A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder.
A genetic network model of cellular responses to lithium treatment and cocaine abuse in bipolar disorder.
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DOI：
10.1186/1752-0509-4-158
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发表时间：
2010-11-19
影响因子：
--
通讯作者：
McInnis MG
中科院分区：
文献类型：
--
作者：
McEachin RC;Chen H;Sartor MA;Saccone SF;Keller BJ;Prossin AR;Cavalcoli JD;McInnis MG
锂是双相情感障碍 (BD) 的有效治疗方法，可显着降低自杀风险，但锂有效性的分子基础尚不清楚。我们寻求通过基于新的实验数据和已发表的数据提出假设，在计算机中测试这些假设，并提出新的假设在未来的研究中进行验证，来提高我们对这种有效性的理解。我们最初假设基因与环境之间存在相互作用，其中锂作为环境影响因素，影响信号转导途径，导致 BD 狂热病因中重要基因的差异表达。使用微阵列和 rt-QPCR 测定，我们鉴定了在锂处理下差异表达的候选基因。我们使用系统生物学方法来识别这些候选基因之间的相互作用，并开发与差异表达候选基因相互作用的基因网络。值得注意的是，我们还发现可卡因对网络具有潜在影响，这与观察到的双相情感障碍和可卡因滥用的高合并症率一致。由此产生的网络代表了一种新的假设，即锂治疗和可卡因使用如何影响双相情感障碍的多重遗传影响。测试该网络与 BD 和相关表型的关联，我们发现参与信号转导的基因明显过多，这与我们假设的基因与环境相互作用一致。此外，它还模拟相关的药物基因组、精神病学和化学依赖性表型。我们提供了一个基因与环境相互作用的网络模型，该模型与锂治疗 BD 躁狂症的有效性以及观察到的 BD 和可卡因滥用的高共病率相关。我们在该网络中确定了代表治疗药物测试的直接候选药物靶标。为了在未来的工作中验证提出新的假设，我们根据功能注释优先考虑网络中基因附近的 SNP。我们还为网络中的基因开发了“概念签名”，并确定了可能影响系统的其他候选基因，因为它们与签名显着相关。
Lithium is an effective treatment for Bipolar Disorder (BD) and significantly reduces suicide risk, though the molecular basis of lithium's effectiveness is not well understood. We seek to improve our understanding of this effectiveness by posing hypotheses based on new experimental data as well as published data, testing these hypotheses in silico, and posing new hypotheses for validation in future studies. We initially hypothesized a gene-by-environment interaction where lithium, acting as an environmental influence, impacts signal transduction pathways leading to differential expression of genes important in the etiology of BD mania. Using microarray and rt-QPCR assays, we identified candidate genes that are differentially expressed with lithium treatment. We used a systems biology approach to identify interactions among these candidate genes and develop a network of genes that interact with the differentially expressed candidates. Notably, we also identified cocaine as having a potential influence on the network, consistent with the observed high rate of comorbidity for BD and cocaine abuse. The resulting network represents a novel hypothesis on how multiple genetic influences on bipolar disorder are impacted by both lithium treatment and cocaine use. Testing this network for association with BD and related phenotypes, we find that it is significantly over-represented for genes that participate in signal transduction, consistent with our hypothesized-gene-by environment interaction. In addition, it models related pharmacogenomic, psychiatric, and chemical dependence phenotypes. We offer a network model of gene-by-environment interaction associated with lithium's effectiveness in treating BD mania, as well as the observed high rate of comorbidity of BD and cocaine abuse. We identified drug targets within this network that represent immediate candidates for therapeutic drug testing. Posing novel hypotheses for validation in future work, we prioritized SNPs near genes in the network based on functional annotation. We also developed a "concept signature" for the genes in the network and identified additional candidate genes that may influence the system because they are significantly associated with the signature.
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影响因子：
3.3
作者：
Clerici, Mario;Arosio, Beatrice;Altamura, A. Carlo
通讯作者：
Altamura, A. Carlo
DOI：
10.1080/01443610400022983
发表时间：
2005-06-01
影响因子：
3.1
作者：
Choi, SH;Shapiro, H;Stewart, D
通讯作者：
Stewart, D
影响因子：
2.9
作者：
BRADY, KT;LYDIARD, RB
通讯作者：
LYDIARD, RB
影响因子：
14.9
作者：
Huang DW;Sherman BT;Tan Q;Kir J;Liu D;Bryant D;Guo Y;Stephens R;Baseler MW;Lane HC;Lempicki RA
通讯作者：
Lempicki RA
DOI：
10.1111/j.1742-7843.2009.00416.x
发表时间：
2009-08-01
影响因子：
3.1
作者：
Hammonds, Michael D.;Shim, Seong S.
通讯作者：
Shim, Seong S.