Abstract
Genome-wide association studies (GWASs) have discovered association of several loci with Type 2 diabetes (T2D), a common complex disease characterized by impaired insulin secretion by pancreatic β cells and insulin signaling in target tissues. However, effect of genetic risk variants on continuous glycemic measures in nondiabetic subjects mainly elucidates perturbation of insulin secretion. Also, the disease associated genes do not clearly converge on functional categories consistent with the known aspects of T2D pathophysiology. We used a systems biology approach to unravel genome to phenome correlation in T2D. We first examined enrichment of pathways in genes identified in T2D GWASs at genome-wide or lower levels of significance. Genes at lower significance threshold showed enrichment of insulin secretion related pathway. Notably, physical and genetic interaction network of these genes showed robust enrichment of insulin signaling and other T2D pathophysiology related pathways including insulin secretion. The network also overrepresented genes reported to interact with insulin secretion and insulin action targeting antidiabetic drugs. The drug interacting genes themselves showed overrepresentation of insulin signaling and other T2D relevant pathways. Next, we generated genome-wide expression profiles of multiple insulin responsive tissues from nondiabetic and diabetic patients. Remarkably, the differentially expressed genes showed significant overlap with the network genes, with the intersection showing enrichment of insulin signaling and other pathways consistent with T2D pathophysiology. Literature search led our genomic, interactomic, transcriptomic and toxicogenomic evidence to converge on TGF-beta signaling, a pathway known to play a crucial role in pancreatic islets development and function, and insulin signaling. Cumulatively, we find that GWAS genes relate directly to insulin secretion and indirectly, through collaborating with other genes, to insulin resistance. This seems to support the epidemiological evidence that environmentally triggered insulin resistance interacts with genetically programmed β cell dysfunction to precipitate diabetes.
Highlights
Our understanding of genetic basis of disease risk has greatly improved in recent years owing to the advent of genome-wide association studies (GWASs) [1,2]
GWAS Genes A catalog of single nucleotide polymorphisms (SNPs) associations up to a p value cutoff of 161025, a threshold commonly used for preliminary selection of SNPs in GWASs, exists in public domain [25]
As genes at this cutoff are considered meaningful for enrichment analysis [26], we retrieved genes reported in Type 2 diabetes mellitus (T2D) GWASs at p value thresholds up to 1025 (Dataset S1) and examined enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways therein
Summary
Our understanding of genetic basis of disease risk has greatly improved in recent years owing to the advent of genome-wide association studies (GWASs) [1,2]. The genes influencing common complex or multifactorial diseases and quantitative traits were largely unknown before GWASs came into being in the year 2006 [2,3]. Results obtained from these studies suggest that multiple genetic architectures, including common genetic variants with small effects and rare variants with large effect sizes, underlie susceptibility to common diseases [1]. Numerous multifactorial mechanisms that include genetic and environmental factors related to obesity are involved in the development of insulin resistance and impaired insulin secretion [8,9]. Derangements in both insulin secretion and doi:10.1371/journal.pone.0053522.g002
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