Hot topic: GP2 and underrepresented populations

[00:00:40] Dr. Andrew Singleton: It's a pleasure, Sarah.

[00:00:41] Dr. Sarah Camargos: You were recently awarded with the Stanley Fahn Lecture at the last MDS conference. In your talk, you mentioned an ASAP project named GP2. Our audience is highly heterogeneous, so could you explain to our [00:01:00] listeners what these acronyms stand for and the origin of this project?

[00:01:05] Dr. Andrew Singleton: Sure, of course, Sarah. So it was a great fun to give the David Morrison lecture at MDS. And the thing that I primarily spoke about was the Global Parkinson's Genetics Project, or GP2 for short, and really in its simplest form, the aim of this project is to dramatically increase our understanding of the genetic basis of Parkinson's disease, but to do so in a global context.

So much of our understanding of disease is focused in Northern European ancestry populations and clearly if we are to understand and treat disease around the world, we need a better understanding of disease around the world. So that's the aim of the GP2 project.

[00:01:45] Dr. Sarah Camargos: Yes. And do you have an idea of the approximate numbers in regard to researchers, trainees, countries, and also patients engaged?

[00:01:56] Dr. Andrew Singleton: Yeah, approximate numbers were growing all of the [00:02:00] time, of course. I mean, a good frame of reference is that just before the movement disorders meeting we had our annual investigators meeting. We had about 270 attendees from 60 different countries. I would say in total, within GP2, we probably have somewhere in the region of a thousand researchers involved.

In the context of patients, we're aiming for about 200,000 individuals enrolled in the GP2 program, I suspect we'll be larger than that actually. We're already close to that in terms of the numbers of patients that are in the pipeline. But we've also expanded to include lewy body dementia, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome. So those will increase numbers too.

[00:02:45] Dr. Sarah Camargos: Yes. Wow. And can you tell us about the GP2 structure the workgroups and how it is organized?

[00:02:55] Dr. Andrew Singleton: Yeah, sure. So GP2 has been around for about three years and I would say the first [00:03:00] two years were really focused on operational and organizational challenges. You can imagine setting up a global consortium like this is pretty challenging because of course the rules and regulations are different in each country.

So we have a fairly large organizational structure that includes the kinds of things you'd imagine, like a steering committee and oversight committee groups that work on training and networking, groups that focus primarily on issues related to underrepresented populations, groups working on genetic analysis, all sorts of things. And really the aim of all of this structure is to democratize genetics as much as possible. The model for GP2 is that investigators join by contributing samples, but once they join, their job is not just to contribute samples, it's also to get involved and do analysis and lead papers lead new initiatives within GP2, so it's really aimed at leveling the playing field for investigators around the world and [00:04:00] getting everybody involved as much or as little as they'd like to be.

[00:04:03] Dr. Sarah Camargos: And you have data sharing as well. So if I would like, for example, to analyze your data, I can ask for it.

[00:04:14] Dr. Andrew Singleton: Yeah, there's a project proposal working group. So anyone who's a member of GP2 can propose a project, and we encourage a few things for project proposals. Primarily inclusion. So including individuals who you think would be relevant to doing that work. So when I mean relevant, I mean, in terms of expertise, but also in terms of who contributed the samples, right?

We really want representation from the groups that have contributed the samples. If an analysis is being done in, let's say, an African data set, we think the African investigators should be deeply involved in that. So that's one part. The other part is training. A really large part of GP2 is training the next generation of [00:05:00] investigators, so every project includes a training component where young investigators are taught how to do this work and have a major role in the effort. As part of the project proposal process, we also ask what resources you need. So, do you need additional expertise? Do you need computational resources? Do you need something else? So all of those things are taken into consideration and anyone and everyone within GP2 can propose projects.

[00:05:27] Dr. Sarah Camargos: And how can people, researchers and trainees enroll in the project?

[00:05:34] Dr. Andrew Singleton: Well, the first thing to do is to reach out. So if you go to our website, which is gp2.org, there's a button there where you say you're interested in contributing cohorts or samples. Then we'll contact you. We'll set up a meeting, talk over the idea behind GP2 and figure out if there's a path forward. And then once you're in, we do a whole series of things to keep people connected, newsletters, email blasts, annual meetings. We also [00:06:00] do site visits. So we'll go to regions and give training courses on data analysis, some clinical training courses too. There are also PhD studentships within GP2 that can be applied for, master's studentships. So there's lots of ways to stay involved.

[00:06:15] Dr. Sarah Camargos: Yeah. And I saw at the website that you have also a learning platform for trainees.

[00:06:23] Dr. Andrew Singleton: Yeah, so one of the things that we have tried to do is democratize data, and I think we've talked a lot about data sharing in the past, but this is a bit more than just making data available. It's making data available and accessible. And what I mean by that is not only is the data available, but we attach it to compute resources.

So if you have an internet connection, you can access thousands of processors to analyze your data. We support and pay for the data processing or the analysis that you need to do. There is a platform there that allows you to write code, share code with anyone else within the network. But of course, to do all of [00:07:00] that, you need training.

