Genetics of type 2 diabetes
The main challenge for GWAS studies remains the identification of the causal gene(s) within a locus. Through functional analysis in the mouse, we aim to overcome this hurdle in order to translate information from such studies into benefits for type 2 diabetes patients.
Given the number of GWAS loci and our finite capacity to analyse candidates within them, we are focusing our efforts by collaborating with human geneticists and clinicians, including those at the University of Oxford (Oxford Centre for Diabetes Endocrinology and Metabolism) and other institutions around the UK to help identify the most likely causal genes or transcripts at each locus.
Together with our collaborators, we use information from the identification of coding mutations from exome sequencing, fine genetic mapping in different human populations, expression QTL analysis in relevant cells and from tissues and experiments with patient samples of a known genotype. In this way, findings in human studies can be cross-validated in the mouse and specific genes selected for further analysis. Selected genes are then functionally analysed in the mouse by making conditional overexpression, knockout and genome-edited alleles.
Finally, we intend to use technologies such as CRISPR to introduce mutations in multiple genes that have a small effect on diabetes to investigate their interaction, as diabetes is a genetically complex condition. The aim is to use this technique to test any equivalent human mutations in the mouse and determine the function of the gene in terms of its effect on whole body physiology. In addition, we intend to use cells and tissues from the mouse to study the mechanisms and pathways involved, and determine how the mutations identified could disrupt the function of the gene.
This type of systematic analysis has allowed us to validate genes such as the FTO gene, originally identified in a GWAS for type 2 diabetes due to its association with obesity. Using various models of the mouse FTO gene, we discovered that reduced function of the gene led to lean mice, whereas overexpression resulted in overeating and obesity. In the future, this research could lead to therapies that inhibit FTO or target other genes identified.