Type 2 diabetes (T2D) is a complex disease that involves multiple

Type 2 diabetes (T2D) is a complex disease that involves multiple genes. these 191114-48-4 supplier complexes to be significantly enriched for genes associated with diabetic phenotypes through heterogeneous evidence sources, including genetic variation, methylation, and gene expression in islets. The analysis specifically revealed ten T2D candidate genes with probable roles in islets (= 9.6 10?4, Supplementary Figure 1). These results suggest that coordinated islet gene expression of protein complex members can indicate an important role in islet biology. We therefore defined a subset of 1 1,007 islet-coordinated complexes where at least one of the islet tissue components (whole islets, beta, or non-beta cells) was among the three highest ranked across the 34 tissues tested (see Section Methods). Moreover, the 1,007 complexes were enriched (MWU, = 2.8 10?4) for genes residing in islet regulatory regions defined as having islet-selective open chromatin in the transcription start site or gene-body (Supplementary Table 2; Figure ?Figure1D1D). While these 191114-48-4 supplier 1,007 complexes are of special interest in the context of islet function, previous work related to the cell cycle (de Lichtenberg et al., 2005) has illustrated that protein complexes can be functional even though not fully coordinated due to sophisticated, temporal regulation. We therefore included all 3,692 complexes in the further analyses on T2D dysregulation. Limited overlap of islet diabetes gene sets Having a catalog of 3,692 islet relevant protein complexes we next turned to investigate which of those were most likely to be implicated in T2D (Figure ?(Figure1E).1E). The underlying hypothesis is that complexes exhibiting pronounced convergence of genes originating from different evidence sources related to diabetes are likely to play 191114-48-4 supplier a role in the disease. We thus compiled 13 sets of genes associated with T2D, monogenic forms of diabetes and related metabolic phenotypes (Table ?(Table1),1), hereafter termed islet diabetic phenotype gene sets. Despite all gene sets being related to diabetes, they generally showed surprisingly little direct overlap, although many pairwise overlaps were still larger than expected by chance (Figure ?(Figure2).2). The largest overlaps, ranging from 11 to 55% relative to the size of the shortest list, were observed between gene sets based on genetic variation (Monogenic, OMIM, T2D GWAS/rare variant, Glycemic GWAS/rare variant, PRKD3 191114-48-4 supplier and Glycemic gene-based), which is to some extent expected as many genes causing monogenic forms of diabetes also harbor variants associated with T2D and glycemic traits (Bonnefond and Froguel, 2015). Twenty genes were found to be part of four or more of the 13 gene sets (Supplementary Table 3), many of which are well-known T2D susceptibility genes while others are less well-established in the context of diabetes, some of those examples are highlighted in Box 1. Table 1 Description of the thirteen islet diabetic phenotype gene sets and the four islet biology 191114-48-4 supplier related gene sets. Figure 2 Direct overlap of the thirteen islet diabetic phenotype gene sets. (A) Overlap in terms of gene counts. (B) Overlap in terms of percent overlap relative to the size of the shortest gene sets. (C) BH-adjusted locus on chromosome 2), thus, representing a trans-eQTL (Taneera et al., 2012). In addition, the gene promoter is located in a region that is hypomethylated in T2D islets (Volkmar et al., 2012), and finally the gene itself is differentially expressed in T2D beta-cells (Marselli et al., 2010). Collectively, these heterogeneous data types indicate together a plausible role of in the pathogenesis of T2D in pancreatic islets. Supporting our observation, this gene has been proposed as the causal gene in this GWAS locus through a study of allelic expression profiling (Locke et al., 2015). A variant in this gene is associated with the levels of a peptide derived from the C3 complement protein that plays a role in the innate immune system (Shin et al., 2014). Hydroxyacyl-CoA dehydrogenase (are known to cause familial hyperinsulinism (Glaser, 2013), which motivated a targeted study of common variants in the gene that however did not find any association with T2D (van Hove et al., 2006). Yet, our observations suggest that the expression of the gene is affected in pancreatic islets in T2D and that it may play a role in the disease. The islet expression of Family with sequence similarity 105, member A (was furthermore coexpressed with the T2D genes and (Taneera et al., 2012) while resides in a region of the genome that was differentially methylated in islets when comparing T2D patients and controls (Dayeh et al., 2014). A variant.