How genetics affects Parkinson’s symptoms

Parkinson’s affects people in different ways and it can seem like no two people have exactly the same symptoms. But did you know that symptoms can be influenced by genetics?

Genetics in Parkinson’s is a complicated affair. For the vast majority of people, the condition has not been inherited and is often referred to as idiopathic Parkinson’s. However, in some people, genetic changes can influence the risk of developing the condition as well as the type of symptoms experienced.

To understand how genetics impacts on Parkinson’s, first we have to learn a little more about how we inherit genes and some of the patterns that are important in inherited conditions.

Quick summary if you’re in hurry

  • Most cases of Parkinson’s have no known genetic link. But for a small number of people genetics could have played a role in why they developed Parkinson’s.
  • Some genes may increase risk of early-onset Parkinson’s, influence the rate of progression and even be associated with certain symptoms.
  • There are opportunities to take part in research that aims to study these rare genetic forms of Parkinson’s.

Genetic top trumps

If you have read our previous blog post on the genetics of Parkinson’s you will know that our cells contain 2 copies of each gene, one from each of our parents. This is important as if there is a fault in one gene, the other one may be able to make up for it.

Having two copies of each gene doesn’t just help protect us from faults, all over our DNA subtle differences in our genes help make each of us unique. We can see how different copies of genes work together by looking at eye colour.

When simplified, a person will only have blue eyes if they inherit the blue version of the eye colour gene from both parents. If instead a brown version of the gene is inherited alongside the blue, the person would have brown eyes. When one version of a gene trumps the other it is called ‘dominant’.

In this example, brown is dominant and blue is ‘recessive’. There are only three possible genetics combinations in this situation and two outcomes — if an individual was genetically ‘Bb’ or ‘BB’ they would be brown-eyed, but if they were ‘bb’ they would have blue eyes.

Recessive and dominant genetic conditions

Eye colour is, in reality, a little more complex than this, but some diseases work in this way. For instance, cystic fibrosis is a recessive genetic condition that only affects people if they inherit two copies of the faulty gene.

As we can see in the diagram, if a person has one faulty gene they are not affected but are a carrier.

Should a carrier have a child with another carrier that child would have a 1 in 4 chance of inheriting cystic fibrosis.

Family trees of those with recessive condition tend to have characteristic patterns based on these probabilities, but can be very complicated as it is hard to identify unaffected carriers.

Human diseases can also be caused by dominant genes. One example of this is Huntington’s where inheriting a single version of the faulty gene is sufficient to cause the condition. The pattern within a family tree left by dominant genetic traits or conditions is somewhat easier to identify — at least half of all the children of someone with a dominant inherited condition, who has children with someone without the condition, will also have the condition.

Genetic patterns in Parkinson’s

So what about Parkinson’s? Well, in the vast majority of cases, Parkinson’s is not inherited. Genetic changes in Parkinson’s are very rare. Most with the condition will not carry a faulty gene and will instead have idiopathic Parkinson’s, which means we do not know the cause.

You can read more about the risk of inheriting Parkinson’s in a previous post.

There are, however, a number of mutations in genes such as PINK1, GBA, DJ1, LRRK2 and SNCA that are linked to the condition. Changes in these genes can be passed from one generation to another and also occasionally pop up at random. But, unlike other types of inherited conditions, inheriting one or two copies of a faulty gene doesn’t mean you will definitely develop the condition.

In most cases, inheriting a faulty gene simply increases risk of potentially developing the condition, sometimes only marginally. So, when we look at a family tree of someone with a genetic type of Parkinson’s it is not as clear-cut as most genetic conditions.

Research is starting to unravel the potential consequences of having changes within genes commonly associated with Parkinson’s. But an added complication comes from the fact that in any one of these Parkinson’s associated genes there can also be a variety of different changes to the DNA code. Not only does this make it hard to detect people who have a genetic mutation, but it makes calculating how different changes may affect risk very difficult.

