Diverse type 2 diabetes genetic risk factors functionally converge in a phenotype-focused gene network

• DOI: 10.1371/journal.pcbi.1005816
• Publication Date: 2017-10-23T17:36:39Z
• Authors: Cynthia Sandor; Nicola L. Beer; Caleb Webber
• Keywords: Exome; Genetic Association; Genetic linkage

Type 2 Diabetes (T2D) constitutes a global health burden. Efforts to uncover predisposing genetic variation have been considerable, yet detailed knowledge of the underlying pathogenesis remains poor. Here, we constructed T2D phenotypic-linkage network (T2D-PLN), by integrating diverse gene functional information that highlight genes, which when disrupted in mice, elicit similar T2D-relevant phenotypes. Sensitising phenotypes enabled significant convergence be detected between genes implicated monogenic or syndromic diabetes and lying within genomic regions associated with common risk. We extended these analyses recent multiethnic case-control exome 12,940 individuals found no evidence risk association for rare frequency variants outside previously known loci. Examining associations involving protein-truncating (PTV), most at low population frequencies, T2D-PLN was able identify convergent set biological pathways were perturbed four five independent case/control ethnic sets 2000 5000 exomes each. These same over-represented among both T2D-associated Our study demonstrates biology amongst representing different classes Although observed pathway level, few contributing cohorts variant classes, notably suggests future studies may better focusing their power onto single ancestry.