Identification of pathways for bipolar disorder: a meta-analysis.
Identification of pathways for bipolar disorder: a meta-analysis.
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DOI：
10.1001/jamapsychiatry.2014.176
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发表时间：
2014-06
期刊：
影响因子：
25.8
通讯作者：
Psychiatric Genomics Consortium Bipolar Group
中科院分区：
文献类型：
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作者：
Nurnberger JI Jr;Koller DL;Jung J;Edenberg HJ;Foroud T;Guella I;Vawter MP;Kelsoe JR;Psychiatric Genomics Consortium Bipolar Group
全基因组研究提供了有关精神疾病神经生物学的系统信息。使用多个全基因组关联研究（GWAS）中具有一致关联证据的基因，确定导致双相情感障碍（BP）风险的生物学途径。沿着于2011年7月提供的四个独立数据集（包含个体全基因组数据）以及所有数据集均在2012年5月之前提供给精神病基因组学联盟双极组。先前的荟萃分析被用作脑基因表达数据的来源。4个已发表的GWAS包括在初始样本中。所有独立的BP数据集提供的全基因组数据在精神病基因组学联盟被纳入作为一个复制样本。我们在4个GWAS数据集中的3个中鉴定了966个基因，其中包含2个或更多与BP相关的变异，P <0.05（n = 12127 [5253例病例，6874例对照]）。使用这些数据集的10 000个重复的模拟校正了基因大小，并允许计算每个基因的经验P值;经验显著的基因被输入到通路分析中。然后使用单核苷酸多态性的基因集富集分析在复制样本（n = 8396 [3507例病例，4889例对照]）中测试这些途径中的每一个。这226个基因还与背外侧前额叶皮层基因表达的荟萃分析结果进行了比较。具有经验意义的基因和生物学途径。在966个基因中，226个基因具有经验显著性（P < .05）。在对初始数据集的分析中，17种途径被过度代表。在初始和复制样本中，17种途径中的6种与BP相关：促肾上腺皮质激素释放激素信号传导、心脏β-肾上腺素能信号传导、磷脂酶C信号传导、谷氨酸受体信号传导、内皮素1信号传导和心脏肥大信号传导。在226个基因中，9个在BP患者的背外侧前额叶皮层中表达不同：CACNA 1C，DTNA，FOXP 1，GNG 2，ITPR 2，LSAMP，NPAS 3，NCOA 2和NTRK 3。参与BP遗传易感性的途径包括激素调节、钙通道、第二信使系统和谷氨酸信号传导。基因表达研究也涉及神经元发育途径。这些结果倾向于加强关于BP神经生物学的特定假设，并可能为治疗和预防的新方法提供线索。
Genome-wide investigations provide systematic information regarding the neurobiology of psychiatric disorders. To identify biological pathways that contribute to risk for bipolar disorder (BP) using genes with consistent evidence for association in multiple genome-wide association studies (GWAS). Four independent data sets with individual genome-wide data available in July 2011 along with all data sets contributed to the Psychiatric Genomics Consortium Bipolar Group by May 2012. A prior meta-analysis was used as a source for brain gene expression data. The 4 published GWAS were included in the initial sample. All independent BP data sets providing genome-wide data in the Psychiatric Genomics Consortium were included as a replication sample. We identified 966 genes that contained 2 or more variants associated with BP at P < .05 in 3 of 4 GWAS data sets (n = 12 127 [5253 cases, 6874 controls]). Simulations using 10 000 replicates of these data sets corrected for gene size and allowed the calculation of an empirical P value for each gene; empirically significant genes were entered into a pathway analysis. Each of these pathways was then tested in the replication sample (n = 8396 [3507 cases, 4889 controls]) using gene set enrichment analysis for single-nucleotide polymorphisms. The 226 genes were also compared with results from a meta-analysis of gene expression in the dorsolateral prefrontal cortex. Empirically significant genes and biological pathways. Among 966 genes, 226 were empirically significant (P < .05). Seventeen pathways were overrepresented in analyses of the initial data set. Six of the 17 pathways were associated with BP in both the initial and replication samples: corticotropin-releasing hormone signaling, cardiac β-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling. Among the 226 genes, 9 differed in expression in the dorsolateral prefrontal cortex in patients with BP: CACNA1C, DTNA, FOXP1, GNG2, ITPR2, LSAMP, NPAS3, NCOA2, and NTRK3. Pathways involved in the genetic predisposition to BP include hormonal regulation, calcium channels, second messenger systems, and glutamate signaling. Gene expression studies implicate neuronal development pathways as well. These results tend to reinforce specific hypotheses regarding BP neurobiology and may provide clues for new approaches to treatment and prevention.