Genome-wide association studies (GWASs) have discovered >50 risk loci for type 1 diabetes (T1D). However, those variations only have modest effects on the genetic risk of T1D. In recent years, accumulated studies have suggested that gene-gene interactions might explain part of the missing heritability. The purpose of our research was to identify potential and novel risk genes for T1D by systematically considering the gene-gene interactions through network analyses. We carried out a novel system network analysis of summary GWAS statistics jointly with transcriptomic gene expression data to identify some of the missing heritability for T1D using weighted gene co-expression network analysis (WGCNA). Using WGCNA, seven modules for 1852 nominally significant (P ≤ 0.05) GWAS genes were identified by analyzing microarray data for gene expression profile. One module (tagged as green module) showed significant association (P ≤ 0.05) between the module eigengenes and the trait. This module also displayed a high correlation (r = 0.45, P ≤ 0.05) between module membership (MM) and gene significant (GS), which indicated that the green module of co-expressed genes is of significant biological importance for T1D status. By further describing the module content and topology, the green module revealed a significant enrichment in the "regulation of immune response" (GO:0050776), which is a crucially important pathway in T1D development. Our findings demonstrated a module and several core genes that act as essential components in the etiology of T1D possibly via the regulation of immune response, which may enhance our fundamental knowledge of the underlying molecular mechanisms for T1D.

中文翻译：

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基因组学和转录组学数据的系统网络分析确定了 1 型糖尿病相关通路和基因。

全基因组关联研究 (GWAS) 已发现 1 型糖尿病 (T1D) 的风险位点超过 50 个。然而，这些变异对 T1D 的遗传风险只有适度的影响。近年来，累积的研究表明基因-基因相互作用可能解释了部分缺失的遗传力。我们研究的目的是通过网络分析系统地考虑基因 - 基因相互作用来识别 T1D 的潜在和新风险基因。我们对总结 GWAS 统计数据与转录组基因表达数据进行了新的系统网络分析，以使用加权基因共表达网络分析 (WGCNA) 来识别 T1D 的一些缺失遗传力。使用 WGCNA，1852 的七个模块名义上显着（P ≤ 0。05) GWAS 基因是通过分析基因表达谱的微阵列数据来确定的。一个模块（标记为绿色模块）显示模块特征基因与性状之间存在显着关联（P ≤ 0.05）。该模块还显示模块成员 (MM) 和基因显着性 (GS) 之间的高度相关性 (r = 0.45, P ≤ 0.05)，这表明共表达基因的绿色模块对 T1D 状态具有重要的生物学重要性。通过进一步描述模块内容和拓扑结构，绿色模块揭示了“免疫反应调节”（GO：0050776）的显着丰富，这是 T1D 发展中至关重要的途径。我们的研究结果证明了一个模块和几个核心基因，它们可能通过调节免疫反应，在 T1D 的病因学中充当重要组成部分，