Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.
Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0013950
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发表时间：
2010-11-15
期刊：
影响因子：
3.7
通讯作者：
Williams J
中科院分区：
文献类型：
--
作者：
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;Heun R;Kölsch H;van den Bussche H;Heuser I;Peters O;Kornhuber J;Wiltfang J;Dichgans M;Frölich L;Hampel H;Hüll M;Rujescu D;Goate AM;Kauwe JS;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
晚发性阿尔茨海默病（LOAD）是痴呆症的主要原因。自20世纪90年代初发现APOE参与以来，最近的大基因组关联研究（GWAS）首次确定了强有力的LOAD易感基因。我们现在已经利用这些GWAS数据集来揭示关键的LOAD病理生理过程。我们将最近开发的用于挖掘GWAS数据以获得生物学上有意义的信息的工具应用于LOAD GWAS数据集。然后在一个独立的GWAS数据集中对主要发现进行了测试。我们发现，在两个最大的全基因组LOAD关联研究中，与胆固醇代谢和免疫反应相关的通路中的关联信号显著过度表达。与胆固醇代谢和先天免疫反应有关的过程先前已被阿尔茨海默病的病理学和流行病学研究所牵连，但尚不清楚这些发现是否反映了主要病因学事件或疾病过程的后果。我们从两项大型研究中获得的独立证据表明，这些过程在病因学上是相关的，并表明它们可能是新的和现有治疗方法的合适靶点。
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. 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. 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. 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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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
14.9
作者：
Harris, MA;Clark, J;White, R
通讯作者：
White, R
影响因子：
34.7
作者：
Bu, Guojun
通讯作者：
Bu, Guojun
影响因子：
3
作者：
Camon EB;Barrell DG;Dimmer EC;Lee V;Magrane M;Maslen J;Binns D;Apweiler R
通讯作者：
Apweiler R