This is because in genetics not all changes are equal. Depending on what the change is and where it is in a gene means, some mutations have more harmful consequences for the protein that the gene makes. You can think of this as the consequence of different types of mistakes in a recipe. A small change, say altering 30 to 39 minutes baking time, will probably still result in an edible cake, albeit slightly dry. But if you were to substitute the word sugar for salt there would be more of a problem.

Despite this complexity, one of the findings that has come out of genetic research is that mutations in different genes can affect symptoms. The genes that are affected all make proteins that have a specific role in the cell. So when the protein is altered, different processes in the cell can become compromised. This is linked to how the condition starts and spreads, which is, in turn, linked to what symptoms appear and when.

How genetics affect symptoms

So, now we’ve covered the background, let’s take a look at how some of these rare changes in specific genes affect symptoms when compared to idiopathic Parkinson’s. Or, if you’re not interested in the specifics, you can scroll down to the next section to find out about genes that may decrease risk.

Recessive Parkinson’s genes

There are a number of genes — including PRKN, PINK1, DJ1 and FBXO7 — that have a recessive inheritance pattern in Parkinson’s. For each of these genes, having two copies of the faulty gene is linked to an increase risk of Parkinson’s.

1. PRKN gene (also known as PARK2)

Symptoms: stiffness, slowness, tremor and dystonia, some evidence of increased risk of dyskinesia
Onset: early
Progression: slow

The most frequent recessive form of Parkinson’s is caused by inheriting mutations in the PRKN gene. This gene is responsible for making the protein parkin, which plays important roles in the quality control, turnover and maintenance of the cellular powerhouses known as mitochondria.

Having two altered PRKN genes significantly increases risk of developing an early onset form of the condition with an average age at onset in the 30s, although people may develop late-onset Parkinson’s. And recent research suggests inheriting just one faulty copy of the PRKN gene may also have a slight impact on risk of developing Parkinson’s, although other studies have previously suggested no increase in risk.

As with all types of Parkinson’s, there is much variability in symptoms, but stiffness, slowness and resting tremor are common, and the progress of the condition is often slow. There is also some evidence that those with mutations in PRKN may be at an increased risk of developing levodopa induced dyskinesia.

2. PINK1 and DJ1 genes

Symptoms: stiffness, slowness, tremor and dystonia
Onset: early
Progression: slow

Other recessive forms of the condition can be caused by inheriting changes in both copies of either the PINK1 or DJ1 genes. The PINK1 gene makes the protein PINK1, which interacts with parkin to control mitochondria turnover, and the DJ1 protein is thought to play a role in protecting cells from oxidative stress.

You can read more about oxidative stress in our previous blog, ‘Time to turn science into new treatments’.

Those carrying either DJ1 or PINK1 mutations have an increased risk of early onset Parkinson’s, which may be slower to progress, and are likely to experience symptoms similar to those caused by changes in PRKN. Additionally, those carrying a PINK1 mutation may experience more cognitive and psychological symptoms.

3. FBXO7 gene

Symptoms: same as idiopathic Parkinson’s
Onset: early

The final gene in this section also has a role in keeping mitochondria working and plays a fundamental role in brain cell health. Mutations in the FBXO7 gene seem to be extremely rare, but having two copies of this faulty gene is linked to early-onset Parkinson’s. It has also been linked to a very rare juvenile and fast progressing Parkinsonism called pallido-pyramidal syndrome, which can cause dystonia to be present in childhood.

When it comes to symptoms, there is much still to learn but report suggest symptoms may be similar to idiopathic Parkinson’s with both motor symtpoms and common non-motor symptoms such as anxiety, sleep problems and cognitive decline.

There is still much to learn about how this gene is linked to Parkinson’s. Fortunately, Dr Heike Laman, from the University of Cambridge, has even started a Parkinson’s UK-funded to find what this gene does.

“I believe that Fbxo7 may be essential for keeping brain cells healthy so the goal of this project is to understand how and why Fbxo7 is so important for these brain cells. If successful, this project could lead to the development and testing of new treatments, potentially using our Fbxo7-deficient mice, which could provide an important new tool in the search for better treatments” — Dr Heike Laman

Discover more genetic research projects on the Parkinson’s UK website.

