Approved Research

The contribution of loss of function (LOF) variants to clinically relevant phenotypes

Lay summary

It is common knowledge that some people are more prone to certain disease than others.  Studying individuals affected by certain diseases has been crucial to our understanding of the mechanism of these diseases.  However, little attention has been paid until recently to those who are less prone to diseases.  We all know some people who have every reason to develop a particular disease because they have the risk factors and yet they do not.  Although we know that genetics plays a major factor, we used to lack the tools that allow us to pinpoint these genetic factors.  Not only does understanding these factors improve our understanding of disease risk, but it may direct us to novel therapies.  A great example is PCSK9, a gene that normally functions in all of us to regulate the activity of the receptor that removes bad lipids from blood.  It was one of the greatest breakthroughs in heart disease research when it was identified that there individuals who are naturally protected from coronary artery disease because they lacked the activity of this gene.  This has inspired the development of a totally new line of treatment of hypercholesterolemia.  Consanguineous populations are populations where marriage between cousins is common as in Saudi Arabia.  These populations are far more likely to have individuals who lack the function of some genes.  Thus, we are currently cataloging these individuals to identify gene functional losses that can be beneficial to health just like the PCSK9 story.  Our goal of accessing UKBB is to validate these preliminary findings using a very large set of individuals with and without the trait in question by examining their genome information.