Common copy number variations unlikely to contribute significantly towards common diseases

A study of the genetics of common diseases, including diabetes, heart disease and bipolar disorder, has found that commonly occurring copy number variations - duplicated or missing chunks of DNA in our genome - are unlikely to play a major role in such diseases.

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Professor Patricia Munroe
Professor Patricia Munroe

Scientists at Barts and The London School of Medicine and Dentistry (Mark Caulfield, Graham Hitman, Philip Howard, Toby Johnson, Abiodun Onipinla and Patricia Munroe), who are part of the Wellcome Trust Case Control Consortium (WTCCC), led the study which is published online in the journal Nature.

In 2007, the WTCCC published the results of the largest ever study of the genetics of common diseases, revealing for the first time a number of genes which were found to increase the risk of developing certain diseases. Since then, dozens more genes have been found.

Despite the large numbers of genes discovered, scientists are still some way off explaining all of the heritability of the diseases. For example, for type 2 diabetes, there are now around 30 genetic variants known to influence susceptibility to the disease, but these only account for about 10 per cent of the known inherited risk of developing these conditions.

One theory for this so-called 'missing heritability' was that it might have been caused by copy number variations (CNVs). These mainly occur when copies of the genome are passed down from parent to child. Just as mutations in the genome can give rise to different forms of genes, so whole segments of the genome may end up being duplicated or deleted - these are known as CNVs. CNVs have already been found, however, to cause disease in rare cases. For example, deletions of part of chromosome 16 have previously been shown to lead to severe obesity from a young age.

Researchers from the WTCCC analysed common CNVs in DNA samples from 3000 healthy volunteers and compared them to 16 000 patients - 2000 each with bipolar disorder, breast cancer, coronary artery disease, Crohn's disease, hypertension, rheumatoid arthritis, type 1 diabetes and type 2 diabetes.

The team identified and confirmed three loci (genetic regions) that contained a commonly occurring CNV and were also associated with common disease. However, all three loci had been identified previously by searching for changes in single letters of the DNA code (known as single nucleotide polymorphisms, or SNPs). By comparison, this technique, used in the original WTCCC study, identified 24 genetic loci. None of the three CNV loci is believed to be a 'functional variant' - in other words, it is unlikely that they contribute to disease.

The research was funded by the Wellcome Trust and the individual disease cohorts were funded by the Medical Research Council, The British Heart Foundation and Diabetes UK.

Mark Caulfield, Director of the William Harvey Research Institute, said: “This study represents a further significant advance in our understanding of the genetic basis of common disease. The ability of the UK to be the first in the world to do an experiment of this scale is a testament to vision of the Wellcome Trust, the Medical Research Council, British Heart Foundation and Diabetes UK who funded creation of the cohorts and this ambitious experiment.”

Professor Graham Hitman from the Blizard Institute of Cell and Molecular Science said: “Around 30 genes have been identified to be associated with type 2 diabetes; all but three in the last three years. In the Nature paper we describe an association between diabetes and a copy number variant of a gene called TSPAN8; this gene had been previously identified by studying SNPs."

Professor Patricia Munroe from the William Harvey Research Institute said: “The hypertension results do not show an association with the CNVs tested. However, significant progress has been made within the past year with the identification of 13 common variants associated with blood pressure.”

"It seems unlikely that common CNVs play a major role in the genetic basis of common diseases, either through particular CNVs having a strong effect or through a large number of CNVs each contributing a small effect," said Dr Matt Hurles from the Wellcome Trust Sanger Institute. "This is certainly the case for the diseases that we studied, but is likely to be the case for other common diseases, too."

"There was a strong view that CNVs would be important for common disease, and that they would explain much of the missing heritability," says Professor Peter Donnelly from the University of Oxford, who chairs the WTCCC. "We now believe this is not the case. Our results will be surprising and disappointing for some parts of the community."

Professor Donnelly believes that the estimates of heritability may have been overstated, and there is consequently less missing than was previously thought. The remaining genetic contribution to disease will likely comprise rare CNVs and rare SNPs, and epigenetic factors, as well as many more common gene variants and, to a lesser extent, common CNVs.

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Joel Winston
Faculty Communications Manager (Medicine and Dentistry)