Duplicated DNA unlikely to play role in common disease

Duplicated DNA unlikely to play role in common disease

Chunks of DNA that can frequently be duplicated or missing in our genomes are unlikely to play a major role in many common conditions, a study of the genetics of diseases including diabetes, heart disease and bipolar disorder has found. This type of genetic variation had been proposed as a possible source of some of the inherited risk of developing these conditions.

In 2007, the Wellcome Trust Case Control Consortium (WTCCC) published the results of the largest ever study of the genetics of common diseases. For the first time, this study revealed a number of genes that increased 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, there are now around thirty genetic variants known to influence susceptibility to type 2 diabetes, but these only account for about 10 per cent of the known inherited risk of developing this condition.

Just as mutations in the genome can give rise to different forms of genes, so whole segments of the genome may end of being duplicated or deleted – these are known as CNVs. CNVs mainly occur when copies of the genome are passed down from parent to child, and they have already been found 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 3,000 healthy volunteers and compared them to CNVs in samples from 16,000 patients – 2,000 each with bipolar disorder, breast cancer, coronary artery disease, Crohn’s disease, hypertension, rheumatoid arthritis, type 1 diabetes and type 2 diabetes.

However, all three regions 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 original technique used in the original WTCCC study identified 24 genetic regions. None of the three regions including a CNV is believed to contribute to disease.

‘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,’ says 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 of the Wellcome Trust Centre for Human Genetics in Oxford 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.

‘Understanding bipolar disorder and other complex diseases is as much about ruling out possible suspects as it is about identifying new ones,’ says Nick Craddock, Professor of Psychiatry at Cardiff University and a researcher involved in the study. ‘We now know that we can likely focus our attention away from common CNVs and focus on other common and rare genetic variations, which we hope will provide biological insights that will lead to important advances in human physical and mental health.’

One such study recently received funding from the Wellcome Trust and the National Institutes of Health in the US. Led by Professor Mark McCarthy from the University of Oxford, it will search for contributions of rarer SNPs towards type 2 diabetes.


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