A significant proportion of drugs that enter clinical development fail because they are either toxic or ineffective. A series of studies have suggested that genetically supported targets have a significantly higher success rate in clinical development. In contrast drug targeting genes that are more constrained in human populations are more likely to be impacted by safety concerns. These findings have provided impetus to use human genetics to evaluate targets for drug discovery programs.
We plan to use UK Biobank data identify and characterize therapeutic targets causally linked to cardio-metabolic diseases such as obesity, Type 2 diabetes, stroke, heart failure, hypertension and fatty liver disease.
The key aims of the project are as follows:
1. We will perform exome-wide gene-based tests across relevant medical conditions and quantitative cardiometabolic traits from WES data in UK Biobank to identify disease-associated genes.
2. We will map the disease-associated genes to publicly available protein-protein interaction networks to identify enriched biological processes and sub-networks associated with a role in these diseases.
3. We will investigate the expression of these targets across difference tissue types (GTEx database). Several obesity-linked genes have previously found to be highly expressed in neural tissue (Akbari et. al., 2021). We will build coexpression networks to understand how expression of these genes in the brain drives the physiological effects observed in peripheral tissues such as liver and pancreas.
4. We also would like to understand the toxicity associated with modulating these targets by investigating phenotypes associated with each target and their relationship to tissue types where the target is highly expressed.
5. Finally, we will integrate extensive genetic and biomedical data to identify physiologically-informed clusters of a particular cardio-metabolic disease and develop strategies for patient stratification.