New approach to link genome-wide association signals to biological function

One step closer to understanding the biology behind disease-associated genetic variants

James Nisbet, Genome Research Limited
Cartoon of open chromatin structure showing DNA transcription enabled by regulatory factors.
Researchers have developed a new strategy to improve the outcome of genome-wide association (GWA) studies.

GWA studies involve rapidly scanning markers across the genomes of many people. By doing this, scientists can look for the association between certain genetic markers or variants within the population, and a particular trait, including disease. However, the challenge is to take these initial association signals and identify the functional DNA changes and their molecular consequences. This is an important step in translating these findings into clinical benefits.

The researchers validated a generic framework to streamline discovery of functional DNA variants underlying GWA signals. The team sought to understand the complexity of genomes and sequence variation leading to a better understanding of the affected gene function and biological pathways involved at the cellular level.

As a result, this will benefit many scientists around the world who are currently applying GWA studies to search for genes that affect countless common traits and diseases. It is estimated this new strategy could shed light on around one in four GWA signals for a given trait, but this will depend heavily on the knowledge of the relevant cell types.

The collaborative study was led by Dirk Paul, a Marie Curie PhD Fellow at the Wellcome Trust Sanger Institute, and Dr Panos Deloukas, who leads the Institute’s Genetics of Complex Traits in Humans Group. Their approach was based on a technique to map regions of the genome that are ‘open for business’, in an open conformation that allows it to be easily activated. DNA in cells is packed tightly with proteins into a structure called chromatin. The team used a method called FAIRE (formaldehyde-assisted isolation of regulatory elements) to find the open chromatin regions and study variants picked up by GWA studies.

With the knowledge that many associated variants are not located inside protein-coding regions, but outside – possibly at regions that are involved in gene regulation – the researchers studied variants by screening genetic regions associated with blood traits in two blood cell types.

“GWA studies have been very successful in allowing us to home in on the biologically relevant parts of the genome, but we need to build functional data sets in all human cell types to convert initial findings into biological mechanisms. This study is one such example and shows the power of integrating genomic and biological data.”

Dr Panos Deloukas Wellcome Trust Sanger Institute

The scientists investigated one region on chromosome 7 that was ‘open for business’ and contained a variant associated with platelet characteristics. This region was open in cells that form the platelets found in blood (megakaryocytes), but not in cells that form red blood cells themselves (erythroblasts).

The scientists showed that this variant is functional by affecting the binding affinity of EVI1, a transcription factor controlling gene activity. The regulatory variant influences the expression of PIK3CG, a gene involved in platelet biology. Mice depleted of PIK3CG showed expression differences in several key platelet genes including Von Willebrand factor (VWF). Mutations in VWF cause the most common bleeding disorder called Von Willebrand disease1. The researchers found candidate functional variants at a further six GWA regions, providing opportunities for further discoveries with biological consequences.

“The initial success of our strategy has given us confidence that we can apply it to uncover genetic variants associated with different cardiometabolic traits, in particular coronary artery disease, which we are currently studying. We are finding many associations and we need a pathway to identify the functional variants and understand their biological meaning. We have shown this approach is one promising route towards that goal.”

Dirk Paul Sanger Institute, who led the research

This successful study is the results of a collaboration between investigators at the Wellcome Trust Sanger Institute; members of Professor Willem Ouwehand’s research team at the Department of Haematology, University of Cambridge; NHS Blood and Transplant, as well as investigators from the MRC Biostatistics Unit, Cambridge; Cambridge Institute for Medical Research, University of Cambridge; Department of Vascular Medicine, Academic Medical Centre Amsterdam; Department of Twin Research and Genetic Epidemiology, King’s College London; and the two international consortia, CARDIOGENICS and MuTHER.

More information

1. Von Willebrand disease produces the most common hereditary coagulation abnormality in humans as a result of a deficiency of a protein that is required for platelet adhesion. It causes a bleeding tendency, usually in the form of easy bruising, nosebleeds and bleeding gums and women may experience heavy menstrual periods and blood loss during childbirth.


This work was funded by the Marie Curie Initial Training Network ‘NETSIM’ and supported by the Wellcome Trust.

Participating Centres

  • Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
  • Department of Haematology, University of Cambridge, Cambridge, UK
  • National Health Service Blood and Transplant, Cambridge, UK
  • MRC Biostatistics Unit, Cambridge, UK
  • Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  • Department of Vascular Medicine, Academic Medical Centre Amsterdam, Amsterdam, The Netherlands
  • Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK


Loading publications...

Selected websites

  • The Wellcome Trust Sanger Institute

    The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.

  • The Wellcome Trust

    The Wellcome Trust is a global charitable foundation dedicated to achieving extraordinary improvements in human and animal health. We support the brightest minds in biomedical research and the medical humanities. Our breadth of support includes public engagement, education and the application of research to improve health. We are independent of both political and commercial interests.