Current Findings from PD GENEration

GBA (or GBA1) is the most common Parkinson’s-related gene, with variants found in 5-10% of people with PD. In contrast to the other six genes tested through PD GENEration, variants within GBA are considered risk factors of PD, as they only increase the likelihood of someone developing PD.  

Many carriers of a GBA variant will never develop PD, even if they have a family member with PD who carries the same GBA variant. Other risk factors, such as age and environment, may be needed for an individual to develop PD in addition to carrying a GBA variant.

While carrying a single heterozygous GBA variant in one of your two copies of the gene is enough to increase the risk of developing PD, having two variants in the gene — a homozygous variant seen in both copies of GBA — further increases the risk for developing PD, and in some cases, causes Gaucher’s disease.

Those who carry a GBA variant may experience:

• PD symptoms at an earlier age
• More rapid progression of dementia symptoms
• Greater motor difficulties compared to people who don’t have a genetic form of PD

Ongoing Research

Researchers are exploring exactly how GBA variants increase PD risk in brain cells. One theory suggests that the protein produced by the GBA gene, which has a role in the cell's garbage disposal system and is called GCase (glucocerebrosidase), may not work properly due to a variant in the gene. This would lead to the build-up of toxic clumps of the protein alpha-synuclein, which is known to happen in the brain of people with PD.

Pharmaceutical companies are testing drugs that target  GBA to help slow or stop the progression of Parkinson's, and the clinical trials will enroll people with PD that carry variants in this gene.

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For more information read the GBA Gene Information fact sheet.

Variants in the LRRK2 gene are found in about 1% of all people with PD and 5% of those with a family history. Certain ethnic groups have higher prevalence of LRRK2 variants among people with PD, like Ashkenazi Jews (about 15%) and North African Berbers (about 40%).

Although variants in LRRK2 are largely considered causative of PD, there are some people who carry variants in the gene that never develop PD. The risk of developing PD increases with age and varies depending on the specific LRRK2 variant a person has.

LRRK2 has a dominant inheritance pattern for PD (a person only needs to have a single heterozygous variant in one copy of the gene to cause the disease).

People with PD with a LRRK2 variant often experience:

• Symptoms similar to those with a form of PD with an unknown cause
• On average, milder symptoms of dementia and depression
• Less frequent motor difficulties
• Slower progression
• Symptoms vary from person-to-person, and researchers are still working to better understand why

Ongoing Research

Researchers are studying the mechanisms of how LRRK2 variants lead to Parkinson’s. Evidence suggests a change in the protein function from variants in the gene. One theory is that LRRK2 variants can increase the frequency at which the encoded protein triggers specific pathways that lead to cell death, particularly in dopaminergic neurons, which is a known cause of PD. 

LRRK2 variants may also interfere with a cell waste disposal method (called autophagy) that may lead to the buildup of a toxic protein called alpha-synuclein found in the brains of people with PD.

Pharmaceutical companies are testing drugs that block the abnormal activity of this gene to treat Parkinson's, and the clinical trials will enroll people with PD that carry variants in LRRK2.

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Explore GeneReviews for additional information about the symptoms and genetic counselling of LRRK2 PD.

Read the LRRK2 Gene Information fact sheet.

Genetic variants in PRKN are the most common cause of young-onset Parkinson’s, which appears before age 50. Although rarer than GBA or LRRK2, variants in PRKN are more common in certain ethnic groups, such as a group from Malaysia with a high rate of young-onset PD, of whom more than 50% have variants in PRKN.

More than 200 PRKN gene variants have been identified that are related to PD.

PRKN displays a recessive inheritance pattern (the person with PD must have a homozygous variant in both copies of the gene to cause the disease). Although, researchers are questioning whether people with PD with only a single PRKN variant may also have an increased risk of the disease.

Those with variants in this gene may experience:

• Early symptoms such as bradykinesia (slowness of movement) and rigidity
• Lower likelihood of dementia
• A good response to levodopa treatment

Ongoing Research

The PRKN gene provides instructions for making a protein called parkin in cells. Studies have found some of the variants in PRKN lead to a defective version of parkin or prevent the production of the protein. A loss of parkin may affect the production of dopamine. In people with Parkinson’s, the brain gradually stops making dopamine leading to abnormal movements and balance problems. Variants in the PRKN gene may also disrupt the proper disposal of damaged mitochondria (the powerhouse of the cell). Some research suggests that this dysregulation could play a key role in causing Parkinson’s symptoms.

