The associate vice president of clinical research at the Parkinson's Foundation discussed a large-scale replication of rs3115534-G, a noncoding GBA1 variant tied to Parkinson disease in people of African ancestry.
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The replication drew on PD GENEration, which provides free genetic testing and counseling to people with PD in 10 countries.4 Of 26,637 participants with sequencing data, 548 carried the variant, and heterozygous carriers developed symptoms about 3 years earlier than noncarriers. Carriers made up 43.2% of participants who self-reported as Black or African American and 51.1% of those with African genetic ancestry.1 Adding the variant to the study's primary panel would raise the positive result rate in participants of African genetic ancestry from 9.9% to 56.7%.
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Kamalini Galvelis, MS: I want to start by saying that the work I presented was predominantly done by our genomics lead, Allison Dilliott, PhD. She is a brilliant scientist, and I feel very lucky to have her. We have been working together to allow PD GENEration to act as a replication or validation study for a lot of the research that's out there. This poster is specifically called "Evaluating the GBA1 Intronic rs3115534-G PD Risk Variant in the PD GENEration Cohort."
For some background, a couple of years ago, through Aligning Science Across Parkinson's and the Global Parkinson's Genetics Program, researchers found a novel GBA1 intronic variant that was carried by over 50% of the West African cohort of people living with PD in their study.3 This was really novel and interesting, because traditionally, when you look at new genes and new variants within the PD space, you tend to find them within the classically studied cohort, which is the European cohort. The fact that we found something so brand new in a diverse cohort means that there is so much more that we don't know, and we need to learn more.
That finding opened the door to a lot of conversations. What does the intronic variant actually mean in the PD space? GBA1 itself is still something we're trying to piece together and understand in its relation to PD. When we add an intronic variant to it, and the introns are also really unknown, it allows us to question what we missed and what we can learn. So, what we did in PD GENEration is try to see whether there were any individuals in our cohort who also carried the GBA1 intronic variant.
PD GENEration is a clinical research study that was started by the Parkinson's Foundation. We offer genetic testing and counseling to anyone who has a diagnosis of PD across 10 different countries. Our main goal is to collect genetic information and pass it on to researchers and scientists so that they have this big library to work from. We also take those results, validate them against a few different gene panels, and give those results back to participants on the individual level, so that participants can understand their own genetic status in PD.
What we found was really interesting. Out of the 37,000 individuals in our study, we evaluated about 26,000 of them for this GBA1 intronic variant and found that 548 of them have it. So we thought, okay, that's really interesting. Why don't we take this a step further, just like the original researchers and scientists, and compare that to self-reported race and ethnicity, as well as genetically defined ancestry?
When we looked at self-reported ancestry, over 50% of the individuals who have that intronic variant self-identified as Black or African American. When we looked even further at genetic ancestry, we found something very similar. Again, over 50% of those individuals are genetically considered African, African admixed, or complex admixed. That acted as the first validation study for the results found in the original study a couple of years ago.
I think this is important because had the original researchers not looked at diverse populations, we might never have found that GBA1 intronic variant. For us to now validate this in a completely different cohort, in a different part of the world, and still find similar results allows us to ask a lot more questions.
This is our first go at acting as a validation cohort, and that's really what PD GENEration wants to do. We want to provide genetic information so that we can help other researchers and scientists learn more about genetics in the PD space. What we discovered, too, is that there's a lot to learn about this GBA1 intronic variant. This shows that there should be more interest in understanding the mechanism of how it works, the impact it has on PD, and potentially the risk of eventually developing PD if someone has this intronic variant.
Even with all of the unknowns around this intronic variant, we're trying to understand what we need to learn for us and the community to feel comfortable giving these results back to participants. Right now, this is all done through research, so we haven't linked it back to each individual yet. To do that, we have to go back to our lab and make sure there's 99.9% certainty that this result is going to this person. But before taking those steps, we decided we need to bring the community together to talk about the pros and cons of the information we know and the information we don't know so far.
So our next step is to bring together researchers, scientists, genetic counselors, people living with PD, and basically the whole community in a focus group setting. We'll explain the pros and cons of what we know and what we don't know. Then we'll make a concrete decision: is this something we should give back to our individual participants so they learn about their genetic status, or do we need to learn a little more before we take that step? That step is a pretty finite one for a person learning their genetic status, and we take that seriously. We want to make sure that what we give back is actionable for the participant.
This was also our chance to further show that diversity in research is really important. We learn more when we include everyone who has a diagnosis of PD in the research space.
Transcript edited for clarity.
