Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Av, Manuel Siurot s/n, Seville, 41013, Spain.
Orphanet J Rare Dis. 2013 Dec 2;8:187. doi: 10.1186/1750-1172-8-187.
Despite it has been reported that several loci are involved in Hirschsprung's disease, the molecular basis of the disease remains yet essentially unknown. The study of collective properties of modules of functionally-related genes provides an efficient and sensitive statistical framework that can overcome sample size limitations in the study of rare diseases. Here, we present the extension of a previous study of a Spanish series of HSCR trios to an international cohort of 162 HSCR trios to validate the generality of the underlying functional basis of the Hirschsprung's disease mechanisms previously found. The Pathway-Based Analysis (PBA) confirms a strong association of gene ontology (GO) modules related to signal transduction and its regulation, enteric nervous system (ENS) formation and other processes related to the disease. In addition, network analysis recovers sub-networks significantly associated to the disease, which contain genes related to the same functionalities, thus providing an independent validation of these findings. The functional profiles of association obtained for patients populations from different countries were compared to each other. While gene associations were different at each series, the main functional associations were identical in all the five populations. These observations would also explain the reported low reproducibility of associations of individual disease genes across populations.
尽管已有报道称多个基因座与先天性巨结肠症有关，但该病的分子基础仍基本未知。对功能相关基因模块的整体特性进行研究提供了一个高效、敏感的统计框架，可以克服罕见病研究中样本量的限制。在此，我们将先前对西班牙先天性巨结肠症三核苷酸系列的研究扩展到了一个包含 162 个三核苷酸的国际队列中，以验证先前发现的先天性巨结肠症发病机制的潜在功能基础的普遍性。基于途径的分析（PBA）证实了与信号转导及其调控、肠神经系统（ENS）形成以及与疾病相关的其他过程相关的基因本体论（GO）模块之间存在强烈的关联。此外，网络分析恢复了与疾病显著相关的子网络，其中包含与相同功能相关的基因，从而为这些发现提供了独立验证。将来自不同国家的患者群体的关联功能谱进行了相互比较。虽然每个系列的基因关联都不同，但所有五个群体的主要功能关联都是相同的。这些观察结果也可以解释为什么在不同人群中报道的个体疾病基因的关联重复性低。