Dominant Parkinson’s genes

For Parkinson’s associated genes that have a dominant inheritance pattern, a change in just one of copy of the gene is sufficient to increase risk. Changes in the genes such as SNCA, LRRK2 and, recently discovered, VPS35 all fall into this category.

1. Alpha synuclein gene (SCNA)

Symptoms: variable but often show slowness and stiffness early on, may be more non-motor symptoms and dementia is common
Onset : early
Progression: variable, can be faster

SNCA is the name of the gene that makes the alpha synuclein protein. This protein is believed to play a role in how Parkinson’s spreads from one cell to another. Changes in this gene were first linked to Parkinson’s in 1997. Alterations in the DNA at this location allow altered, damaging forms of this protein to be made, which have been linked to dominant forms of the condition. In some cases these can lead to a form of the condition with faster progression and cognitive symptoms including dementia, although there is a lot of variability between people with different types of SNCA mutations.

In addition to changes in the SCNA gene, researchers have now discovered over 40 cases, linked to 31 families, where Parkinson’s can be traced back to a duplication of this gene, which causes too much alpha synuclein protein to be present inside cells. Only one of the SNCA genes needs to be duplicated for too much protein to be present, and as such this genetic form of Parkinson’s is dominant and an affected individual has a 50% chance of passing the duplicated gene on to an child. But in individuals with this duplicated gene, only around 40% go on to develop Parkinson’s (this is called the penetrance of the mutation).

While extremely rare, Parkinson’s cases caused by duplication of the SNCA gene tend to be early-onset and feature more non-motor symptoms, such as rapid eye movement sleep behavior disorder (RBD), hallucinations and thinking problems which can lead to dementia.

When it comes to developing new and better treatments for Parkinson’s, alpha-synuclein is high on the agenda as sticky clumps of this protein form in every person with Parkinson’s. Researchers are working on a number of therapies that may be able to slow or stop the spread of Parkinson’s by targeting this protein with new drugs and even a vaccine.

Read more about how a vaccine for Parkinson’s could work in this previous post.

2. LRRK2 gene (also known as PARK8)

Symptoms: same as idiopathic Parkinson’s, tremor and dystonia common
Onset : late
Progression: average

Because the LRRK2 protein interacts with parkin, it is believed to play a role in keeping mitochondria healthy. However, it also seems to influence many other processes in the cell and mutations in the LRRK2 gene are linked to problems with cellular recycling, the build up of alpha-synuclein as well as oxidative stress.

The symptoms of those who have inherited a change in the LRRK2 gene known as G2019S can look the same as idiopathic Parkinson’s, although there is some evidence that symptoms relating to instability may be more common. And the condition often develops later in life.

This single change in the LRRK2 gene is probably the most common genetic variant linked to Parkinson’s — in the UK, around 1 in 100 people with Parkinson’s may carry it. And people who carry this variant have around a 70% chance of being diagnosed by the age of 80 making it one of the highest penetrance mutations in Parkinson’s.

Like alpha synuclein, researchers are also interested in developing new treatments that target the LRRK2 protein. There are a number of pharmaceutical companies currently working in this area, and late last year Denali Therapeutics announced positive results from its first-in-human LRRK2 inhibitor clinical trial.

3. VPS35 gene

Symptoms: same as idiopathic Parkinson’s, cognitive symptoms less common
Onset : late
Progression: average

Researchers have recently discovered that changes in a gene called VPS35 are linked to increased risk of late-onset Parkinson’s. While research into this mutation is still in its infancy, studies suggest that, like LRRK2 mutations, there is no major difference in symptoms compared to those with idiopathic Parkinson’s although cognitive symptoms, such as dementia, may be less common.

