In March 2022, the World Parkinson Coalition (WPC) hosted a webinar on genetics in Parkinson’s disease (PD) with neuroscientist Dr. Andrew Singleton. Dr. Singleton discussed how genetics can influence the onset and progression of PD, and what other risk factors exist. PD is a combination of genetic and environmental factors. Genetic factors account for 25% of risk on average. Additionally, Dr. Singleton explained how genetic research is conducted.
According to Dr. Singleton, genetics is seen as a route to discovering disease progression on a molecular level. Knowing genetic factors can predict disease and allow people to take preventative measures and therapies before showing symptoms, and can delay progression. Genetics can help identify people before they have the disease.
There are very few cases where simply having a mutation causes a PD diagnosis. For the majority of cases, other factors can cause someone to have PD. These include other mutations that haven’t been discovered, environmental factors such as pesticides, pollutants and well water, and random effects. Age may also be a large risk factor because age is related to the number of things someone is exposed to that can cause the body to break down.
This webinar was largely a question-and-answer with Dr. Singleton. Dr. Singleton was asked whether those with PD should be tested to see what risk their children have of developing PD. His answer was:
“On average, a good rule is that if a person has PD, their child is twice as likely to get PD than someone in the general population. Sounds scary, but only one in 200 get PD, so it only increases your risk to 1 in 100 (1%) which is still low. Unless you have a very strong family history of PD, then the increased risk is higher.”
For a recording of this webinar, please see this WPC YouTube webpage
My notes of the March webinar are below.
“Genetics and PD” – Webinar Notes
Speaker: Andrew Singleton, PhD, neuroscientist, National Institute of Aging, NIH
Webinar Host: World Parkinson Coalition
Webinar Date: March 24, 2022
Summary by: Joëlle Kuehn, Stanford Parkinson’s Community Outreach
What has changed in genetic research in PD in the last few decades?
Discoveries on genetics of PD. There are genes there that give you PD, and genes that increase the risk (but don’t guarantee it)
How many genes are there that actually cause PD?
There is a range of genetics. There are mutations where if you carry them and live long enough, you will probably get PD. On the other end, there are things that cause a small amount of risk. There is also everything in between.
There are around a dozen genes that cause disease. In truth, for some of those, they don’t mean you will always get the disease.
Example: LRRK2. Mutations in LRRK2 only cause PD in 30-40% of people who carry the mutation. Does not cause it, but highly increases risk.
If you select 100 people who have PD, how many would have genes that carry a high risk?
- Around 2 or 3 in 100
- There is a gene in the middle, called GBA (glucocerebrosidase) that is a risk factor mutation that is fairly frequent in the PD population
- Vast majority of patients have a risk factor gene, but the gene that has a high risk/guarantee of PD is not common
- Alpha synuclein mutation: 1 in 1,000 PD patients (maybe less, some say 1 in 5,000) carry that mutation
- Very rare but relevant in terms of understanding disease
If 95% of people don’t have these genes, why are we interested in these 5%? How does it help us understand the disease?
- There is good evidence that at least some of the genes are relevant to typical to PD
- Mutations in alpha synuclein looks different than PD clinically, and is very rare. Why is it relevant? This was the first mutation discovered. Alpha synuclein aggregation, called Lewy bodies, are the pathological hallmark of PD. Every other case of PD, by definition, has pathological hallmark in their brain that contains this protein that is encoded by this gene. It provided a lot of evidence that studying these rare familial forms can tell us about the rest of the disease.
How do you prove that genes are related to getting the disease?
Look for circumstantial evidence. Does disease look similar? Do patients who have the mutation get the same pathological hallmarks than rest of patients get. As you move through research, you start to find other clues that tie mechanisms together.
Do you rely on cells or animals to make discoveries? How informative have they been?
They have been very helpful. The creation of induced pluripotent stem cells (taking tissue punch from patients and turning it into a nerve cell) and then being able to study it has been useful to understanding the mechanism. Also creates early understanding of disease process.
How do you know which gene influences which part of the disease?
