Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.
Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes.
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DOI：
10.1093/schbul/sbu171
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发表时间：
2015-07
影响因子：
6.6
通讯作者：
Takeda M
中科院分区：
文献类型：
--
作者：
Ohi K;Hashimoto R;Ikeda M;Yamamori H;Yasuda Y;Fujimoto M;Umeda-Yano S;Fukunaga M;Fujino H;Watanabe Y;Iwase M;Kazui H;Iwata N;Weinberger DR;Takeda M
认知障碍是精神分裂症患者的一个核心特征。这些缺陷可能成为理解精神分裂症基因结构的有效工具。这项研究调查了与认知障碍相关的遗传变异是否聚集在与精神分裂症的发病相关的功能基因网络中。在这里，对411名健康受试者进行了一系列与精神分裂症相关的认知表型的全基因组关联研究。我们试图在257名精神分裂症患者中复制GWAS的数据，并对GWAS的发现和重复的结果进行荟萃分析。因为基因网络，而不是单个基因或遗传变异，可能与精神分裂症和认知障碍的易感性密切相关，所以对复制变异附近的基因进行了基因网络分析。我们在P<；1.0x10−4的阈值下观察到3054个变异与认知表型之间的名义关联。在3054个变异中，191个变异的关联在复制样本中重复(P<；0.05)。然而，在荟萃分析(P>；5.0x10−8)中，没有变异体达到全基因组意义。此外，在191个重复的单核苷酸多态(SNPs)中，有115个基因位于SNPs的10kb以内(60.2%)。这些变异与认知表型呈中度相关，范围为P=2.5 0×10−5~P=9.40×10−8。位于10kb以内的基因在谷氨酸受体活性(假发现率Q=4.49×10−17)和免疫系统与主要组织相容性复合体I类(FdR Q=8.76×10−11)网络方面显著归类。我们的发现表明，与精神分裂症认知特征障碍相关的遗传变异涉及N-甲基-d-天冬氨酸谷氨酸网络。
Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 × 10− 4. Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P < .05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 × 10− 8). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 × 10− 5 to P = 9.40 × 10− 8. The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 × 10− 17) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 × 10− 11) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network.
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影响因子：
5.3
作者：
Green, Michael F.
通讯作者：
Green, Michael F.
DOI：
10.1002/ajmg.b.31123
发表时间：
2010-12-01
影响因子：
2.8
作者：
Hashimoto, Ryota;Ohi, Kazutaka;Takeda, Masatoshi
通讯作者：
Takeda, Masatoshi
影响因子：
11
作者：
Lencz, T.;Knowles, E.;Davies, G.;Guha, S.;Liewald, D. C.;Starr, J. M.;Djurovic, S.;Melle, I.;Sundet, K.;Christoforou, A.;Reinvang, I.;Mukherjee, S.;DeRosse, Pamela;Lundervold, A.;Steen, V. M.;John, M.;Espeseth, T.;Raikkonen, K.;Widen, E.;Palotie, A.;Eriksson, J. G.;Giegling, I.;Konte, B.;Ikeda, M.;Roussos, P.;Giakoumaki, S.;Burdick, K. E.;Payton, A.;Ollier, W.;Horan, M.;Donohoe, G.;Morris, D.;Corvin, A.;Gill, M.;Pendleton, N.;Iwata, N.;Darvasi, A.;Bitsios, P.;Rujescu, D.;Lahti, J.;Hellard, S. L.;Keller, M. C.;Andreassen, O. A.;Deary, I. J.;Glahn, D. C.;Malhotra, A. K.
通讯作者：
Malhotra, A. K.
影响因子：
4.5
作者：
Mueller, HT;Meador-Woodruff, JH
通讯作者：
Meador-Woodruff, JH
影响因子：
4.2
作者：
Cox AJ;Hugenschmidt CE;Raffield LM;Langefeld CD;Freedman BI;Williamson JD;Hsu FC;Bowden DW
通讯作者：
Bowden DW