A role for noncoding variation in schizophrenia.
A role for noncoding variation in schizophrenia.
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DOI：
10.1016/j.celrep.2014.10.015
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发表时间：
2014-11-20
期刊：
影响因子：
8.8
通讯作者：
Sklar P
中科院分区：
文献类型：
--
作者：
Roussos P;Mitchell AC;Voloudakis G;Fullard JF;Pothula VM;Tsang J;Stahl EA;Georgakopoulos A;Ruderfer DM;Charney A;Okada Y;Siminovitch KA;Worthington J;Padyukov L;Klareskog L;Gregersen PK;Plenge RM;Raychaudhuri S;Fromer M;Purcell SM;Brennand KJ;Robakis NK;Schadt EE;Akbarian S;Sklar P
很大一部分与精神分裂症遗传风险相关的常见变异位点位于未知功能的非编码序列中。在这里，我们展示了精神分裂症变异中与表达数量性状基因座(EQTL)相关的启动子和增强子的丰富。当使用来自人脑的功能注释相对于周围组织时，丰富程度更大。基于风险SNP、eQTL和调节元件序列的共同定位，调节特性一致性分析对精神分裂症全基因组显著基因座中的基因进行了潜在功能作用的排名。我们确定了不连续的近端和远端调控元件的潜在物理相互作用。这在前额叶皮质和诱导L型钙通道(CACNA1C)风险基因的多能干细胞衍生神经元中得到了证实。我们的发现指出了精神分裂症相关的非编码SNPs和与染色体环和大脑转录调节相关的三维基因组结构之间的功能联系。
A large portion of common variant loci associated with genetic risk for schizophrenia reside within non-coding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on co-localization of a risk SNP, eQTL and regulatory element sequence. We identified potential physical interactions of non-contiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated non-coding SNPs and 3-dimensional genome architecture associated with chromosomal loopings and transcriptional regulation in the brain.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
30.8
作者：
Fairfax, Benjamin P.;Makino, Seiko;Radhakrishnan, Jayachandran;Plant, Katharine;Leslie, Stephen;Dilthey, Alexander;Ellis, Peter;Langford, Cordelia;Vannberg, Fredrik O.;Knight, Julian C.
通讯作者：
Knight, Julian C.
影响因子：
11
作者：
Gershon, E. S.;Grennan, K.;Busnello, J.;Badner, J. A.;Ovsiew, F.;Memon, S.;Alliey-Rodriguez, N.;Cooper, J.;Romanos, B.;Liu, C.
通讯作者：
Liu, C.
影响因子：
4.5
作者：
Innocenti F;Cooper GM;Stanaway IB;Gamazon ER;Smith JD;Mirkov S;Ramirez J;Liu W;Lin YS;Moloney C;Aldred SF;Trinklein ND;Schuetz E;Nickerson DA;Thummel KE;Rieder MJ;Rettie AE;Ratain MJ;Cox NJ;Brown CD
通讯作者：
Brown CD