Genetics of Parkinson’s Disease in Latino Populations

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Although genetic studies have identified several gene variants linked to Parkinson's disease, most of these studies have been conducted in populations of European and Asian ancestry. As a result, not much is known about the genes that may influence Parkinson's disease risk in Latinos. In today's episode of Neuro Pathways, we're discussing the Latin American Research consortium on the genetics of Parkinson's disease, a multi-center collaboration that aims to uncover the genetic risk factors that play a role in the development of Parkinson's disease in Latinos. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Ignacio Mata. Dr. Mata is assistant staff in the Genomic Medicine Institute within Cleveland Clinic's Lerner Research Institute. Nacho, welcome to Neuro Pathways.

Ignacio Mata, PhD:

Thank you.

Glen Stevens, DO, PhD:

So for our listeners that are out there, why don't you tell us a little bit about your background and why you came to the Cleveland Clinic?

Ignacio Mata, PhD:

Sure. So I'm originally from Spain. I grew up in Spain, in a northwest part of Spain. No very tourist area. I studied biology in college and I got really interested in genetics, especially human genetics during my degree. And I was lucky enough to get a PhD position to work in the local hospital to study human genetics. At the time, there were two different research projects that they had. They had cardiovascular research, and then they also have neurological research. And I also became intrigued about the brain during my neurology classes in college, and I decided that maybe Parkinson's or Alzheimer's could be a good topic to study, especially because it was not very well understood what the genetic factors of those two diseases was. This was back in the 2000s. So yeah. So that's how I got interested in neurogenetics. And then I came to the Mayo Clinic for a PhD fellowship for about two years, and then I decided that I wanted to be in the US.

I thought that, that was the best place for me to develop my research career. So when I was here, I did a few interviews on the West Coast. I didn't enjoy the sun in Florida as much as I thought I would, coming from a place where there's a lot of rain. So I ended up doing a postdoc fellowship at the University of Washington in Seattle, which is much more similar to where I grew up. And I really enjoyed it, and I went through the ranks, all the way to assistant professor there. And serendipity brought me to Cleveland. I came here to give a talk, invited by a old colleague that used to work at the University of Washington, and I found out that the Genomic Medicine Institute was looking for a new geneticist, and I talked to a few of the faculty. I thought that the environment here was incredible, and I thought it would be a really good opportunity for me to start my own career as an independent researcher. I applied for the job and I was lucky enough to be selected, and that's how I came here five years ago.

Glen Stevens, DO, PhD:

Well, great. Well, you're a smart man, looking at the graying population, picking neurodegenerative diseases to look at. Seems like job security.

Ignacio Mata, PhD:

Yes. Yes, yes, for sure. There was a lot of things to understand and to find. The only problem is that their funding was really bad because people didn't really believe that there was any genetic component for most of those neurodegenerative diseases that appear later on. Most of the genetic diseases are earlier on in life. So that was the hardest part, probably for the first 10 years or so.

Glen Stevens, DO, PhD:

So before we get into the genetic component about it, why don't you just tell me the scope of the disorder? How many Parkinson's patients are there out there?

Ignacio Mata, PhD:

So there's about a million in the US, about 10 million in total around the world. It affects all populations, affects both genders. Although, it looks like males, we have a higher risk, about 1.5 more than women. It affects mostly people over the age of 60, but there's also individuals even in their teens. I've seen as young as 12, that can develop the disease.

Glen Stevens, DO, PhD:

And the TV's been inundated with Camp Lejeune, and I think there was a paper published very recently that looked at an association of a chemical in the water there with Parkinson's disease. So I'm hearing a lot about Parkinson's disease. Anything you want to share about that?

Ignacio Mata, PhD:

Yeah, no, no, I think that's great. And I mean, this is really the most important part of understanding the diseases that is very complex. It's very complex from the clinical point of view. Every patient is different in the terms of what symptoms they develop, when they develop it, how they develop the progression. There's a lot of heterogeneity between individuals with Parkinson's disease. So I think that's a big signal of how complex the disease is. And now we know, now that we know a lot of the genetic causes, we know that biologically is very heterogeneous as well. I don't believe that genetics is going to explain the whole risk of the disease.

