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'Are we there yet?' ask geneticists of disease prediction

20 April 2009
Appeared in BioNews 504

One of the most innovative developments to arise from the completion of the Human Genome Project in 2003, and the International HapMap Project in 2005 has been the exploration of how and why changes in DNA can predispose individuals to disease. A popular method for identifying causative sequences has come under reappraisal by an international panel of geneticists, writing in last week's edition of the New England Journal of Medicine. It represents that for the first time the debate has reached the public forum.

Genome-wide association studies (GWAS) involve the search for genetic associations with observable traits, including disease. When a single change in DNA can be held culpable (this is called a monogenic disease), an association is relatively straightforward to make. Huntingdon's disease and cystic fibrosis are now both well-characterised monogenic conditions. Other heritable diseases are more complicated, since they are usually caused by a number of genetic subtleties. This finding has come as no surprise. The current dispute arises because the majority of DNA variations identified in studies so far transpire to carry only little risk for individuals, typically in the range of 1.1 to 1.5-fold increase in risk.

Dr David Goldstein, of Duke University, North Carolina, US, emphasised that the burden of genetic disease is carried by hundreds of very rare DNA variations. This could explain why so little correlative information has been gleaned from such studies. For drug companies hoping that a specific biochemical pathway will be implicated in any given disease, this is depressing news.

'In pointing at everything', Dr Goldstein writes, 'genetics would point at nothing'. He preaches only 'diminishing returns' will result from further association studies, and supports instead investment in sequencing entire genomes of affected patients. 'If you ask what is the fastest way for us to make progress in genetics that is clinically helpful', he says, 'I am absolutely certain it is to marshal our resources to interrogate full genomes, not in fine-tuning our analyses of common variations'.

Dr John Hardy, of University College London, UK, and Dr Andrew Singleton, of the Laboratory of Neurogenetics in Bethesda, MD, US, disagree. 'Although the complex interplay of macromolecules is a certainty, there is benefit in taking a reductionist approach when envisioning common molecular routes toward disease'.

The Genetic Association Information Network (GAIN), a public-private partnership, has funded GWAS since 2006. The enterprise is primarily lead by the US National Institutes of Health and Pfizer Global Research & Development.

Future of disease gene hunting studies questioned
Medpage Today |  16 April 2009
Gene shows limited value in predicting diseases
The New York Times |  15 April 2009
Genetic Risk Prediction - Are We There Yet?
The New England Journal of Medicine |  15 April 2009
Genome-wide Association Studies
National human Genome Research Institute |  27 January 2009
Personal gene tests show limited use, researchers say |  16 April 2009
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