Aim
To understand the phenotypic impact of disruptive variation in protein-coding genes.
Scientific rationale
Predicted loss-of-function (pLoF) variants – variants predicted to break the normal function of protein-coding genes – are a genetic model of gene disruption and can be extremely powerful tools for understanding the potential impact of pharmaceutical inhibition of human genes. As such, pLoF variants have been used extensively to discover and validate therapeutic targets and explore the potential efficacy and adverse events associated with the inhibition of those targets. The UK Biobank data represents by far the largest available data set of humans with both complete exome sequencing and deep clinical data, and therefore the most powerful available source of information on the impact of pLoF variants.
Project duration
A rolling 3-year period during which annual updates would be provided.
Public health impact
Further improving our understanding of the genetic basis of disease and the overall phenotypic impact of disruptive mutations in human genes will allow our team, and other teams of researchers, to work towards developing therapeutics for the treatment and management of several human diseases.