Missense variant in TREML2 protects against Alzheimer's disease.
Missense variant in TREML2 protects against Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2013.12.010
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发表时间：
2014-06
影响因子：
4.2
通讯作者：
Cruchaga C
中科院分区：
文献类型：
--
作者：
Benitez BA;Jin SC;Guerreiro R;Graham R;Lord J;Harold D;Sims R;Lambert JC;Gibbs JR;Bras J;Sassi C;Harari O;Bertelsen S;Lupton MK;Powell J;Bellenguez C;Brown K;Medway C;Haddick PC;van der Brug MP;Bhangale T;Ortmann W;Behrens T;Mayeux R;Pericak-Vance MA;Farrer LA;Schellenberg GD;Haines JL;Turton J;Braae A;Barber I;Fagan AM;Holtzman DM;Morris JC;3C Study Group;EADI consortium;Alzheimer's Disease Genetic Consortium (ADGC);Alzheimer's Disease Neuroimaging Initiative (ADNI);GERAD Consortium;Williams J;Kauwe JS;Amouyel P;Morgan K;Singleton A;Hardy J;Goate AM;Cruchaga C
TREM和TREM样受体是由聚集在染色体6p21.11上的基因编码的结构相似的蛋白质家族。最近的研究已经确定了TREM2中的一种罕见的编码变体（p.R47H），该变体赋予阿尔茨海默病（AD）的高风险。此外，该基因组区域中常见的单核苷酸多态性与AD的脑脊液生物标志物相关，并且在TREML 2基因附近发现的常见基因间变异已被鉴定为对AD具有保护作用。然而，很少有人知道后者协会或其与p.R47H的关系的功能变异。在这里，我们报告了使用全外显子组测序数据、脑脊液生物标志物分析、荟萃分析（16，254例病例和20，052例对照）和基于细胞的功能研究的综合分析，以支持TREML2编码错义变体p.S144G（rs3747742）作为荟萃分析AD相关全基因组关联研究信号的潜在驱动因素的作用。此外，我们证明了TREML2在AD中的保护作用独立于TREM2基因作为AD风险因素的作用。
TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD.
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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
影响因子：
--
作者：
Cruchaga, Carlos;Nowotny, Petra;Goate, Alison M.
通讯作者：
Goate, Alison M.
影响因子：
5.2
作者：
Heath, Simon C.;Gut, Ivo G.;Lathrop, Mark
通讯作者：
Lathrop, Mark
影响因子：
7
作者：
Ford JW;McVicar DW
通讯作者：
McVicar DW