- 90 genetic regions
- It’s even more complicated for the risk gene because we don’t know which the gene is that is causing the risk
- We have a region that contains several genes and we don’t know which gene is the culprit
- It is hard because we are talking about risks, not causal, so the effects are small
- Looking for small effect in a region where you aren’t sure which gene is being affected
- We have ideas about what the function of particular genes is, so can look across 90 genetic regions and look for related functions
How can you find mutations?
- Where do you start? One family, multiple families, 600 people, entire populations?
- 25 years ago: Rely on families where disease occurs much more often than you would expect. Involves working with clinicians who would obsessively track down families and work with them to identify affected individuals.
- Now, instead of having studies involving the genetics of around 500 people, we have genetic analysis of 1.4 million people: 40,000 had PD; 20,000 had relative with PD; Rest were control
- Change with technology and number of patients we have to work with
- Didn’t sequence whole 1.4 million, but are close to do that
- We are all going to have our genome sequenced at one point or another, so it will soon be entire populations
Why would people want to be told they have a risk gene, if it doesn’t tell them what they are going to get, only an elevated risk?
Why would I want to know if there’s nothing I can do to prevent it? It is a very personal opinion, it comes down to the individual.
Genetics tells you risk. What turns risk into disease?
We’re now able to estimate what risk genetics imparts. Heredity accounts for 25% of risk on average. Since it isn’t 100%, tells us something else is going on.
Other things could be:
- Mutations we haven’t discovered yet
- Environment: Pesticides, pollutants, well water
- Effect of random effects: More theoretical
It’s risk + other factors.
Can the environmental factors change gene / symptom expression? Do all environmental factors speak through genes?
The environment is not only what you are exposed to, but also when in life and for how long. If an early exposure can lead to PD, it must be having a persistent effect. The idea that the environment affects genetics is reasonable.
Are risks different in different populations?
Vast majority of genetic work (not just PD) has been done in people of northern European ancestry. Vast majority of PD studies have been done in people from across Europe and North America. We see differences within the populations too. Example – LRRK2 is common in people with Ashkenazi Jewish ancestry, but not common in those that are not Ashkenazi Jewish. Starting to find out now more about populations outside of Europe
1-3% of DNA is coding, meaning the remainder is non-coding. How many genetic studies are on the coding sections in comparison to the non-coding sections?
- Remainder is called junk DNA. Means we don’t know what it is
- Non coding regions provide which regions the stimulation affects, and if the stimulation increases and decreases
- Information not only is needed to know where stimulation goes, but also needed to know where the information should be applied
- Genetic studies look at both coding and non coding sections
- Coding regions have the big effects seen in families high rates of PD
- Larger studies look at as much DNA as possible, including non-coding section
How much epigenetic sequencing can we do?
- We can look at a fair amount now
- Can look at epigenetic marks – things that alter the genome- using a survey
- Issue is have to look at the tissue that is relevant. Blood is the most accessible tissue, but isn’t really relevant to PD. Want to look at brain tissue and large numbers of samples which is harder.
- There is new technology that allows you to sequence data and get epigenetic information at the same time
- Can now sequence DNA in individual cell while keeping package together, so can sequence just that specific type of neuron that we look at for PD or PD risk factors
How does gender factor into your studies?
From a genetic perspective, we don’t see any real consistent differences between men and women. There are differences in disease progression and presentation but not genetically.
Should people get genetic testing? Should they test to see the risks they may give to their children?
It’s a personal decision, speak to a genetic counselor before seeking genetic testing. In terms of knowing overall risk for future generations, it depends on what and how much of your genetic material is passed on.
On average, a good rule is that if a person has PD, their child is twice as likely to get PD than someone in the general population. Sounds scary, but only one in 200 get PD, so it only increases your risk to 1 in 100 (1%) which is still low. Unless you have a very strong family history of PD, then the increased risk is higher.
Are PD and Alzheimers similar genetically?
No, they have very little in common genetically. The disease in the midway point between these two is Dementia with Lewy Bodies. There are a lot of benefits to studying the 3 together.
Age is the biggest risk factor. Why is it such a big part of why we get the disease? Does age have an effect on the genome?
Age is an important risk factor for all diseases of the brain. That’s a very hard question to answer properly. My suspicion is that age is related to the amount of things you are exposed to, and the general breakdown in regulation of your biology. Your body and genes are not designed to function well after a certain age.