A glutamatergic network mediates lithium response in bipolar disorder as defined by epigenome pathway analysis
A glutamatergic network mediates lithium response in bipolar disorder as defined by epigenome pathway analysis
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DOI：
10.2217/pgs.15.106
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发表时间：
2015-01-01
期刊：
影响因子：
2.1
通讯作者：
Athey, Brian D.
中科院分区：
文献类型：
--
作者：
Higgins, Gerald A.;Allyn-Feuer, Ari;Athey, Brian D.
目的：通过分析全基因组关联研究（GWAS）和已发表的基因关联研究中的功能SNP，以及随后的表观基因组作图，揭示了双相情感障碍患者中人脑介导锂反应的调控网络。研究方法：在相同的人群中研究了与前导SNP连锁不平衡的初始23，312个SNP，以及通过途径分析拯救的亚阈值GWAS SNP。这些是使用我们的工作流程和表观基因组路线图联盟的注释进行评估的。结果如下：与锂反应相关的802个SNPs（13个已发表的研究，基因关联研究和两个GWAS）中有27%与来自18个GWAS的1281个SNPs共有，这些GWAS检查了与锂治疗相关的精神疾病和不良事件。它们分别位于ANK 3、ARNTL、CACNA 1C、CACNG 2、CDKN 1A、CREB 1、GRIA 2、GSK 3B、NR 1D 1和SLC 1A 2等10个基因的非编码区。在基因集富集和途径分析之后，发现这些基因与人脑中的AMPA 2谷氨酸受体网络显著相关（p = 10（-27）; Fisher精确检验）。我们的工作流程结果显示与表观基因组路线图中调控元件的注释一致。同源mRNA和增强子RNA的分析表现出与人脑中的整合途径一致的模式。结论：这一药物表观基因组调控通路位于双相情感障碍中表现出组织体积损失的相同脑区。尽管计算机模拟分析需要生物学验证，但该方法为鉴定候选变异体提供了价值，这些变异体可用于药物基因组学检测，以鉴定可能对锂有反应的双相情感障碍患者。
Aim: A regulatory network in the human brain mediating lithium response in bipolar patients was revealed by analysis of functional SNPs from genome-wide association studies (GWAS) and published gene association studies, followed by epigenome mapping. Methods: An initial set of 23,312 SNPs in linkage disequilibrium with lead SNPs, and sub-threshold GWAS SNPs rescued by pathway analysis, were studied in the same populations. These were assessed using our workflow and annotation by the epigenome roadmap consortium. Results: Twenty-seven percent of 802 SNPs that were associated with lithium response (13 published studies gene association studies and two GWAS) were shared in common with 1281 SNPs from 18 GWAS examining psychiatric disorders and adverse events associated with lithium treatment.Nineteen SNPs were annotated as active regulatory elements such as enhancers and promoters in a tissue-specific manner. They were located within noncoding regions of ten genes: ANK3, ARNTL, CACNA1C, CACNG2, CDKN1A, CREB1, GRIA2, GSK3B, NR1D1 and SLC1A2. Following gene set enrichment and pathway analysis, these genes were found to be significantly associated (p = 10(-27); Fisher exact test) with an AMPA2 glutamate receptor network in human brain. Our workflow results showed concordance with annotation of regulatory elements from the epigenome roadmap. Analysis of cognate mRNA and enhancer RNA exhibited patterns consistent with an integrated pathway in humanbrain. Conclusion: This pharmacoepigenomic regulatory pathway is located in the same brain regions that exhibit tissue volume loss in bipolar disorder. Although in silico analysis requires biological validation, the approach provides value for identification of candidatevariants that may be used in pharmacogenomic testing to identify bipolar patients likely to respond to lithium.