Exploiting the population isolate jackpot effect

Exploiting the population isolate jackpot effect

In collaboration with Prof Jim Wilson (Usher Institute) we exploit the “jack-pot effect” of human population isolates to empower genome wide association studies to identify new genes that regulate fat distribution; a major risk factor for type 2 diabetes and cardiovascular disease (CVD). We investigate the impact of the candidate genes on cellular function and whole animal physiology as part of a pre-clinical validation pipeline geared towards discovery of novel medicines for CVD.

We use genome wide association studies in people from population isolates such as the Orkney and Shetland Islands (collaboration with Prof Jim Wilson, Usher Institute for Population Health Sciences and Informatics) who have given their DNA and numerous indices of health in cross-sectional studies. In our case, we focussed on indices of adiposity gathered using non-invasive and anatomically accurate Dual-Energy X-ray absorptiometry (DEXA). Combining these powerful approaches in a population whose genetic architecture has some unique features that result from isolation from other large populations at certain times in history creates a “jack-pot” effect of allele enrichment that can reveal novel genetic associations for the inherited traits of fatness and fat distribution. We then take candidate genes and validate/model them pre-clinically using transgenic mice and state-of-the-art metabolic phenotyping techniques (e.g. indirect calorimetry) to explore the physiological mechanisms underpinning their effect on adiposity and metabolic health. We aim to exploit our pre-clinical pipeline to assess the potential of targeting the causal genes therapeutically in collaboration with our drug discovery team (Prof Scott Webster, CVS).

Principal Investigator: Prof Nik Morton

Key collaborators: Prof Valur Emilsson (Icelandic Heart Association: replication of Northern haplotypes), Dr Pau Navarro (Institute for Genetics and Molecular Medicine; GWAS), Prof. Wendy Bickmore and Dr Iain Williamson (IGMM: genomics of the variant intervals) and Prof Scott Webster (Chair of Medicines Discovery; CVS: translation into small molecule inhibitors of potential targets; MRC CiC funding).

Team members involved in this programme: Dr Katharine Schraut, Ms Rongling Wang (PhD candidate)