Programme Leader – Dr Inês Barroso
Type 2 diabetes (T2DM) and obesity are complex disorders which result from the interplay of genetic variants and lifestyle and behavioural factors. To date, large-scale genetic studies called genome-wide association studies (GWAS) have identified hundreds of genes influencing T2DM and/or obesity risk, and related traits. However, mechanistic insight of how those variants affect disease remains largely unknown.
This programme complements the Unit MRC-funded Aetiology and Mechanisms and Early Life Aetiology and Mechanisms programmes in addressing this knowledge gap. Jointly, these programmes aim to generate insights which may be helpful in providing human genetic validation for drug target discovery, or drug repositioning (where a drug already exists but it is used for a different disease and new data allows it to be repurposed to metabolic disease), and in gaining new insights into disease diagnosis and prevention.
This programme stems from long standing collaborative work between the Programme Lead (Inês Barroso), members of the MRC Epidemiology Unit (Claudia Langenberg, Nick Wareham), and members of the Institute of Metabolic Sciences (Sadaf Farooqi, Stephen O’Rahilly and David Savage). The programme aims to provide functional and mechanistic insights to metabolic disease by linking Barroso’s expertise in human genetics and genomics, to the aetiology work within the Unit, and the clinical and functional research within the IMS Metabolic Research Laboratories, specifically Farooqi and O’Rahilly’s work on severe childhood onset obesity, and Savage’s on lipodystrophy.
Since 2009, Barroso has led MAGIC, a large international consortium that has identified the vast majority of loci influencing continuous glycaemic traits (e.g. fasting glucose and insulin, two hour post-challenge glucose, and glycated haemoglobin–HbA1c) as a complementary approach to studies of T2DM. Genetic studies of these measurements have provided insights into T2DM relevant pathways, have identified ancestry-specific variants affecting the diagnostic accuracy of HbA1c, and are beginning to cluster T2DM patients into distinct groups with different prognostic outcomes. In parallel, collaborative work between Barroso, Farooqi and O’Rahilly in severe childhood onset obesity, has identified genes not previously linked to obesity. These genes may yield new insights into pathways important in energy homeostasis.
The proposed programme builds on these foundations, and will continue to explore the causal genes and variants at trait and disease-associated loci. It will utilise large-scale gene expression datasets, combined with rare forms of disease, and functional work to gain further insights into the mechanisms underlying disease, with a view to identify new pathways for therapeutic intervention.