T2DCREBBP · Defining the molecular basis of type 2 diabetes predisposition through targeted sequencing of the CREBBP-interacting gene network

Type 2 diabetes (T2D) represents a major challenge to global health. In recent years, over 60 genetic loci have been confidently implicated in T2D predisposition: however, there has been only limited progress in defining the biological mechanisms responsible. Recent work led by the host institution has revealed that these T2D-associated loci are substantially enriched for genes whose protein products interact with CREBBP, identifying this transcriptional co-activator as a key node linking processes involved in T2D development. The research I propose to conduct aims to explore the overall contribution of the CREBBP interactome in T2D predisposition, through integration of existing and novel genetic data. The former is provided by extensive genome wide association (n~100,000 individuals), exome sequence (n~14,000) and exome chip (n~60,000) available to the host institution; the latter will be generated by the applicant through large-scale (>20,000 individuals), targeted resequencing of genes coding for key CREBBP-interacting proteins. Through these data, I expect to generate a comprehensive evaluation of the genetic evidence linking CREBBP-interacting proteins to T2D pathogenesis, laying the foundation for further functional studies. As well as the intrinsic scientific merit of this proposal, the research outlined will provide extensive training in state-of-the-art experimental and analytical methods in human genetics