It was a sort of perfect storm that led to the publication of the first whole-genome map of genetic variability in Parkinson’s disease. Demetrius Maragnore, professor of neurology at the Mayo Clinic, has been studying the disease since 1989, he says, and has had grants for genetic work in the field for going on 10 years. Until recently, his team approached Parkinson’s with “traditional genetic studies” looking at candidate genes and familial aggregation, he says. “Frankly, those approaches have been very disappointing for Parkinson’s disease,” he adds.
But with the introduction of high-throughput, whole-genome technology focused on SNP discovery and exploration, Parkinson’s looked much more manageable. “We jumped at the first opportunity to go forward with just such a study,” says Maraganore, who responded to a Perlegen ad he saw in Science seeking academic collaborators. That quickly led to a team effort, and Maraganore was able to track down an RFA from the Michael J. Fox Foundation for Parkinson’s Research aimed at funding “high-risk and expensive projects,” he says. His team’s proposal was chosen out of some 70 preapplications with a one-year grant for $2.8 million.
The work took less than a year. In the first two months, Perlegen genotyped “about 200,000 SNPs in 443 sibling pairs,” says Maraganore. Researchers combed through the data and narrowed the SNPs down to a second group of about 3,000; Perlegen made custom chips and performed the genotyping on those as well. The first analysis of the data was completed this summer.
The key take-home message of the study, Maraganore says, really has nothing to do with Parkinson’s. “A lot of brilliant minds in the field have been arguing [about whether we can] do whole-genome associations — when is the time, how many markers does it take,” he says. “That debate can end. The bottom line is yes, you can do whole-genome association studies with existing technologies. … Now’s the time; it’s not five years from now.”
As far as Parkinson’s goes, the upshot is that “it’s very clear that there isn’t a single gene that plays a large role in the cause” of the disease, Maraganore says. His team reported on 12 genes in their recent paper in The American Journal of Human Genetics, but he sees that as “the first 12 doubloons on the surface. The real treasure is buried beneath.” Next, Maraganore will look at various SNP combinations as well as environmental factors in the hopes of finding a clear connection between variability and outcome.
Meanwhile, the Fox Foundation is funding an international consortium to replicate the findings of Maraganore’s whole-genome scan. Maraganore, a PI for one of the groups, says he is recusing himself from the effort to encourage “truly unbiased replication.”
— Meredith Salisbury