Pharmaceutical companies are studying treatments that could boost or repair parkin protein activity.

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Explore GeneReviews for additional details regarding the symptoms and genetic counselling of PRKN PD.

Read the PRKN Gene Information fact sheet.

SNCA was the first Parkinson’s-related gene to be identified. In 1997, Parkinson's Foundation research fellow Roger Duvoisin, MD, identified the gene as playing a role in developing PD. There are at least 30 variants in the SNCA gene that can alter the SNCA protein, although they are considered a relatively rare cause of PD in comparison to genes such as LRRK2 and GBA.

Disease-causing variants in SNCA display a dominant inheritance pattern (the person with PD only needs to have a variant on one copy of their two SNCA genes to cause disease).

People with a SNCA variant:

• Usually have a parent with Parkinson’s, from which they inherited the variant
• Often have young-onset Parkinson’s, which typically appearing before age 50
• May progress more rapidly than people with PD without a genetic cause
• Can experience early non-movement symptoms, such as cognitive decline

Ongoing Research

SNCA produces the protein alpha-synuclein. When there is too much of this protein it can clump into deposits called Lewy bodies in neuron cells and contribute to their death. These clumps are seen even in people with PD that do not have a SNCA variant and are considered potential causes of Parkinson’s symptoms and/or Lewy body dementia.

Researchers have found that SNCA variants can lead to the accumulation of Lewy bodies by two different mechanisms:

1. The variants cause the alpha-synuclein protein to not fold properly and clump together, or
2. The variants result in an overproduction of alpha-synuclein that cannot be destroyed quickly enough and the proteins clump together. 

Researchers are studying the SNCA gene to design treatments that can reduce levels of toxic alpha-synuclein clumps in people with Parkinson's.

Learn More

Read the SNCA Gene Information fact sheet.

PINK1 is the second most common cause of young-onset Parkinson’s. There are more than 70 variants in the PINK1 gene that can cause Parkinson’s.

PINK1 displays a recessive inheritance pattern (the disease being caused when the person with PD has a homozygous variant, meaning a variant in both copies of their PINK1 gene). Yet, researchers have also found that people with PD with only a single PINK1 heterozygous variant may have an increased risk of the disease.

PINK1 Parkinson’s and PRKN Parkinson’s have some similarities. PINK1 carriers often experience:

• Early symptoms such as bradykinesia and rigidity
• Less common non-movement symptoms, such as dementia
• Generally slow disease progression
• Good response to the PD medication levodopa

Ongoing Research

PINK1 provides the instructions for the cell to make a specific kinase protein (proteins that activate or inactivate other proteins), which has roles in similar cell pathways as the parkin protein produced from PRKN. The variants within PINK1 seem to cause a loss of the protein’s function, resulting in decreased dopamine production and selective death of neuron cells, which can contribute to the loss of movement control. Variants in PINK1 may also be involved in disrupting the regulation of mitochondria (the powerhouse of the cell).

Researchers are working to understand the role of these gene variants in mitochondrial dysfunction, and how it may lead to PD.

Pharmaceutical companies are studying treatments that could boost PINK1 protein activators to help clear out mitochondria and keep cells healthy.

Learn More

Explore GeneReviews for additional details regarding the symptoms and genetic counselling of PINK1 PD.

Read the PINK1 Gene Information fact sheet.

Variants in PARK7, also referred to as DJ-1, are a rare cause of young-onset Parkinson’s, accounting for 1-2% of people that are diagnosed with PD before age 50. Even rarer, variants in the gene have been found to cause juvenile-onset Parkinson’s (under 21 years of age) as well as late-onset Parkinson’s (after 50 years of age).

PARK7 displays a recessive inheritance pattern (the person with PD must have a homozygous variant, in both copies of their gene, to cause the disease).

People with PD that have variants in PARK7:

• Typically have similar experiences to people with non-genetic Parkinson’s
• Often respond well to levodopa medication

Ongoing Research

The protein encoded by PARK7 is called DJ-1, and variants within the gene typically cause there to be a decrease in the amount of functional protein produced. Under normal circumstances, DJ-1 helps protect from a destructive process called oxidative stress that damages dopamine-producing neuron cells. But PARK7 variants impair the protein’s ability to protect the cell, resulting in a large reduction in dopamine neurons, known to result in abnormal movements and balance problems in people with PD.