So we've developed a series of about 70 different videos and translated those into, I think now 109 different languages, where you can learn how to do genetic analysis from the most basic things up to pretty complex genetics.

[00:07:15] Dr. Sarah Camargos: Wow. And what were the outcomes of GP2 so far in terms of papers and findings and samples.

[00:07:23] Dr. Andrew Singleton: Yeah, sure. So it's really early days, of course, right? I mentioned that we're about three years in and the first two years were really dealing with operational issues. We are supported currently through 2029. So we've got a fair way to go, but we're now really starting to see all of this payoff.

In terms of samples, we have somewhere in the region of about 170,000 samples at somewhere in the pipeline. There are genetic data available on about 35,000 samples. If you go to the AMP PD platform, you can access that, data. We're also starting to [00:08:00] see results. So there's two fairly high profile results at the moment.

One led by Nacho Mata. Looking at genetic differences and similarities across populations. It's called a multi ancestry meta analysis of genome wide association studies. And this has identified around a dozen or so new risk loci and helped find maps of additional loci. And then also recently work in collaboration with UCL and University of Lagos and sites throughout the US, has led to the identification of a new risk locus in the African ancestry population, specifically from West Africa. And this is a really exciting finding. It's a new risk factor at the GBA1 locus. But it's striking in that the mechanism seems to be different to previously identified GBA1 risk alleles, and it's amazingly common.

So about half of all Parkinson's disease cases [00:09:00] from Nigeria carry this risk factor. So it's really quite striking result.

[00:09:04] Dr. Sarah Camargos: And it is also in GBA1 so it's more interesting.

[00:09:09] Dr. Andrew Singleton: Yeah, certainly. I think the mechanism is different too. So it potentially highlights some therapeutic opportunities that are a bit different in GBA1 to what we'd normally consider.

[00:09:21] Dr. Sarah Camargos: Yeah. So when you talk about opportunities, I think everybody can reach out through the website, and all the opportunities are there, right?

[00:09:32] Dr. Andrew Singleton: Yeah, you can find pretty much everything there. Of course, you can also feel free to reach out to me or any other member of GP2 who can tell you about the work that we're doing. The work is truly global. It focuses on both familial forms of Parkinson's disease, but also typical sporadic forms of Parkinson's disease.

And again, we've expanded into these other diseases that I mentioned earlier too.

[00:09:56] Dr. Sarah Camargos: Yes. Another Parkinsonism. A typical parkinsonisms. [00:10:00] Why do you think it's important to analyze underrepresented population? What's the importance beyond that?

[00:10:08] Dr. Andrew Singleton: I think that there are several reasons. First of all, I think just understanding more about disease in general is going to help us understand disease in everybody. And of course a large part of the point of genetics is to understand mechanism so that we can come up with viable points for therapeutic intervention.

I think perhaps even more importantly is as we start to move towards this era of precision medicine where we're matching the therapeutic to the mechanism in the individual. We really need to understand the basis of disease in all individuals, not just those of Northern European ancestry, right? We want to treat Parkinson's disease around the world, not just in one particular population.

So understanding the basis of disease and the mechanism of disease across populations is going to be absolutely critical if we're to realize the promise of precision medicine.

[00:10:59] Dr. Sarah Camargos: [00:11:00] Yes. And what about your predictions for a near future? Do you think we're going to get there?

[00:11:07] Dr. Andrew Singleton: Yeah, we're going to get there for sure. I mean, I think there's always going to be more that can be done. Genetics is just the start. I think we need to understand a lot more about disease in underrepresented groups, right? We know surprisingly little about disease in populations outside of northern Europe.

But this is just the start, and you can imagine, actually, that the framework that we're creating here in GP2 for genetics, could be used for so many other things. 

[00:11:35] Dr. Sarah Camargos: Epigenetics as well. 

[00:11:37] Dr. Andrew Singleton: Yeah, understanding disease course, getting biologics, looking at things like imaging, things like dementia, falls, all sorts of things like that in different populations.

But this is information we really need to gather.

[00:11:50] Dr. Sarah Camargos: Also biomarkers of the disease and progression of Parkinson's disease, what is related to progression. So you have a [00:12:00] huge amount of data to analyze and to work with.

[00:12:03] Dr. Andrew Singleton: Yeah, we do. We're creating a massive resource. And of course, we can't analyze it by ourselves. So we're looking for people to join get involved and really take advantage of this resource.

[00:12:14] Dr. Sarah Camargos: Perfect. So thank you so much, Andy, for your time with us. I think you're gonna find a lot more researchers and trainees after this.

[00:12:26] Dr. Andrew Singleton: I hope so. That's one of the most fun parts about this actually is seeing all of these new investigators come up and hopefully take our jobs in the next few years.

[00:12:34] Dr. Sarah Camargos: Yes. Thank you, Andy. Bye bye.

[00:12:37] Dr. Andrew Singleton: You're welcome. Thanks, Sarah.

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