Park Jisoo, Wick Heather C, Kee Daniel E, Noto Keith, Maron Jill L, Slonim Donna K
Department of Computer Science, Tufts University, Medford, Massachussetts, United States of America.
Department of Pediatrics, The Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, United States of America.
PLoS Comput Biol. 2014 May 29;10(5):e1003578. doi: 10.1371/journal.pcbi.1003578. eCollection 2014 May.
Identifying molecular connections between developmental processes and disease can lead to new hypotheses about health risks at all stages of life. Here we introduce a new approach to identifying significant connections between gene sets and disease genes, and apply it to several gene sets related to human development. To overcome the limits of incomplete and imperfect information linking genes to disease, we pool genes within disease subtrees in the MeSH taxonomy, and we demonstrate that such pooling improves the power and accuracy of our approach. Significance is assessed through permutation. We created a web-based visualization tool to facilitate multi-scale exploration of this large collection of significant connections (http://gda.cs.tufts.edu/development). High-level analysis of the results reveals expected connections between tissue-specific developmental processes and diseases linked to those tissues, and widespread connections to developmental disorders and cancers. Yet interesting new hypotheses may be derived from examining the unexpected connections. We highlight and discuss the implications of three such connections, linking dementia with bone development, polycystic ovary syndrome with cardiovascular development, and retinopathy of prematurity with lung development. Our results provide additional evidence that TGFB lays a key role in the early pathogenesis of polycystic ovary syndrome. Our evidence also suggests that the VEGF pathway and downstream NFKB signaling may explain the complex relationship between bronchopulmonary dysplasia and retinopathy of prematurity, and may form a bridge between two currently-competing hypotheses about the molecular origins of bronchopulmonary dysplasia. Further data exploration and similar queries about other gene sets may generate a variety of new information about the molecular relationships between additional diseases.
识别发育过程与疾病之间的分子联系能够催生关于生命各阶段健康风险的新假说。在此，我们引入一种新方法来识别基因集与疾病基因之间的显著联系，并将其应用于几个与人类发育相关的基因集。为克服将基因与疾病联系起来的信息不完整和不完善的局限性，我们将医学主题词表（MeSH）分类法中疾病子树内的基因进行汇总，并证明这种汇总提高了我们方法的效力和准确性。通过排列检验来评估显著性。我们创建了一个基于网络的可视化工具，以方便对这大量显著联系进行多尺度探索（http://gda.cs.tufts.edu/development）。对结果的高级分析揭示了组织特异性发育过程与那些组织相关疾病之间的预期联系，以及与发育障碍和癌症的广泛联系。然而，有趣的新假说可能源自对意外联系的研究。我们突出并讨论了三个这样的联系的意义，即痴呆与骨骼发育、多囊卵巢综合征与心血管发育、早产儿视网膜病变与肺部发育之间的联系。我们的结果提供了额外证据，表明转化生长因子β（TGFB）在多囊卵巢综合征的早期发病机制中起关键作用。我们的证据还表明，血管内皮生长因子（VEGF）途径和下游核因子κB（NFKB）信号传导可能解释支气管肺发育不良与早产儿视网膜病变之间的复杂关系，并可能在目前关于支气管肺发育不良分子起源的两个相互竞争的假说之间架起一座桥梁。对其他基因集进行进一步的数据探索和类似查询可能会产生关于更多疾病之间分子关系的各种新信息。