Current studies are looking to better understand how the reduction in DJ-1 triggers the death of nerve cells that produce dopamine. Researchers are studying whether treatments focused on DJ-1 could delay nerve cell death.

Learn More

Read the PARK7 Gene Information fact sheet.

Discovered in 2011, variants in VPS35 are considered a relatively rare cause of late-onset of Parkinson’s, which begins after age 50. Although different variants have been reported in the gene in people with PD, most research studies have found that the risk of Parkinson’s results from one specific variant within VPS35.

The gene displays a dominant inheritance pattern (people with PD only need one copy of their VPS35 gene to have a variant to cause Parkinson’s).

People with a VPS35 variant:

·        Tend to have similar symptoms as people with non-genetic PD

·        In some cases, may have milder PD and/or slower progression

Ongoing Research

VPS35 variants result in a dysfunctional protein that interrupts the brain’s Retromer system, which helps brain proteins communicate.  Some researchers also think that the variants can result in reduced breakdown of alpha-synuclein, which may lead to it clumping into Lewy bodies in the brains of people with PD.

The Parkinson’s Foundation PD GENEration team is studying how variants in VPS35 contribute to the symptoms of PD. Understanding more about the gene can lead to the development of treatment strategies.

Learn More

Explore GeneReviews for additional details regarding the symptoms and genetic counselling of VPS35 PD.

Read the VPS35 Gene Information fact sheet.

• ATP13A2: Associated with recessive, juvenile-onset Kufor-Rakeb syndrome, which has symptoms of parkinsonism and dementia. Researchers are also investigating whether the gene may be associated with risk of dominant late-onset PD.
• ATP1A3: Associated with dominant, rapid-onset dystonia with parkinsonism symptoms.
• ATP7B: Associated with recessive Wilson disease, which can sometimes have parkinsonism symptoms. Researchers are also investigating whether the gene is associated with risk of dominant early-onset PD.
• CHCHD2: Research suggests a potential association with dominant, late-onset PD.
• DCTN1: Associated with dominant, adult-onset Perry syndrome, which can have parkinsonism symptoms. Researchers are also investigating whether the gene may be associated with dominant progressive supranuclear palsy, which can sometimes have parkinsonism symptoms.
• DNAJC6: Associated with recessive juvenile-onset and young-onset PD.
• FBXO7: Associated with recessive, young-onset PD.
• GCH1: Associated with dominant and recessive dystonia, which can have parkinsonism symptoms. Research also suggests that the gene may be associated with an increased risk of dominant PD without dystonia.
• GRN: Associated with dominant and recessive frontotemporal dementia that sometimes has parkinsonism symptoms. Research also suggests that the gene could be associated with dominant Lewy body dementia, which is related to PD.
• MAPT: Associated with dominant frontotemporal dementia that sometimes has parkinsonism symptoms. Research also suggests the gene may be associated with an increased risk of PD.
• PLA2G6: Associated with recessive, late-onset PD.
• POLG: Associated with dominant and recessive forms of progressive external ophthalmoplegia, which can have parkinsonism symptoms.
• PTRHD1: Associated with recessive neurodevelopmental disorder with young-onset PD.
• RAB32: New research suggests a potential association with increased risk of dominant, late-onset PD.
• RAB39B: Associated with X-linked recessive Waisman syndrome with young-onset PD.
• SLC6A3: Associated with recessive, infant-onset parkinsonism-dystonia.
• SYNJ1: Associated with recessive, young-onset PD.
• TBK1: New research suggests a potential association with parkinsonian-pyramidal syndrome, as well as a potential association with amyotrophic lateral sclerosis with symptoms of parkinsonism.
• TH: Associated with recessive, infant onset Segawa syndrome with parkinsonism symptoms.
• VCP: New research suggests a potential association with PD, as well as a potential association with amyotrophic lateral sclerosis and/or frontotemporal dementia with symptoms of parkinsonism.
• VPS13C: Associated with recessive, young-onset PD.
   

• Two genes, BRCA1 and BRCA2, associated with hereditary breast and ovarian cancer syndrome
• Five genes, MLH1, MSH2, MSH6, PMS2 and EPCAM, associated with Lynch syndrome (or hereditary nonpolyposis colorectal cancer syndrome)
• Three genes, LDLR, APOB and PCSK9, associated familial hypercholesterolemia (hereditary high cholesterol)