Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP).
Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP).
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DOI：
10.1038/tp.2013.13
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发表时间：
2013-05-14
影响因子：
6.8
通讯作者：
Alzheimer's Disease Genetics Consortium (ADGC)
中科院分区：
文献类型：
--
作者：
Reitz C;Tosto G;Vardarajan B;Rogaeva E;Ghani M;Rogers RS;Conrad C;Haines JL;Pericak-Vance MA;Fallin MD;Foroud T;Farrer LA;Schellenberg GD;George-Hyslop PS;Mayeux R;Alzheimer's Disease Genetics Consortium (ADGC)
分拣蛋白相关受体（SORL 1）和分拣蛋白相关空泡蛋白分选10（VPS 10）结构域受体1（SORCS 1）中的遗传变异与阿尔茨海默病（AD）风险增加、认知功能下降和淀粉样前体蛋白（APP）加工改变相关。我们探讨了含有（VPS 10）结构域的受体蛋白家族的其他成员（分拣蛋白相关的含有VPS 10结构域的受体2和3（SORCS 2和SORCS 3）和分拣蛋白（SORT 1））是否会单独或一起具有类似的作用。我们在一个大型白人病例对照数据集（n=11 840例，10 931例对照）中进行了分析，以确定所有5个同源基因的单核苷酸多态性（SNP）与AD风险之间的关联。在上位统计模型中确定了5个VPS 10结构域受体家族基因中SNP之间相互作用的证据。我们还利用基因表达谱芯片分析比较了SORCS 2、SORCS 3和SORT 1在AD和对照脑中的表达水平，并评估了这些基因对APP γ-分泌酶加工的影响。SORL 1、SORCS 1、SORCS 2和SORCS 3中的几个SNP与AD相关。此外，SORCS 1、SORCS 2和SORCS 3中的4个连锁不平衡区对AD的发病风险具有加性上位效应（P <0.0006）。与对照组相比，SORCS 3，而不是SORCS 2或SORT 1，在AD中的表达降低，但是在HEK 293细胞中使用短发夹RNA敲低所有三个基因导致APP加工显著增加三倍（从P<0.001到P<0.05）。这些发现表明，除了SORL 1和SORCS 1，VPS 10结构域受体家族的其他成员（即SORCS 1，SORCS 2，SORCS 3）的变异与AD风险相关，并改变APP处理。更重要的是，结果表明这些基因中的变异对AD风险具有上位性影响。
Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11 840 cases, 10 931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on γ-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P⩽0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk.
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影响因子：
11.2
作者：
Reitz C;Tokuhiro S;Clark LN;Conrad C;Vonsattel JP;Hazrati LN;Palotás A;Lantigua R;Medrano M;Z Jiménez-Velázquez I;Vardarajan B;Simkin I;Haines JL;Pericak-Vance MA;Farrer LA;Lee JH;Rogaeva E;George-Hyslop PS;Mayeux R
通讯作者：
Mayeux R
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：
4.8
作者：
Cao, XW;Südhof, TC
通讯作者：
Südhof, TC
DOI：
10.1006/bbrc.1999.1822
发表时间：
1999-12-20
影响因子：
3.1
作者：
Hermey, G;Riedel, IB;Hermans-Borgmeyer, I
通讯作者：
Hermans-Borgmeyer, I
影响因子：
4.7
作者：
Hermey, G;Plath, N;Hermans-Borgmeyer, I
通讯作者：
Hermans-Borgmeyer, I