I think environment plays a huge role. And originally, when I started, most people thought that it was 100% environmental. They thought it was a virus exposure, an environmental exposure that created this manmade disease. Now, we know that there's really a combination of both ends in most cases. There's some individuals that are only genetic, so monogenic, familial forms of Parkinson's. There's others, for example, people that work in the fields with pesticides or even individuals that have gone to war, Agent Orange, seems to be also a risk factor, but then in most people, it's a combination of both ends. It's a genetic predisposition, together with some kind of environmental trigger, probably.

Glen Stevens, DO, PhD:

So certainly, it's shining a bright light on Parkinson's disease this day, specifically, from the environmental related. So we'll see what happens with that. But today, we're going to really focus on the genetics. I think there was a lot of interest in Parkinson's disease when Michael J. Fox developed Parkinson's disease, and we can maybe get to that in a little bit because he was quite young when he got it, so obviously, then you start being a little more concerned about genetic risks and those types of things, but can affect a lot of different ages, doesn't have to be just older patients, right?

Ignacio Mata, PhD:

That's correct. Yeah.

Glen Stevens, DO, PhD:

So as we move closer here, you have the distinction of being the US coordinator of the Latin American Research consortium on the genetics of Parkinson's disease. That's a mouthful. So I think you break that down to large PD.

Ignacio Mata, PhD:

That's acronym.

Glen Stevens, DO, PhD:

Makes it a lot easier using that acronym. But tell us about large PD, why it was established and what you're looking to accomplish short-term and long-term with it.

Ignacio Mata, PhD:

So this is something that I started as a PhD student, and a lot of people are surprised that a young investigator came up with this plan. And it is probably because now, it looks like a huge thing. But when I started, that was not the goal. My goal was not to have the largest consortia of non-European individuals. So I started this with a trip to Peru, actually, my first trip to Latin America, I got invited to give a talk about one of the genes that I found in Parkinson's disease back in 2005. And after my talk, I had a lot of clinicians that came to talk to me and asked me if I knew that, that particular gene had also families of Latino origin. I had to pause for a minute and I realized that I wasn't sure if there were any studies outside of European populations because I had been to study a lot of people from Spain, many countries in Europe, and then most of my patients came from the US and most of them were actually European ancestry individuals.

So I went, that night, to PubMed and looked, and there was zero papers on Latinos and this gene, specifically. And there were no, really, done on the genetics of Parkinson's disease in Latinos at all. I think there was maybe four or five papers looking at specific genes. So I talked to the clinician aside, I said, look, the truth is that I don't think this has been studied. And they said, okay, how can we do this? We don't have the resources to be able to screen. This gene is very large, it has 51 exon, is one of the biggest genes in the genome. So I talked to my boss, at the time, at the Mayo Clinic. We were screening close to two or 300 patients a week. And I said, hey, would it be okay if I ask them to send me the samples and we'll just put them with the other samples and see if we can find any carriers?

And he was nice enough to say, sure. I mean, the cost wasn't going to be huge because we already had a nice budget to be able to do this in Europeans. And that's how this got started. It was a way for me to help then identify any possible patients that had mutations in this gene. And we started to publish, more patients just started to hear about this project. Other countries in Latin America heard about what we were doing, and they started emailing me and they said, hey, we want to participate, how can we get our patients screened? And I realized that there was an opportunity for me to, perhaps, find my niche. As researchers, we're always trying to find something that might separate us to our former mentors without having to leave the disease. I felt really attached to Parkinson's disease, but I thought that it will be great to be able to create this group of researchers and clinicians that, together, could work towards understanding the genetics of Parkinson's disease in this population.

And again, we started in 2005. Nobody wanted to study populations outside of Europe, mostly because we always think about genetics, about homogeneous populations. Is the easier way to find new genes, is when you have a population that is very similar to one another and then is easier to find those small variants that might distinguish people that have a disease versus people that don't have a disease. When you have a population like Latinos where there's a mixture of the native individuals that live there, together with a lot of European, different European countries that had invaded them through the years and then even African with a slave trade. So it is a very mixed population that, from the genetic point of view, we always look like a very hard population to study.

