The Sequence 9/25-10/1

Parkinson's Disease Risk Variant Identified in People of African Ancestry

Revealing the Faces and Voices of Parkinson’s Disease; Illustration by Randell Pearson for PD Movers, supported by Columbia University Department of Neurology

Parkinson's disease risk variant identified in people of African ancestry

Parkinson’s disease (PD) is a movement disorder characterized by stiffness and trembling of the arms and legs that eventually affect’s one’s ability to walk, talk, and do simple tasks. Up to 40% of affected individuals in certain populations carry a pathogenic variant, or harmful change in the DNA, in one of the two genes that most commonly cause PD: GBA1 or LRRK2.

Today we focus on a genetic variant in the GBA1 gene that was newly identified by an international team of researchers who are part of the Global Parkinson’s Genetic Program. The variant was identified among affected people of African ancestry and not among affected Europeans.

We’ll discuss why the variant itself is interesting, what clinical value it has, and the relevance of this discovery as it relates to the importance of diversity in genetic research.

Why is this genetic variant interesting?

Let’s start with the gene in which it was found. The GBA1 gene codes for β-glucocerebrosidase, a protein that acts as a recycling center in the cell; it breaks down toxic substances in the cell. If GBA1 is not working properly, and therefore there is a loss of β-glucocerebrosidase, there will be a build-up of toxic substances; namely alpha-synuclein protein. This build-up of toxic protein causes neurodegeneration and the symptoms we see in PD. To be clear, there have been genetic variants previously associated with PD in GBA1, but none associated with a higher risk for PD specifically among people of African descent. 

Now let’s discuss this specific variant. Prior variants have all been found in the coding region of GBA1 (i.e. the part of the DNA in the gene that makes protein), and so it has been safe to say that β-glucocerebrosidase (the protein), was disrupted in the manufacturing process. The new variant, however, is intronic. This means it falls outside the coding region and likely has a different mechanism of causing PD. It might be responsible for messing with that recycling activity in the cell in a different way. For example, instead of affecting the manufacturing of the protein, it could be affecting the expression of the gene. Important, because a different mechanism of disease means a different mechanism of researching potential treatments. Additionally, potential treatments could be harder to study, as it’s a little more difficult to pinpoint the way intronic variants affect gene expression in comparison to coding variants. I’ll talk about this more later. 

What does this mean for genetic testing on the day-to-day

At the most basic level, it means that we know about a new genetic variant that increases the risk for PD in people with African ancestry that we didn’t know about before. Therefore, there’s a greater possibility of being able to detect that variant when testing someone with PD, allowing for proper counseling on the cause of the patient’s PD and the risks for family members (in addition to PD, risks include the potential to develop Gaucher disease).

But like many things, it’s a bit more complicated than that. 

Remember that I said this is an intronic variant. Depending on the sequencing technology being used by the lab performing testing, it may not be picked up. Tests that are using either an exome sequencing backbone, i.e. looking at only the coding regions of DNA, and most definitely tests that are only looking for targeted variants, will miss this variant. So will tests that may be looking at introns, but using reference datasets that do not adequately match an individual’s genetic ancestry. All this to say: the variant can still be easily missed.

Seems like it’s a big deal that this variant was only identified in people with African ancestry. Why is that?

It is. That’s because there is a lack of information about the genetics of PD in non-European populations. The reason is that there is a lack of research on PD in non-European populations. The studies that have identified genetic variants that explain 16 to 36 percent of the heritable risk of Parkinson's disease have mostly included people of European descent. This study, however, analyzed genetic data from 197,918 individuals with African or African admixed ancestry.

This is why efforts in ensuring diversity in datasets like the human pangenome as well as research efforts like the All of Us research program are so important.

What’s the takeaway?

The identification of a genetic variant among affected people of African ancestry with PD is undoubtedly exciting, but I wanted to take the opportunity here to speak on some practical implications that may be missed.

This finding doesn’t mean that people with African ancestry can immediately expect more efficient diagnoses of PD. It still takes the work of an up-to-date lab, an informed genetic counselor, and and/or an aware patient to make sure this information is fruitful. Additionally, although a step in the right direction, the study certainly highlights the need to include more diverse populations in genetic research so that even more variation like this can be identified.

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Newsletter Sources:

1. https://www.neurology.columbia.edu/file/1518/download?token=kcHPdnW7

2. https://medlineplus.gov/parkinsonsdisease.html

3. https://www.gimjournal.org/article/S1098-3600(23)00920-6/pdf

4. https://n.neurology.org/content/70/24/2277

5. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(08)70117-0/fulltext

6. https://www.ncbi.nlm.nih.gov/books/NBK1223/

7. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00283-1/fulltext

8. https://gp2.org/

9. https://medlineplus.gov/genetics/gene/gba/

10. https://theweeklysequence.substack.com/p/the-sequence-51-57

11. https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-022-01073-3

12. https://www.genomeweb.com/neurological-psychological-disorders/gwas-links-gene-variant-parkinsons-disease-risk-people-african?utm_source=Sailthru&utm_medium=email&utm_campaign=GWDN%20Thurs%20PM%202023-08-24&utm_term=GW%20Daily%20News%20Bulletin

13. https://theweeklysequence.substack.com/p/the-sequence-58-514

14. https://allofus.nih.gov/

15. https://www.genome.gov/genetics-glossary/Intron

16. https://www.rarediseasereview.ca/publications/2018/3/8/an-unexpected-link-between-gaucher-and-parkinsons-disease