Tip 2 Diyabet'te Etkilenen Yolak Alt Ağlarını Bulmak İçin Yukarıdan Aşağıya İşleyen Bir Yaklaşım

Abstract

Diabetes Mellitus (DM) is a metabolic disorder caused by dysfunction of insulin-producing pancreatic beta cells, insulin resistance, or impairment of insulin functionality. Type 2 Diabetes Mellitus (T2D) is a complex multifactorial disease that accounts for 90% of diabetes cases. In recent years, genome-wide association studies (GWAS) have successfully identified genetic variants associated with T2D risk. However, while conventional GWAS analyses focus on 'the tip of the iceberg' single nucleotide polymorphisms (SNPs), new analysis methods are needed to uncover hidden variations in these studies. In our previous study, we developed a post-GWAS analysis methodology to find disease-associated marker pathways by integrating human protein-protein interaction network, known biological pathways and potential SNPs. In this study, via adding different in-silico approaches to our methodology, we aim to identify affected pathway subnetworks and affected pathway clusters in addition to the affected protein subnetworks in T2D, and consequently to enlighten molecular mechanisms of T2D. Using this proposed method, we analyzed T2D GWAS meta-analysis data including 12.931 cases ye 57.196 controls. The approach we presented here is based on both the significance value of affected pathway and its topological relationship with other neighbor pathways. In the functional enrichment stage of our method, important pathways were obtained using hypergeometric test and gene-pathway matrix was formed. Then pathway-pathway similarity values were calculated using Jaccard index. Using the scores obtained in the similarity matrix, pathway-pathway network was constructed, and disease-related pathway modules were obtained using subnetwork search algorithms. As a result, genes, pathways and pathway subnetworks that might have a potential role in T2D development were identified, and the categories and classes that are related with these affected pathways were determined.