And that's how we got started. And we didn't get, really, funding until 2011. So for six years, we were working with no funding, again, because nobody really believed that we could find anything studying such a diverse ethnic's population. So once we got the money and then we really started recruiting patients, and now we have close to 6,000 individuals for, as you mentioned, from 40 different institutions in about 13 different countries all across the Americans in the Caribbean.

Glen Stevens, DO, PhD:

So what I'd like to know now is what have you found? What surprised you? What's interesting? What did you expect? And that's what it was? Or was it all quite surprising or it's too early to tell?

Ignacio Mata, PhD:

No, no, no. We have, definitely, results, which is very... It's very nice because now we're seeing the result of all the work that we put for the last 16 years. The first studies were just looking at specific genes. And some of the things that we started to realize is that this huge mixture that exists and the different ancestries that these individuals carry, predispose them in a different way to, in this case, Parkinson's but really all the diseases. And for example, so the first study that we did with this gene LRRK2, which is very common in Europeans, was that when we studied in different countries in Latin America, we saw, almost, perfect correlation between the amount of carriers that we had for that specific variant and the percentage of European ancestry. So most of these variants actually came from Europe. It comes from one single funder, we call it a funder effect.

So probably some of the individuals from Europe that traveled to Latin America to conquer the continent, actually, brought with them some of these mutations and individuals that are mostly Europeans in some of these Latin American countries have a much higher risk to carry one of these variants. And in countries like Peru, for example, where most of the individuals have about 75% indigenous and meridian ancestry, there was a lot of these variants that we didn't find. That didn't mean that they didn't have Parkinson's. In fact, it seems like they have the same amount of Parkinson's that we see in other countries, but it looks like, at least, genetically, the cause is different. It might be a different variant in the same gene or different genes that we haven't identified. So those were the original studies that we did because our cohort was not large enough. Now, we're getting to having thousands of numbers and our cohort is allowing us to do much larger studies.

So the latest one that we have done is a genome-wide association study or GWAS, we call GWAS, where you compare a very large number of cases with the disease that you are trying to study and a large number of controls that are match in age, gender, and hopefully, where they're coming from in terms of ancestry. And then you look for variants that are in a different frequency between the two groups, telling you that if it's more frequent in cases, then it might be a risk variant versus something that it might become more common in controls, where maybe it's a protective variant. And this association studies has allowed us to really start to understand what the genetic architecture of Parkinson's disease is in Latinos. And we know that it's about 80% similar to Europeans, but there are new genes that we have identified, mostly associated to the ancestry that is not the European ancestry. So mostly associated to both the indigenous and the African ancestry.

Glen Stevens, DO, PhD:

And average number of causal genes?

Ignacio Mata, PhD:

So in total for Parkinson's disease, we have about 24 that are familial. If you have a variant in those genes, you are mostly going to develop the disease. So we call them causal variant. And then there's probably over 100 that we have identified that are risk variants. This means that these variants do not cause Parkinson's but increase your risk. And most of us carry several of these variants. So we use something called polygenic risk score. So we calculate how much each of them add and how many you carry, and then we can tell what is your actual total risk comparing all those variants. So again, it's very complex, as I mentioned at the beginning, biologically, it's very complex disease and probably, every patient has a different combination of different variants in different genes, different pathways affected, and that's why I think it's very hard to understand the cost and also to treat it because we are really treating patients as a whole, as one disease. But most of us believe that Parkinson's disease is actually multiple diseases, is not only just one.

Glen Stevens, DO, PhD:

One of my fellows said I should ask you about LRRK2 because that's always involved. You mentioned it briefly, do you see it in other disorders as well, or?

