Enabled by technological advances, genomewide association studies recently have come into their own. (See BioWorld Today, April 17, 2007, and May 7, 2007.)
This week, they set another size record, with the largest ever study of genetic factors for Caucasians that underlie seven common diseases being published by the British Wellcome Trust Case Control Consortium in Nature and Nature Genetics.
The findings are another step along the way toward moving from the consideration of genes in isolation, to how multiple genes interact to provide overall risk profile.
"It's been possible for some time now to identify rather rare genetic variants that cause major genetic disorders," Wellcome Trust Director Mark Walport told reporters at a press conference announcing the publications. Such major genetic disorders include conditions like cystic fibrosis, or genes like BRCA1 and BRCA2, where a mutation in a single gene makes developing a disease close to inevitable.
But in the bigger picture, that's a rare situation. For most common diseases, "it's your entire genotype that counts," consortium chairman Peter Donnelly told reporters at a press briefing. "And that's what makes these genomewide studies so important." Developing or not developing a specific condition, he added, "is not about one gene - it's about hundreds of genes that give you a risk threshold."
Indeed, though the specific findings presented, including a link between Type I diabetes and Crohn's disease, certainly point to new therapeutic possibilities, the most promising result to come out of the study may be its demonstration of proof of principle: that it is now feasible to uncover genetic loci that have a real but small impact on the risk of developing a disease.
The Wellcome Trust Case Control Consortium, which consists of more than 50 research groups located throughout Great Britain, focused on seven diseases - bipolar disorder, coronary heart disease, Crohn's disease, hypertension, rheumatoid arthritis and Type I and Type II diabetes - because, as the authors wrote in their paper, all seven are "common familial diseases of major public health importance both in the UK and globally."
The researchers analyzed roughly half a million single nucleotide polymorphisms, or SNPs, in DNA samples taken from 2,000 patients for each disease and one set of 3,000 control samples.
A total of 12 new strong statistical associations, or those with a probability of less than 1 in 10 million of occurring by chance, were newly discovered, and another dozen previously identified risk loci were confirmed by the study. The number of new associations uncovered at this level of significance range from none for hypertension to nine for Crohn's disease.
But many more slightly weaker associations also were uncovered, including almost 60 with a probability value of between 1 in 100,000 and 1 in 10 million. Some of those now are being investigated in even larger samples.
Again in contrast to diseases like cystic fibrosis, the newly discovered genes and their effects "are completely dominated by environmental factors," Donnelly said. He gave the example of a recent mass media headline about genes related to obesity, "Science Discovers Gene That Makes You Fat,' as an example of how not to interpret the findings. "Of course, it's not the gene that makes you fat. It's eating that makes you fat," he said.
Instead, Donnelly said, the new crop of genetic associations identifies risk factors that make developing a condition more or less likely, but cannot predict with any sort of certainty who will develop a disorder. "For the common diseases, genetics is only part of the story," he added.
That also means that screening tests for the newly discovered risk loci are unlikely to appear in the near future. Donnelly noted that for now, knowing which variant a person possesses is unlikely to lead to behavior changes - nor is it possible to say what sorts of behavior changes would be useful in the absence of understanding the underlying biology that leads to elevated risk.
Further studies by the consortium will be published later this year on tuberculosis, breast cancer, autoimmune thyroid disease, multiple sclerosis and ankylosing spondylitis.