Australasian Science: Australia's authority on science since 1938

Genome–Disease Association Studies Defended

By Stephen Luntz

"Failure of candidate gene studies showed how little we knew about the basic causes of most common diseases."

Australian scientists are part of an international defence of genome-wide association studies (GWAS), a technique for determining the causes of disease that they argue has been wrongfully maligned.

GWAS compare the genomes of thousands of people with and without particular diseases. Using single nucleotide polymorphism (SNP) chips, variations in the genome are matched with the presence or absence of a disease trait.

Prof Matthew Brown of the University of Queensland admits that GWAS studies are expensive, and that this has contributed to the criticism of the approach. However, Brown argues that in the space of 7 years GWAS has produced ample results to justify the cost.

Prior to GWAS, scientists identified SNPs they thought likely to be involved in a disease based on the proteins expressed, and made direct comparisons of the health of people with different genetic combinations. However, Brown says that the guesses made as to which SNP might be involved in a disease generally proved unreliable, and few diseases were defeated this way.

“The failure of candidate gene studies showed how little we knew about the basic causes of most common diseases,” Brown says. “Even in an advanced field such as immunology, animal models of disease have not translated well to human conditions. He adds that “they have also not been very successful in identifying genes” because of the size of the animal breeding programs required.

Since 2007, when the Wellcome Trust Case Control Consortium (WTCCC) study launched the GWAS era, more than 2000 genetic loci have been associated with common human diseases. Yet even before the results of the WTCCC study were published, and tripled the number of known disease-associated genes, it was subject to attack.

Critics of GWAS have alleged a lack of therapeutic outcomes, which Brown considers extraordinary given the long delays between most forms of medical research and results.

Moreover, he says that the claim is untrue. Drugs to treat osteoporosis, arthritis, obesity and Type 2 diabetes are either in trials or already on the market as a result of the original project.

“In a period of only 5 years, a fantastic treasure trove of new, biologically relevant discoveries has been generated, and we can be confident that this will continue for the foreseeable future,” says Prof Peter Visscher of the University of Queensland’s Diamantina Institute.

Some criticism appears to arise from excessively high expectations, with some hoping that GWAS would quickly lead to the identification of the sources of all genetic diseases.

“GWAS does not do well where multiple diseases masquerade as one, for example schizophrenia, where larger studies are required to make progress,” Brown says. “There is also a school of thought that some of the studies have been too small, and we need hundreds of thousands of individuals to capture some diseases.

“An alternative theory is that the chips are designed for SNPs where the less common variation exists in at least 5% of people. We’re looking at using more dense chips that can pick up rarer variations.”

Brown says it is hard to do a proper GWAS for under $1 million dollars, and attempts at cutting costs have led to underpowered studies. However, given the results so far he draws comparisons of the number of diseases tackled in this manner with the cost of stealth fighters or military submarines.