus, S.

AU - Jockel, K.H.

AU - Klopp, N.

AU - Wichmann, H.E.

AU - Ruther, E.

AU - Carrasquillo, M.M.

AU - Pankratz, V.S.

AU - Younkin, S.G.

AU - Hardy, J.

AU - O'Donovan, M.C.

AU - Owen, M.J.

AU - Williams, J.

PY - 2010/11/15

Y1 - 2010/11/15

N2 - BackgroundLate 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.MethodologyWe 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 FindingsWe 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.SignificanceProcesses 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 - BackgroundLate 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.MethodologyWe 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 FindingsWe 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.SignificanceProcesses 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.

U2 - 10.1371/journal.pone.0013950

DO - 10.1371/journal.pone.0013950

M3 - Article

C2 - 21085570

SN - 1932-6203

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

Abstract

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