In a new Parkinson’s UK-funded study starting in October, Dr Eva Kevei, of the University of Reading is aiming to better understand how this gene increases Parkinson’s risk. Eva explains:

“Understanding why and how mutation in genes cause brain cells to die in Parkinson’s is one of the most important ways we can gain an insight into what causes people to develop Parkinson’s.
“I am studying molecule mechanisms of VPS35-linked Parkinson’s to identify how the VPS35 mutation leads to Parkinson’s in the simple but powerful worm model and directly transfer this knowledge to human cell-based research.” — Dr Eva Kevei

4. GBA gene

Symptoms: both motor and non-motor symptoms, including dementia, are common
Onset : early
Progression: rapid

The final gene to fall in this category is the GBA gene, although research often uses the term pseudo-dominant mutation, highlighting the way it isn’t easily pigeonholed.

Changes in the GBA gene are one of the more common genetic risk factors associated with Parkinson’s, and previous research has shown that these mutations lead to alpha-synuclein building up in brain cells.

While they are associated with increase risk, mutations in GBA have low penetrance. Only around 30% of people with a single affected gene develop Parkinson’s, however two copies of a mutated GBA gene causes a condition known as Gaucher disease.

Those who do develop the Parkinson’s often do so around the ages of 40–60 and have more rapid progression of motor symptoms alongside memory and thinking problems. Indeed, GBA mutations in Parkinson’s are linked to an increase in the risk of early dementia, and in those with more severe mutations the symptoms of dementia may pre-date movement symptoms — leading to a diagnosis of Lewy body dementia rather than Parkinson’s.

Genes that reduce Parkinson’s risk

Most of the time genetics is referred to in relation to increase in risk, however there are also genetic changes that can decrease risk of Parkinson’s.

People with Parkinson’s have helped researchers find Parkinson’s risk genes. But to find protective genes we need to look at people who haven’t developed the condition. The best possible group to study to find protective genes are those who carry a risk gene but do not develop Parkinson’s in their lifetime. Something hidden in them is protecting them from the condition — if we can find it, this could help researchers design therapies to protect others.

Research into protective genes in Parkinson’s is still in its early stages, but in other conditions some genes have already been identified. For example scientists at Harvard discovered that a protein called REST can protect people from dementia. Similarly variants of other genes have been found to protect against heart disease and type 2 diabetes. These findings could help scientists develop new therapies that have the potential to treat and even protect people from various conditions.

In 2015, Parkinson’s UK awarded a Dr Emmanouil Metzakopian of the Sanger Institute in Cambridge a fellowship award for a research project that aims to understand more about why some people get Parkinson’s while others don’t. Using cells grown in the lab and specially designed viruses, the team have individually changed single genes inside brain cells. Emmanouil explains more:

“My team use state-of-the-art technology called ‘genetic editing’ to change the DNA in brain cells grown in the lab. We use thousands of brain cells and change a different part of the DNA in each of them. This will help us find genes that are protective in Parkinson’s.
“The long-term goal of my research is to understand how genes can protect against Parkinson’s and ultimately use this information to develop new and better treatments.” — Dr Emmanouil Metzakopian

Towards better treatments

At the moment, our understanding of the genetics of Parkinson’s is incomplete. The latest research suggests that the interaction between different genes, rather than the presence or absence of a single gene, could play a vital role in the development of many conditions. And the low penetrance of many genetic changes in Parkinson’s highlight the role that other factors — such as exposure to environmental and lifestyle risk factors — play in the condition.

With the complexity of Parkinson’s genetics, and the involvement of many different genes, teasing apart the contribution of different risk factors could take some time. Fortunately, large scale studies alongside ever advancing computing techniques are helping us to understand the way different factors, including genetics, influence Parkinson’s.

These in turn are driving forward ideas on how research can develop better treatments. And those with recessive and dominant forms of Parkinson’s, where a faulty gene has led to the condition developing, could be first to benefit from the next generation of treatments that are designed to target the individual causes of Parkinson’s — such as those which target LRRK2 or alpha synuclein.

And while most people will not carry a mutation in any of the genes mentioned in this post, these therapies still hold hope as they combat problems seen in many with idiopathic Parkinson’s.

Read more about research that suggests LRRK2 inhibitors could benefit many with Parkinson’s.

Could you help us better understand the genetics of Parkinson’s by taking part in the The Parkinson’s Families Project?