A fundamental challenge in developing new therapies for human diseases is identifying the genes and genetic variants that are involved and the biological mechanisms through which they cause diseases, including whether the diseases result from increases or decreases in the functional activity of the genes. This is especially difficult for many common diseases, such as heart disease, because hundreds of genes can contribute to disease risk. Although rare variants are believed to have an important role in causing common diseases, historically, this has been difficult to investigate. Recently, as the costs of genome sequencing have decreased, and biobanks have been established that contain medical records and genetic data for hundreds of thousands of participants, it has become more feasible to study this topic.
The past few years have seen the publication of multiple research studies using data from hundreds of thousands of biobank participants to examine the role of rare variants in disease. By design, these studies have been expansive, considering rare variants in tens of thousands of genes and their combined effects on thousands or tens of thousands of diseases or related traits. The massive scale of these studies allowed them to produce an incredible volume of results, but also came with limits on the statistical power with which they could detect the associations of rare variants with disease, which made it challenging to translate the results into new therapies.
In this project, which we expect will go on for 24 months, in addition to using latest and largest dataset of rare variants for all of the UK Biobank participants, we’ll apply a very targeted approach, focusing on a small number of common diseases and related clinical measurements, for example heart disease and LDL cholesterol. Furthermore, testing for associations with rare variants in a limited set of genes that are known to be relevant for the selected diseases, will enable a much more fine-grained approach than in previous studies for how the variants and their effects are combined into groups. All together, this project will have increased power to detect rare variants associated with disease and will produce results that can point more directly to the mechanisms through which disease is caused. In particular, the project’s fine-grained approach will help identify the specific parts of proteins where changes affect disease risk, and make it easier to discover variants that have protective effects, facilitating the development of new therapies.
