Department of Bioinformatics - BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands.
PLoS One. 2018 Apr 4;13(4):e0193515. doi: 10.1371/journal.pone.0193515. eCollection 2018.
Genome-wide association studies (GWAS) have become a common method for discovery of gene-disease relationships, in particular for complex diseases like Type 2 Diabetes Mellitus (T2DM). The experience with GWAS analysis has revealed that the genetic risk for complex diseases involves cumulative, small effects of many genes and only some genes with a moderate effect. In order to explore the complexity of the relationships between T2DM genes and their potential function at the process level as effected by polymorphism effects, a secondary analysis of a GWAS meta-analysis is presented. Network analysis, pathway information and integration of different types of biological information such as eQTLs and gene-environment interactions are used to elucidate the biological context of the genetic variants and to perform an analysis based on data visualization. We selected a T2DM dataset from a GWAS meta-analysis, and extracted 1,971 SNPs associated with T2DM. We mapped 580 SNPs to 360 genes, and then selected 460 pathways containing these genes from the curated collection of WikiPathways. We then created and analyzed SNP-gene and SNP-gene-pathway network modules in Cytoscape. A focus on genes with robust connections to pathways permitted identification of many T2DM pertinent pathways. However, numerous genes lack literature evidence of association with T2DM. We also speculate on the genes in specific network structures obtained in the SNP-gene network, such as gene-SNP-gene modules. Finally, we selected genes relevant to T2DM from our SNP-gene-pathway network, using different sources that reveal gene-environment interactions and eQTLs. We confirmed functions relevant to T2DM for many genes and have identified some-LPL and APOB-that require further validation to clarify their involvement in T2DM.
全基因组关联研究(GWAS)已成为发现基因-疾病关系的常用方法,特别是对于 2 型糖尿病(T2DM)等复杂疾病。GWAS 分析的经验表明,复杂疾病的遗传风险涉及许多基因的累积、小效应,只有少数基因具有中等效应。为了探索 T2DM 基因与多态性效应影响下的潜在功能之间关系的复杂性,对 GWAS 荟萃分析进行了二次分析。网络分析、途径信息以及整合不同类型的生物学信息,如 eQTL 和基因-环境相互作用,用于阐明遗传变异的生物学背景,并基于数据可视化进行分析。我们从 GWAS 荟萃分析中选择了一个 T2DM 数据集,并提取了与 T2DM 相关的 1971 个 SNPs。我们将 580 个 SNPs 映射到 360 个基因,然后从经过整理的 WikiPathways 收集物中选择包含这些基因的 460 个途径。然后,我们在 Cytoscape 中创建和分析了 SNP-基因和 SNP-基因途径网络模块。关注与途径有稳健联系的基因,可以识别出许多与 T2DM 相关的途径。然而,许多基因缺乏与 T2DM 相关的文献证据。我们还推测了 SNP-基因网络中特定网络结构中的基因,例如基因-SNP-基因模块。最后,我们从 SNP-基因途径网络中选择了与 T2DM 相关的基因,使用了揭示基因-环境相互作用和 eQTL 的不同来源。我们确认了许多基因与 T2DM 相关的功能,并确定了一些基因,如 LPL 和 APOB,需要进一步验证以澄清它们在 T2DM 中的作用。