Ignacio Mata, PhD:

Yeah. So there are mutations in LRRK2 that affects IBD, for example, some cancers. There are other genes also, especially the early onset genes are also affecting certain types of cancers, especially like melanoma. So there's definitely cross pollination of genetics and different variants. One thing that we're very surprised is that there's not a lot cross in between Alzheimer's and Parkinson's disease. We think that neurogenic diseases are fairly similar. They both have aggregation of a protein that shows up in the neurons of the affected brains. So we always thought that they would maybe be more cross genetic overlap, but we don't see that. But we do see it with other diseases, for sure.

Glen Stevens, DO, PhD:

So you mentioned, initially, that it was thought that 100% of this was genetic and now it's less, where do you sit now? What percentage of patients? I guess maybe, again, you can make the argument, it's all... Everybody has some predisposition.

Ignacio Mata, PhD:

So we thought it was 100% environmental, and now we know that there's some genetics. I don't think we ever believed that it was 100% genetic. So right now, with all the genes that we have, we can explain about one third of the heritability. And we think that heritability in Parkinson's is around 20 or 30%. So that means that 30%, it's probably coming from genetics, 70% is coming from other things, at least with the genetics that we know because we have tunnel vision about what things we're looking in genetics is, we're always looking at the coding variants in the exons. There's other variants outside of the exons, what we call the garbage DNA, that we now know is not garbage. There's also epigenetics that can happen, and a lot of those topics have not been really explored in Parkinson's disease.

Glen Stevens, DO, PhD:

So a lot of people are getting genetic testing, have a kit sent for Christmas, 23andMe, these various things. Does it test any of these genes?

Ignacio Mata, PhD:

Yeah. Actually, that's very funny that you ask this because 23andMe tests for LRRK2, for the most common LRRK2 variant. And the reason why is because actually, so 23andMe is owned by Sergey Brin. And Sergey Brin is the Google guy, and his mom has Parkinson's. She got tested and she has the LRRK2, and he also carries the LRRK2 variant. So he put a lot of money to make sure that 23andMe actually had this variant. And in fact, 23andMe has one of the largest cohorts of Parkinson's patients in the world, because of that, they were offering genetic testing for Parkinson's patients for free. But again, one of the problems with this do at-home testing is that it doesn't come with the genetic education or counseling, and being such a complex disease in terms of genetics, sometimes it's really hard to make up what that means, especially for people that don't have any symptoms because it means that you have a high risk, but it doesn't mean that you are going to develop the disease and you don't even know when.

So I always tell people to be very careful when you do those kind of tests, because you might find something that you don't want to know. But it is definitely included in the 23andMe test.

Glen Stevens, DO, PhD:

My kids got that for my wife and I for Christmas a few years ago, and I think it was just to torture us. And I've been very, very careful not to look very specifically at anything. And I still don't know if that's good or bad. But I never think about it, and I don't worry about in anything.

Ignacio Mata, PhD:

I mean, there are things that, definitely, like cardiovascular disease, there are things that you can do, things to protect yourself. But my bias to people, especially to Parkinson's disease family members, is that if you have a family history of the disease, you might want to avoid some of the environmental factors. The genetics, you can't do anything about it, unfortunately. So just be careful with environmental factors that we know, try to not get exposed to pesticides, some of these chemicals, heavy metals, those things. And then, although, we all should be doing this, you should eat a healthier exercise. We know exercise has a huge protective effect, both for Parkinson's, but also for the progression once you develop the disease.

Glen Stevens, DO, PhD:

So who should be tested?

Ignacio Mata, PhD:

So we recommend that people that have a family history, or if you have a very early age of onset or earlier than 40, for example, 40 years old, those people have a higher likelihood of having a genetic form of Parkinson's. So we think that those individuals should be doing first. However, things are changing a lot. And what I'm saying is because, something that I never thought it would happen in my lifetime, and I always was very careful when I talked to patients about genetic research, was that, oh, I said, well, if we find a gene that might be 20, 30, 40 years before something gets developed, so things go really slow. Now, with the technology and the access and the resources that we have, now, we have, probably, close to 10 different ongoing clinical trials for specific genetic forms of Parkinson's disease. And what that means is that, actually, now having the genetic information might help you or qualify you to participate in one of these clinical trials.

