2017 NETP Investigator Vignette

Title: Whole-Genome Sequencing in Parkinson’s Disease

Investigator: Andrew Singleton, PhD; National Institute on Aging

Our work really centers around understanding the genetics of disease, with the whole idea that, by understanding genetics, we can find points of therapeutic intervention. What are these processes that go awry, and are there places in this process that we can intervene and stop the disease?

The awards that we’ve received from the DoD have really followed a natural path of discovery. So, the work that we did in the initial award has led us to ask additional questions. That work has been supported by the DoD has led us to other ideas and further data sets and, again, that work’s been supported by the DoD.

The technology changes in genetics in general have just been incredible over the last 15 years or so. We were one of the first labs to perform Genome-Wide Association Studies. So we went from a space where we were able to look at two or three variants in a few hundred individuals every day to one where we could look at hundreds of thousands in a hundred, two hundred, three hundred individuals every single day. And it was just an incredible transformation.

The basic idea of GWAS is to look at a very fine scale in the genome in large numbers of patients and large numbers of controls. So you can look at 20 million genetic variants in 20,000 people with disease and 20,000 people without. And you look for differences in the distribution of those genetic variants. So what this gives you is a map of genetic variability that predisposes to or protects from disease. Once you have that map, of course, you have regions of the genome that you know contain genes that play a role in disease or play a role in protecting against disease. And using those to understand the disease process is really what we do.

The current work that DoD supported has really centered on whole genome sequencing, so the ultimate genetic technology in a way, we’re not looking at a focus-type of genetic variability, we’re not looking at a focus-region; we’re sequencing the whole genome in roughly 5,000 individuals. This is completely transformative. It’s the largest genomic study in Parkinson’s disease that I know of. Our idea in doing this is not only to use genetics to understand the disease basis, but also to generate data that can be shared openly with others. So we’ve really created a consortium of willing researchers, willing clinicians, who have contributed samples, contributed patients, and we’re making that data available to all of those researchers and to people outside of the community.

The data production is finished; everyone that is going to be sequenced, for this phase, has been sequenced; but we’re really still working on the analysis.

So we’ve gone from a space where it was hundreds of millions of dollars to sequence a genome to one now where we can do it for $1,000, and you can imagine just the change that that allows that your ability to ask questions that you never thought you’d be able to ask is just incredible and incredibly exciting.

Genome-Wide Association Studies are a very powerful technique, but they require large groups of individuals—20,000, 30,000 individuals. And there’s no way that one lab or one clinician can collect all of those individuals. So we have to be very collaborative, and the types of support that we’ve gotten from the DoD really allows us to be collaborative. It allows us to reach out to other researchers around the world and around the U.S.

We’re part of the International Parkinson’s Disease Genomics Consortium, and this involves groups in France, the UK, Germany, Holland, Iceland, really working together very, very closely and sharing data in an unfettered way.

I love the DoD program. It’s really been a game-changer for my lab. It’s allowed us to do experiments that would have been very, very difficult to do before. But more than that, it’s allowed us to effect collaboration and really act as a hub for collaboration with other labs around the world. This has been a wonderful thing. I think that the genetics community for Parkinson's disease has really benefited a great deal from the DoD program.