The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease.
The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease.
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DOI：
10.3390/genes12030443
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发表时间：
2021-03-20
期刊：
影响因子：
3.5
通讯作者：
Morgan BP
中科院分区：
文献类型：
--
作者：
Carpanini SM;Harwood JC;Baker E;Torvell M;The Gerad Consortium;Sims R;Williams J;Morgan BP
迟发性阿尔茨海默病（LOAD）是一种病因不确定的神经退行性疾病，是痴呆症最常见的病因，也是全球健康面临的巨大挑战。为了提供有效的诊断和治疗，了解疾病的分子基础至关重要。当代大型全基因组关联研究（GWAS）已经确定了超过70个新的LOAD遗传易感位点。大多数与小胶质细胞或炎症途径有关，使炎症成为候选病理途径。在GWAS中最重要的是三个补体基因：CLU，编码液相补体抑制剂簇蛋白；编码补体受体1 (CR1)；最近，C1S编码补体酶C1S。补体激活是炎症的关键驱动因素；补体基因的改变可能通过改变大脑的炎症状态来影响风险。为了评估补体基因与LOAD风险的关联，我们手动创建了一个全面的补体基因列表，并在基因集分析中使用LOAD汇总统计进行测试。我们证实了CLU和CR1基因与LOAD的关联，但在排除CLU和CR1后，补体基因集没有明显的关联。在IGAP数据集中未发现与其他补体基因（包括C1S）的显著关联；然而，这些可能来自更大的数据集。
Late-onset Alzheimer’s disease (LOAD), the most common cause of dementia, and a huge global health challenge, is a neurodegenerative disease of uncertain aetiology. To deliver effective diagnostics and therapeutics, understanding the molecular basis of the disease is essential. Contemporary large genome-wide association studies (GWAS) have identified over seventy novel genetic susceptibility loci for LOAD. Most are implicated in microglial or inflammatory pathways, bringing inflammation to the fore as a candidate pathological pathway. Among the most significant GWAS hits are three complement genes: CLU, encoding the fluid-phase complement inhibitor clusterin; CR1 encoding complement receptor 1 (CR1); and recently, C1S encoding the complement enzyme C1s. Complement activation is a critical driver of inflammation; changes in complement genes may impact risk by altering the inflammatory status in the brain. To assess complement gene association with LOAD risk, we manually created a comprehensive complement gene list and tested these in gene-set analysis with LOAD summary statistics. We confirmed associations of CLU and CR1 genes with LOAD but showed no significant associations for the complement gene-set when excluding CLU and CR1. No significant association with other complement genes, including C1S, was seen in the IGAP dataset; however, these may emerge from larger datasets.
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影响因子：
4.2
作者：
Hazrati, Lili-Naz;Van Cauwenberghe, Caroline;Rogaeva, Ekaterina
通讯作者：
Rogaeva, Ekaterina
影响因子：
2.1
作者：
Baker E;Schmidt KM;Sims R;O'Donovan MC;Williams J;Holmans P;Escott-Price V;Consortium WTG
通讯作者：
Consortium WTG
影响因子：
105.7
作者：
Etminan, M;Gill, S;Samii, A
通讯作者：
Samii, A
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
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