These are really, on my mind, the first trials that are trying to slow or stop the disease. And most of the trials that we have are to deal with the symptoms, but once you try to attack the biology of the disease, I think you have a better chance of actually slowing the progression. So now I'm trying to tell people that, at least, testing for these genes where there's a possible clinical trial, for everybody, might be worth it, because even if you don't have a family member affected, it doesn't mean that you don't have one of these variants because they are common in the Parkinson's cohorts. And again, it will open a lot of doors to participate in this clinical trial. So I think that things are switching all the time depending on all the advances that we have.

Glen Stevens, DO, PhD:

And are there other underserved populations out there that we need to do the same thing with?

Ignacio Mata, PhD:

Yeah. So there's a couple of initiatives here in the US. The main one is called BLAAC PD, which is trying to engage with the African American Black community here in the US. I think that's a big project because it's a big population. Through the Global Parkinson's Genetic project or GP2, we're also trying to go to Asia, but especially Southeast Asia, instead of Mainland China or Japan, where most of the studies in Asia are coming from. And then India, India is a country with more than 1 billion individuals, where there's no genetic research that was being done. So now through GP2, we're also trying to engage with individuals there, and we have about 20,000 samples that have been collected. So I think we're going to be seeing a lot more genetic studies from this underrepresented populations.

Glen Stevens, DO, PhD:

So if somebody wanted to look at an initiative in one of these other populations, any words of wisdom for them that you could share with what you've been through over the years?

Ignacio Mata, PhD:

And I do this a lot for the Parkinson's Foundation and The Michael J. Fox Foundation to try to advise them about how to start, especially with the Latino community, which is the one that I have the most experience. And one of the things that I tell people is that they need to have patience. A lot of the individuals that want to perhaps engage with one of these minority communities in their environment is that they think, for example, for the Latinos, they said, oh, well, I'll just translate my documents to Spanish, maybe hire somebody that speaks Spanish and that should be it. But the truth is that is a lot harder than that because a lot of the times, you encounter a cohort or a community of individuals that are not aware of what research is. They might even be afraid. There's a lot of mistrust in research, especially genetic research, in particular.

So I think there has to be a lot of education that happens before you can actually offer somebody to participate in a research project. And then the other thing that, to me, is very important is you need to bring the research to the participant and not the participant to the research. For example, here in Northeast Ohio, we have Main Campus, we're always looking at Main Campus as the hub for everything. But the truth is that the minority communities might leave one hour or two hours from here, and sometimes it's not possible for them to come all the way here to do a two, three hour research visit. So we need to work with the communities or where the communities are with the small hospitals, where these patients are being seen and bring the research to them to open it up. I think that's the other advice that I will give people, is to try to work better with the communities, and listen to the communities, listen what their needs are and how you can facilitate their participation. And I think if you educate them and you facilitate that, they'll participate.

Glen Stevens, DO, PhD:

Any final takeaways for our audience?

Ignacio Mata, PhD:

So I can tell you the story of how I got involved in Parkinson's disease, because I think it's very interesting and it has made me really, really, as I said, attached to this disease, and is that, so my research started in Spain through a grant that was paid by patients. It was the first research grant in the whole country for any disease that was actually paid by patients. It was not a lot of money but it made me, which is something that there's a big disconnection between the researchers and the patients that have the disease at their studies, that we are in the lab, they're all in other places. The clinicians are the link between the two of them. But because I was working for them, I got to talk to them. I listened to them, I gave talks to them.

So I really learned how to engage with the individuals, and I fell in love with that community. And there's been a couple of opportunities for me to move on and maybe use my skillsets to study other diseases but I always thought that I owe to them, that they put their faith into me to do research. And this fellowship is still going, this was started in 2001, they're now in their eighth different fellow, and three of us are actually in the US doing pretty high quality research. I think we have to owe to them that they put their faith into us, so.

Glen Stevens, DO, PhD:

Well, Nacho, thank you very much for joining us today. It's been very insightful, and I appreciate your time. Thank you very much.

Ignacio Mata, PhD:

Thank you for the invite.

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