Genome-wide significant, replicated and functional risk variants for Alzheimer's disease.
Genome-wide significant, replicated and functional risk variants for Alzheimer's disease.
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DOI：
10.1007/s00702-017-1773-0
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Luo X
中科院分区：
文献类型：
--
作者：
Guo X;Qiu W;Garcia-Milian R;Lin X;Zhang Y;Cao Y;Tan Y;Wang Z;Shi J;Wang J;Liu D;Song L;Xu Y;Wang X;Liu N;Sun T;Zheng J;Luo J;Zhang H;Xu J;Kang L;Ma C;Wang K;Luo X
全基因组关联研究（GWASs）已经报道了风险变异与阿尔茨海默病（AD）之间的许多关联。然而，这些关联并不一定表明存在因果关系。如果风险变异能够被证明具有生物学功能，那么因果关系的可能性就会增加。在本文中，我们回顾了所有已发表的GWASs，以提取全基因组显著性（p<5×10−8）并复制风险变异与AD或AD生物标志物之间的关联。这些风险变异对一类新型非编码rna （piRNAs）和蛋白质编码rna （mrna）表达的调控作用，这些变异引起的蛋白质改变，我们自己的样本中AD和这些变异之间的关联，这些变异靶向的人脑中piRNAs， mrna和蛋白质的表达，风险基因和APOE之间的表达相关性，风险基因所属的途径和网络，分析了可能调控风险基因的长链非编码rna (LncRNAs)，探讨了风险变异的潜在生物学功能，并探讨了SNP-AD关联的潜在机制。令人惊讶的是，我们在8个基因组区域的11个基因/ snrna /LncRNAs中仅发现了17个snp与AD或AD生物标志物的重复和显著关联。这17个snp中的大多数富集了ad相关通路或网络，并可能在调节pirna和mrna方面发挥作用；在我们的样本中，一些snp与AD相关，一些snp改变了蛋白质结构。受危险snp调控的蛋白编码基因大多在人脑中表达，且与APOE表达相关。我们得出结论，这些变异是阿尔茨海默病最可靠的风险标记，它们对阿尔茨海默病风险的贡献可能是因果关系。正如预期的那样，APOE和脂蛋白代谢途径在这些贡献中占有最高的权重。
Genome-wide association studies (GWASs) have reported numerous associations between risk variants and Alzheimer’s disease (AD). However, these associations do not necessarily indicate a causal relationship. If the risk variants can be demonstrated to be biologically functional, the possibility of a causal relationship would be increased. In this article, we reviewed all of the published GWASs to extract the genome-wide significant (p<5×10−8) and replicated associations between risk variants and AD or AD-biomarkers. The regulatory effects of these risk variants on the expression of a novel class of non-coding RNAs (piRNAs) and protein-coding RNAs (mRNAs), the alteration of proteins caused by these variants, the associations between AD and these variants in our own sample, the expression of piRNAs, mRNAs and proteins in human brains targeted by these variants, the expression correlations between the risk genes and APOE, the pathways and networks that the risk genes belonged to, and the possible long non-coding RNAs (LncRNAs) that might regulate the risk genes were analyzed, to investigate the potential biological functions of the risk variants and explore the potential mechanisms underlying the SNP-AD associations. We found replicated and significant associations for AD or AD-biomarkers, surprisingly, only at 17 SNPs located in 11 genes/snRNAs/LncRNAs in eight genomic regions. Most of these 17 SNPs enriched some AD-related pathways or networks, and were potentially functional in regulating piRNAs and mRNAs; some SNPs were associated with AD in our sample, and some SNPs altered protein structures. Most of the protein-coding genes regulated by the risk SNPs were expressed in human brain and correlated with APOE expression. We conclude that these variants were most robust risk markers for AD, and their contributions to AD risk was likely to be causal. As expected, APOE and the lipoprotein metabolism pathway possess the highest weight among these contributions.
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影响因子：
12.3
作者：
Antúnez C;Boada M;González-Pérez A;Gayán J;Ramírez-Lorca R;Marín J;Hernández I;Moreno-Rey C;Morón FJ;López-Arrieta J;Mauleón A;Rosende-Roca M;Noguera-Perea F;Legaz-García A;Vivancos-Moreau L;Velasco J;Carrasco JM;Alegret M;Antequera-Torres M;Manzanares S;Romo A;Blanca I;Ruiz S;Espinosa A;Castaño S;García B;Martínez-Herrada B;Vinyes G;Lafuente A;Becker JT;Galán JJ;Serrano-Ríos M;Alzheimer's Disease Neuroimaging Initiative;Vázquez E;Tárraga L;Sáez ME;López OL;Real LM;Ruiz A
通讯作者：
Ruiz A
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：
11.2
作者：
Chibnik, Lori B.;Shulman, Joshua M.;Leurgans, Sue E.;Schneider, Julie A.;Wilson, Robert S.;Tran, Dong;Aubin, Cristin;Buchman, Aron S.;Heward, Christopher B.;Myers, Amanda J.;Hardy, John A.;Huentelman, Matthew J.;Corneveaux, Jason J.;Reiman, Eric M.;Evans, Denis A.;Bennett, David A.;De Jager, Philip L.
通讯作者：
De Jager, Philip L.
影响因子：
2.7
作者：
Abraham R;Moskvina V;Sims R;Hollingworth P;Morgan A;Georgieva L;Dowzell K;Cichon S;Hillmer AM;O'Donovan MC;Williams J;Owen MJ;Kirov G
通讯作者：
Kirov G
影响因子：
5.1
作者：
Jiang, Teng;Yu, Jin-Tai;Tan, Lan
通讯作者：
Tan, Lan