A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.
A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.
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DOI：
10.1371/journal.pone.0090980
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sibille E
中科院分区：
文献类型：
--
作者：
Chang LC;Jamain S;Lin CW;Rujescu D;Tseng GC;Sibille E
单核苷酸多态性的大规模基因表达（转录组）分析和全基因组关联研究（GWAS）已经产生了相当数量的基因和疾病相关信息，但异质性和各种噪音来源限制了疾病机制的发现。由于系统的数据集整合变得至关重要，我们开发了方法，并进行了11个转录组研究的基因共表达链接的元聚类，这些研究来自于患有重度抑郁症（MDD）的人类受试者和非精神病对照受试者的死后大脑。接下来，我们寻求在前50个荟萃分析的共表达模块中富集基因，否则GWAS会为各种疾病鉴定出基因。88个基因的一个共表达模块与GWAS对MDD、其他神经精神疾病和脑功能以及具有抑郁症临床风险升高的医学疾病的影响一致且显著相关，但与其他疾病无关。为了支持这种新方法的上级鉴别能力，我们观察到从单一研究中提取的共表达模块或使用非精神病对照受试者的基因表达数据的元模块中GWAS相关基因没有显著富集。所鉴定的模块中的基因编码与神经元信号传导和结构有关的蛋白质，包括谷氨酸代谢型受体（GRM1、GRM7）、GABA受体（GABRA2、GABRA4）以及神经营养和发育相关蛋白[BDNF、reelin（EPORN）、Ephrin受体（EPHA3、EPHA5）]。这些结果与目前对MDD分子机制的理解一致，并提供了一组假定的相互作用分子伴侣，可能反映了MDD、其他脑部疾病和MDD相关疾病中同步招募的跨细胞和生物途径的功能模块的组分。总的来说，这项研究证明了整合转录组数据，基因共表达模块和GWAS结果的重要性，为研究MDD和其他复杂脑疾病的分子病理学提供了新的和互补的方法。
Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules and GWAS results for providing novel and complementary approaches to investigate the molecular pathology of MDD and other complex brain disorders.
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影响因子：
7
作者：
Lee, HK;Hsu, AK;Pavlidis, P
通讯作者：
Pavlidis, P
DOI：
10.1111/j.1749-6632.2011.06336.x
发表时间：
2011-01-01
期刊：
ANNALS MEETING REPORTS
影响因子：
--
作者：
Kupfer, David J.;Angst, Jules;Zarate, Carlos A.
通讯作者：
Zarate, Carlos A.
DOI：
10.1073/pnas.0903103106
发表时间：
2009-06-09
影响因子：
11.1
作者：
Hindorff, Lucia A.;Sethupathy, Praveen;Manolio, Teri A.
通讯作者：
Manolio, Teri A.
影响因子：
16.2
作者：
Pan A;Keum N;Okereke OI;Sun Q;Kivimaki M;Rubin RR;Hu FB
通讯作者：
Hu FB
影响因子：
12.3
作者：
Dobrin R;Zhu J;Molony C;Argman C;Parrish ML;Carlson S;Allan MF;Pomp D;Schadt EE
通讯作者：
Schadt EE