The UK's Academy of Medical Sciences, a network of national biomedical scientists from commercial and academic organizations, last week published a report calling for increased investment into genome-wide association studies, and provided recommendations for how findings from the research can be made more useful for pharmaceutical and biotechnology companies.
The report, entitled "Genome-wide association studies: understanding the genetics of common disease," is the result of an October 2008 forum hosted by AMS that drew representatives from academia and industry that discussed how to better design GWA studies and how to better translate their findings into clinical use.
AMS President Sir John Bell told BioArray News this week that the academy hosted the 2008 forum to "engage the pharma and biotech industries" and charities that participate in projects with AMS on topics of interest.
"There was an issue about whether GWAS had anything to offer to industry, what these studies have achieved, and whether they had information that industry should use," Bell said. "It was clear from talking to forum participants that industry didn't really know what to do with the GWAS data, so that was the basis for the meeting," he said. AMS usually publishes reports based on information gathered at its forums with the aim of reaching a global audience. "It’s a place that people turn to for relatively authoritative reports on key biomedical issues," he said.
In the report, available here, the AMS describes GWAS as a "powerful new tool for deciphering the role of genetics in human biology and common disease," but makes a number of recommendations for researchers designing new GWA studies to "further capitalize on the opportunities and secure real benefits for healthcare."
One challenge for GWAS, the AMS states in the report, is "moving from a statistical indication that a gene variant or region of DNA is involved in a disease, to locating and identifying causal variants and the associated biological pathways." This AMS calls for "greater integration between three historically distinct approaches to disease causality: genetic mapping, epidemiology and studies of pathophysiological mechanisms" to meet this challenge.
Additionally, AMS said there is a need to identify additional factors that contribute to genetic variance, including the role of SNPs, CNVs, and epigenetics. Surveying these other variants will require the collection of samples from diverse populations for multiple diseases that have "some commonality of clinical datasets, patient consent and data access arrangements," the group said.
AMS also sees a case for integrated epigenetic GWA studies that would combine sequence-based quantitative genetics and epigenome dynamics. "Crucial to this goal" will be initiatives that develop high-resolution reference epigenome maps such as the Alliance for the Human Epigenome and Disease, it stated in the report.
The group also noted that researchers must have access to high-quality data from prospective studies as well as access to population-based samples such as the UK Biobank and disease registries. There should also be further investment in bioinformatics and statistical methods to interpret sequence data, and tools must be developed to assess gene-gene and gene-environment effects and clinical endpoints, AMS advised.
Who should foot the bill for these investments? Bell said that funding agencies will increasingly demand cooperation between different actors to assure access to quality samples and informatics support before financing a GWA study.
"The money to support these studies should go to those who bring in all the various players, such as those who have patient collections and those with the interest to look at them," Bell said. Studies that have been "successful so far have been ones where the scientific communities have been able to work together," he said, citing as an example research into diabetes.
In its report, AMS also pointed to a need for studies of differences in gene expression using diverse tissue types, and it urged the development of improved in vivo and in vitro models for assessing human causal variants.
The ultimate goal is to begin to translate the "wave of genetic findings" on common diseases into improved diagnostics, preventions, and treatments, AMS said. The academy also believes GWA studies could contribute more to understanding genetic variation if their results were transferred to other populations, if re-sequencing studies were conducted to find rare variants, and if there were more cohort studies, AMS advised.
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To meet these objectives, AMS appeared to endorse a second wave of GWA studies, and Bell agreed that additional GWA studies will be necessary to provide results that could be clinically relevant.
"The first wave of GWA studies illustrated that the effects of variation on disease are real and reproducible but the magnitude of the effect is often small," Bell said. In second-wave studies, researchers will "almost certainly want to look at CNVs, epigenetic modifications, and other sources of variation," he said.
Both Affymetrix and Illumina have predicted a second-round of GWA studies that will look at rare variation across populations. Illumina, for instance, recently launched its 4-million-feature HumanOmniChip, which includes content derived from the 1000 Genomes Project to support such endeavors (see BAN 5/19/2009).
The "real question" for researchers will be how much do these features help explain human disease, Bell said. "I think that gives us [a direction] for where we are likely to go."
According to Bell, pharma and big biotechs have yet to embrace the information from published GWA studies. As the second wave of studies progresses, Bell said that the academy will see how its pharma and biotech members react."It will be interesting to see if they do [take interest in this information] because there are some interesting data being found that could play a role in drug pathways," he said.
Not all scientists involved in GWA studies have endorsed the idea of moving on to a larger, second round. In an article published in the New England Journal of Medicine in April, for instance, David Goldstein, director of the Center for Human Genome Variation at the Institute for Genome Sciences and Policy at Duke University, recommended that researchers turn away from large-scale GWAS and instead focus on looking at rare variation in "thoughtfully selected" individuals.
"Even though genome-wide association studies have worked better and faster than expected, they have not explained as much of the genetic component of many diseases and conditions as was anticipated," Goldstein wrote. "We must therefore turn more sharply toward the study of rare variants" (see BAN 4/21/2009).
Bell said that Goldstein presented at the October 2008 forum and the AMS took his views into consideration when preparing its report. He noted that Goldstein's research focuses on HIV, and especially on genetic resistance to contracting it.
"That’s a disease where if you have environmental exposure and you haven’t acquired the disease that you should have acquired, the chance of you being genetically different from someone who did acquire it is high," said Bell. In that case, it might make sense to use second-generation sequencing to look at a few individuals for the presence of rare variation. "It's harder to do with diabetes, cancer, or vascular disease," he added.
Bell said that Goldstein and others agreed at the October meeting that there was "absolutely a place for both approaches." He also said that it is likely AMS will hold more forums on the topic in the future.
"This is an area that we are likely to come back to;" Bell said. "This space is moving so quickly. You can't pick up a copy of Nature Genetics that isn't full of this stuff."