Wellcome Trust Case Control Consortium
The mapping and sequencing of the human genome and the development of new technologies that allow much larger numbers of patients to be screened have now provided the tools to enable researchers to uncover the genetic origins of common diseases in a robust and reliable way. The Wellcome Trust Case Control Consortium - more than 20 leading groups of researchers from across the UK - pioneered the use of these tools to analyse a dozen common diseases, on a scale never previously attempted.
The Consortium looked at five hundred thousand points of variation in the genome (single nucleotide polymorphisms or SNPs) in 2000 patients for each disease and 3000 controls. Researchers then sifted this mountain of data to pick out variants more common in patients than in matched controls - a sign that the variant is affecting the risk of disease.
The findings
The Consortium identified more than 30 genetic factors contributing to diseases including heart disease, type 1 and type 2 diabetes, Crohn's disease, rheumatoid arthritis and ankylosing spondylitis. The number continues to increase with more detailed analysis and follow-up of the data.
As well as identifying parts of the genome that potentially influence a person's susceptibility to or protection from certain diseases, the data generated have also hinted at previously unknown links between some conditions.
One of the most exciting and unexpected of these links is the discovery that variants in a gene called PTPN2 are common both in people with type 1 diabetes and in people with Crohn's disease. While type 1 diabetes is well known to be associated with rheumatoid arthritis, autoimmune thyroid disease and other immune disorders, a link with Crohn's disease was somewhat surprising.
Crucially, the statistical associations are reliable - the sample numbers are large and the results obtained from one population were replicated in other populations, often in other countries.
The approach also led to the identification of genes associated with other characteristics, such as weight (FTO gene) and height (HMGA2). Someone with two copies of the 'big' FTO allele is on average 3 kg heavier than a similar person with no copies, while having two copies of the 'tall' HMGA2 variant adds just under 1 cm to a person's height.
The individual effects of each susceptibility gene are not large, so they are of limited value as predictors of disease risk in individuals. Far more important are the insights into disease processes they provide, along with the valuable new avenues for drug development they open up.
The importance of the research was reflected in a slew of commendations and awards. Science magazine declared human genetic variation the 2007 breakthrough of the year, while the Consortium's main Nature paper was the Lancet's paper of the year. The Nature paper and the paper on coronary heart disease were the American Heart Association's top two papers of the year. And Scientific American put the work of the Consortium top of its annual 'SciAm 50' awards for research and innovation.
Individual research groups are following up on the exciting leads provided by the Consortium's work, to identify the biological function of the genes identified and their role in disease processes.
Copy number variation
The Consortium was also awarded over £7 million to examine the role of another type of genetic variation in humans called copy number variants (CNVs). While SNP analysis focuses on variation in individual letters of DNA code, copy number variation involves the deletion or duplication of chunks of DNA. CNV appears to be quite common, affecting more than 10 per cent of the genome, and has already been linked to several human conditions.
WTCCC2
In April 2008 the Trust announced a £30 million follow-up to the WTCCC's first phase. The series of studies, which will involve the analysis of DNA samples from 120 000 people, should provide information on the genetic basis of 25 diseases, including multiple sclerosis, asthma and schizophrenia. It will also explore the genes that influence learning in children, and people's responses to statins, drugs used to treat high cholesterol.
The new series of genome-wide association studies involve at least 60 institutions across the world, including over 20 from the UK. Researchers will examine between 500 000 and 1 million SNPs, as well as a comprehensive set of CNVs.
WTCCC3
In January 2009, the Trust provided support for a further round of genome-wide association studies. These include 5 WTCCC-collaborative studies to be carried out in WTCCC3 and 5 independent studies, across a range of diseases. Many of the studies represent major international collaborative networks that have together assembled large sample collections.
WTCCC3 will perform genome-wide association studies on primary biliary cirrhosis, anorexia nervosa, pre-eclampsia, and the interactions between donor and recipient DNA related to early and late renal transplant dysfunction. The WTCCC3 will also carry out a pilot in a study of the genetics of host control of HIV-1 infection.
See also
Related news
- Common copy number variations unlikely to contribute significantly towards common diseases
- Q&A: Copy number variants
- Scientists lift lid on genetics of coronary artery disease
- Feature: Linking genes to disease
