Identification of a schizophrenia-associated functional noncoding variant in NOS1AP.
Identification of a schizophrenia-associated functional noncoding variant in NOS1AP.
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DOI：
10.1176/appi.ajp.2008.08081266
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Brzustowicz LM
中科院分区：
文献类型：
--
作者：
Wratten NS;Memoli H;Huang Y;Dulencin AM;Matteson PG;Cornacchia MA;Azaro MA;Messenger J;Hayter JE;Bassett AS;Buyske S;Millonig JH;Vieland VJ;Brzustowicz LM
作者先前在一组欧洲血统的加拿大家庭中证明了NOS 1AP和精神分裂症之间的标记物之间的显着关联，以及在来自背外侧前额叶皮层的不相关死后样本中NOS 1AP在精神分裂症中的表达显着增加。在这项研究中，作者试图应用新的统计方法并进行额外的生物学实验，以分离NOS 1AP中的至少一个风险等位基因。使用后验概率的连锁不平衡（PPLD）来衡量的概率，单核苷酸多态性（SNP）与精神分裂症的连锁不平衡，作者评估了60个SNPs从NOS 1AP在24个加拿大家庭证明连锁和关联到这个地区。通过荧光素酶报告基因测定来测试表现出连锁不平衡的强有力证据的SNP的调节功能。用含有SNP的每个等位基因变体、NOS 1AP启动子和荧光素酶基因的载体转染两种人神经细胞系（SK-N-MC和PFSK-1）。通过电泳迁移率变动分析进一步评估改变表达的等位基因与核蛋白的结合。三个SNP产生PPLD> 40%。其中之一，rs 12742393，表现出显着的等位基因的表达差异，在两个细胞系测试。该SNP的等位基因变异改变了核蛋白与该DNA区域结合的亲和力。rs 12742393的A等位基因似乎是与精神分裂症相关的风险等位基因，其通过增强转录因子结合和增加基因表达起作用。
The authors previously demonstrated significant association between markers within NOS1AP and schizophrenia in a set of Canadian families of European descent, as well as significantly increased expression in schizophrenia of NOS1AP in unrelated postmortem samples from the dorsolateral prefrontal cortex. In this study the authors sought to apply novel statistical methods and conduct additional biological experiments to isolate at least one risk allele within NOS1AP. Using the posterior probability of linkage disequilibrium (PPLD) to measure the probability that a single nucleotide polymorphism (SNP) is in linkage disequilibrium with schizophrenia, the authors evaluated 60 SNPs from NOS1AP in 24 Canadian families demonstrating linkage and association to this region. SNPs exhibiting strong evidence of linkage disequilibrium were tested for regulatory function by luciferase reporter assay. Two human neural cell lines (SK-N-MC and PFSK-1) were transfected with a vector containing each allelic variant of the SNP, the NOS1AP promoter, and a luciferase gene. Alleles altering expression were further assessed for binding of nuclear proteins by electrophoretic mobility shift assay. Three SNPs produced PPLDs >40%. One of them, rs12742393, demonstrated significant allelic expression differences in both cell lines tested. The allelic variation at this SNP altered the affinity of nuclear protein binding to this region of DNA. The A allele of rs12742393 appears to be a risk allele associated with schizophrenia that acts by enhancing transcription factor binding and increasing gene expression.
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影响因子：
2.7
作者：
Bruse S;Moreau M;Azaro M;Zimmerman R;Brzustowicz L
通讯作者：
Brzustowicz L
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
影响因子：
9.8
作者：
Gurling, HMD;Kalsi, G;Curtis, D
通讯作者：
Curtis, D
影响因子：
2.9
作者：
Ahmadian, A;Gharizadeh, B;Lundeberg, J
通讯作者：
Lundeberg, J
影响因子：
9.8
作者：
O'Connell, JR;Weeks, DE
通讯作者：
Weeks, DE