Molecular Mechanisms of Insulin Resistance Associated Loci

PROJECT SUMMARY Insulin resistance (IR) is necessary for the development of type 2 diabetes (T2D) and is a major cardiovascular diseases risk factor. IR has few therapeutic options and identification of new drug targets and novel IR mechanisms would have a huge impact on public health. Although genome wide association studies (GWAS) have identified hundreds IR-associated genetic loci, there has been limited progress towards identifying causal genes and mechanisms. Our colocalization analysis combined data from GWAS of IR-associated traits (T2D, fasting insulin, fasting glucose, waist-hip ratio adjusted for body mass index, triglycerides and high-density lipoprotein cholesterol) and expression quantitative trait loci (eQTL) within five tissues related to IR or T2D (subcutaneous and visceral adipose tissue, skeletal muscle, liver and pancreas). The analysis identified specific causal IR genes in about 25% of IR loci and in half of these cases, the effects are attributable to effects in adipose tissue. We will extend our findings through larger colocalization studies and use single cell data to identify a credible list of adipose cell specific IR causal genes (Aim 1). In Aim 2, we will functionally characterize IR causal genes for cellular mechanisms of action as well as define gene regulatory networks by employing single cell analyses of transcriptomes and epigenomes following CRISPR gene perturbation. In Aim 3, we will define the physiological role of causal genes in vivo by creating loss of function mouse models by combining a CRISPRi mouse with the delivery of sgRNA and Cre recombinase via the adipose tissue specific AAV delivery system. By combining human genetics, computational analysis, and functional genomics tools, we will establish causal genes and their mechanisms of action in development of IR. This effort will lead to novel mechanisms and drugs targets to address the unmet need posed by IR, T2D and cardiovascular disease.