Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.
<h4>Background</h4>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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2010
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/f60141a186cd4676b259fd600531e266 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:f60141a186cd4676b259fd600531e266 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:f60141a186cd4676b259fd600531e2662021-11-18T07:36:51ZGenetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.1932-620310.1371/journal.pone.0013950https://doaj.org/article/f60141a186cd4676b259fd600531e2662010-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21085570/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology</h4>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.<h4>Principal findings</h4>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.<h4>Significance</h4>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.Lesley JonesPeter A HolmansMarian L HamshereDenise HaroldValentina MoskvinaDobril IvanovAndrew PocklingtonRichard AbrahamPaul HollingworthRebecca SimsAmy GerrishJaspreet Singh PahwaNicola JonesAlexandra StrettonAngharad R MorganSimon LovestoneJohn PowellPetroula ProitsiMichelle K LuptonCarol BrayneDavid C RubinszteinMichael GillBrian LawlorAoibhinn LynchKevin MorganKristelle S BrownPeter A PassmoreDavid CraigBernadette McGuinnessStephen ToddClive HolmesDavid MannA David SmithSeth LovePatrick G KehoeSimon MeadNick FoxMartin RossorJohn CollingeWolfgang MaierFrank JessenBritta SchürmannReinhard HeunHeike KölschHendrik van den BusscheIsabella HeuserOliver PetersJohannes KornhuberJens WiltfangMartin DichgansLutz FrölichHarald HampelMichael HüllDan RujescuAlison M GoateJohn S K KauweCarlos CruchagaPetra NowotnyJohn C MorrisKevin MayoGill LivingstonNicholas J BassHugh GurlingAndrew McQuillinRhian GwilliamPanos DeloukasAmmar Al-ChalabiChristopher E ShawAndrew B SingletonRita GuerreiroThomas W MühleisenMarkus M NöthenSusanne MoebusKarl-Heinz JöckelNorman KloppH-Erich WichmannEckhard RütherMinerva M CarrasquilloV Shane PankratzSteven G YounkinJohn HardyMichael C O'DonovanMichael J OwenJulie WilliamsPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 11, p e13950 (2010) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 Reinhard Heun Heike Kölsch Hendrik van den Bussche Isabella Heuser Oliver Peters Johannes Kornhuber Jens Wiltfang Martin Dichgans Lutz Frölich Harald Hampel 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 Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. |
| description |
<h4>Background</h4>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.<h4>Methodology</h4>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.<h4>Principal findings</h4>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.<h4>Significance</h4>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. |
| format |
article |
| author |
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 Reinhard Heun Heike Kölsch Hendrik van den Bussche Isabella Heuser Oliver Peters Johannes Kornhuber Jens Wiltfang Martin Dichgans Lutz Frölich Harald Hampel 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 |
| author_facet |
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 Reinhard Heun Heike Kölsch Hendrik van den Bussche Isabella Heuser Oliver Peters Johannes Kornhuber Jens Wiltfang Martin Dichgans Lutz Frölich Harald Hampel 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 |
| author_sort |
Lesley Jones |
| title |
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. |
| title_short |
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. |
| title_full |
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. |
| title_fullStr |
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. |
| title_full_unstemmed |
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. |
| title_sort |
genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of alzheimer's disease. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2010 |
| url |
https://doaj.org/article/f60141a186cd4676b259fd600531e266 |
| work_keys_str_mv |
AT lesleyjones geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT peteraholmans geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT marianlhamshere geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT deniseharold geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT valentinamoskvina geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT dobrilivanov geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT andrewpocklington geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT richardabraham geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT paulhollingworth geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT rebeccasims geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT amygerrish geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT jaspreetsinghpahwa geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT nicolajones geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT alexandrastretton geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT angharadrmorgan geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT simonlovestone geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT johnpowell geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT petroulaproitsi geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT michelleklupton geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT carolbrayne geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT davidcrubinsztein geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT michaelgill geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT brianlawlor geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT aoibhinnlynch geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT kevinmorgan geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT kristellesbrown geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT peterapassmore geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT davidcraig geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT bernadettemcguinness geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT stephentodd geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT cliveholmes geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT davidmann geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT adavidsmith geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT sethlove geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT patrickgkehoe geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT simonmead geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT nickfox geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT martinrossor geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT johncollinge geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT wolfgangmaier geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT frankjessen geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT brittaschurmann geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT reinhardheun geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT heikekolsch geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT hendrikvandenbussche geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT isabellaheuser geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT oliverpeters geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT johanneskornhuber geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT jenswiltfang geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT martindichgans geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT lutzfrolich geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT haraldhampel geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT michaelhull geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT danrujescu geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT alisonmgoate geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT johnskkauwe geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT carloscruchaga geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT petranowotny geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT johncmorris geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT kevinmayo geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT gilllivingston geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT nicholasjbass geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT hughgurling geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT andrewmcquillin geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT rhiangwilliam geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT panosdeloukas geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT ammaralchalabi geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT christophereshaw geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT andrewbsingleton geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT ritaguerreiro geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT thomaswmuhleisen geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT markusmnothen geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT susannemoebus geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT karlheinzjockel geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT normanklopp geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT herichwichmann geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT eckhardruther geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT minervamcarrasquillo geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT vshanepankratz geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT stevengyounkin geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT johnhardy geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT michaelcodonovan geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT michaeljowen geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease AT juliewilliams geneticevidenceimplicatestheimmunesystemandcholesterolmetabolismintheaetiologyofalzheimersdisease |
| _version_ |
1718423199060852736 |