Approved Research

Genomics methods development, gene trait association discovery and replication, and rare disease research in UK Biobank

Lay summary

Broadly, our goal is to try to understand how the human genome and environmental factors impact health and disease.  One of the ways we plan to do this is by integrating information on rare severe diseases caused by pathogenic genetic variations with broader measurements of phenotypes in the general population. Even though all humans have the same genes, if we know that a complete loss of function in a particular gene results in a well-known disorder with specific clinical symptoms, we want to discover if incomplete loss of function of that same gene could lead to sub-clinical indications of disease. To achieve our goal, we will team up with rare disease experts and evaluate a wide range of phenotypes collected by UK Biobank. By exploring both known and new Mendelian disorders, we aim to discover the potential health consequences of weakly deleterious genetic variation in genes where known pathogenic versions result in clear genetic disorders.

In a similar approach, we plan to use statistical tools to measure the association between genetic variants and phenotypes in human studies conducted all over the world. Importantly, the credibility of a statistical association between a particular genetic variant and a phenotype, or result, in an association study is strengthened when the same result is observed in an independent study. Replication of results is a common practice in the publication of genetic associations, and a major component of robust and reproducible genetic studies. Our aim is to use the genetic and phenotype information gathered by UK Biobank to replicate interesting findings from other studies and to investigate the broad phenotypic effects of the associated variant and other variants in the gene. With the diverse phenotypes collected by UK Biobank, including hospital-based diagnoses, surveys, specialized biochemical and metabolic measures, imaging, and more, we plan to develop a detailed understanding of the various phenotypic effects motivated from interesting findings from other studies.