Genetics Behind Parkinson's

What genes does PD GENEration test?

PD GENEration: Mapping the Future of Parkinson’s Disease uses the most comprehensive genetic test to detect changes (known as variants) in genes associated with Parkinson’s disease (PD). The test includes all genes that the medical community believes are linked to PD. For an overview of the PD GENEration testing panel, watch this informational video.

The PD GENEration test identifies variants in Parkinson’s-related genes that include: GBA, LRRK2, PRKN, SNCA, PINK1, PARK7 and VPS35.

GBA

GBA is the most common Parkinson’s-related gene. It is also one of the most challenging genes to test. Between 5 to 10% of people with PD have a change in this gene. Most carriers of a GBA variant will never develop PD. Other risk factors, such as age and environment, are needed for an individual to develop PD in addition to carrying a GBA variant. Those who carry a GBA variant may experience PD symptoms at an earlier age compared to people who don’t have a genetic form of PD.

Inheriting a single GBA variant (from either parent) increases the risk for PD. Having two variants in the gene (from both parents) further increases the risk for developing PD, as well as Gaucher’s disease. If you have a GBA variant, speak with your clinician or a certified genetic counselor to discuss how this gene variant may impact your health.

The GBA gene produces a protein responsible for managing the cell's garbage disposal system called GCase (glucocerebrosidase). Variants in GBA are linked to the build-up of toxic clumps of the protein alpha-synuclein, found in the brain of people with PD. Pharmaceutical companies are testing drugs that target this gene to help slow or stop the progression of Parkinson's.

• For more information read the GBA Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

LRRK2

Variants of the LRRK2 gene play a role 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%). While carrying a variant in LRRK2 increases the risk for PD, many people with a LRRK2 variant do not develop PD. In addition, the risk for developing PD increases with age and also varies depending on the specific LRRK2 variant.

Current research reports that people with PD with a LRRK2 variant experience symptoms similar to those without a genetic form of PD. They also have been reported to have milder symptoms of dementia and depression. However, symptoms vary and researchers are still working to better understand how symptoms develop.

Researchers are studying exactly how LRRK2 variants lead to Parkinson’s. LRRK2 variants can lead to the creation of too many proteins in the brain, leading to cell death. 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 brain of people with PD. Pharmaceutical companies are testing drugs that block the abnormal activity of this gene to treat Parkinson's.

• For more information read the LRRK2 Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

PRKN

The PRKN gene provides instructions for making a protein called parkin. More than 200 PRKN gene variants have been identified that are associated with Parkinson’s. PRKN is the most common genetic mutation associated with young-onset Parkinson’s, which appears before age 50. Those who carry this gene may be more likely to experience early symptoms such as bradykinesia (slowness of movement) and rigidity.

Researchers are studying how PRKN gene variants cause Parkinson’s. Studies have found some of the variants lead to a defective version of the parkin protein 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. This leads to abnormal movements and balance problems.

Variants in the PRKN gene may also disrupt the regulation of mitochondria (the powerhouse of the cell). Some research suggests that this dysfunction could play a key role in causing Parkinson’s symptoms. Drug companies are studying treatments that could boost parkin protein activity.

• For more information read the PRKN Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

SNCA

This was the first Parkinson’s-related gene to be identified. In 1997, Parkinson's Foundation research fellow Roger Duvoisin, MD, was the first person to identify SNCA as playing a role in developing PD. SNCA produces the protein alpha-synuclein. When there is too much of this protein in may clump (called Lewy bodies). These clumps may cause Parkinson’s symptoms and/or Lewy body dementia. People with a SNCA variant usually have a parent with Parkinson’s. SNCA variants are a rare cause of Parkinson’s.

There are at least 30 variants in the SNCA gene that can alter the SNCA protein. These variants are often associated with young-onset Parkinson’s, which typically appears before age 50. Researchers have found two types of variants in the SNCA gene in people with Parkinson’s. Certain variants can cause alpha-synuclein protein to misfold, while others may cause over-production of alpha-synuclein.

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

• For more information read the SNCA Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

PINK1

This is the second most common genetic mutation associated with young-onset Parkinson’s. Gene carriers experience early symptoms such as bradykinesia and rigidity, and non-motor symptoms may be more common. Those with a PINK1 mutation who have Parkinson’s generally experience slow disease progression and respond well to the PD medication levodopa.

Researchers have found more than 70 variants in the PINK1 gene that can cause Parkinson’s. PINK1 variants cause the selective death of nerve cells that occurs in Parkinson’s. The loss of these cells weakens communication between the brain and muscles. This leads to the brain becoming unable to control muscle movement.

Variants in PINK1 may, along with PRKN, be involved in disrupting the regulation of mitochondria (the powerhouse of the cell). Researchers are studying the role of these gene variants in mitochondrial dysfunction, and how it may lead to PD. Drug companies are studying treatments that could boost PINK1 activators to help clear out mitochondria and keep cells healthy.

• For more information read the PINK1 Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

PARK7

Variants in this gene are tied to young-onset Parkinson’s and lead to a decrease in a protein called DJ-1 that is essential for nerve cell health. This interferes with the production of dopamine. In people with Parkinson’s, there is a large reduction in dopamine neurons, which leads to abnormal movements and balance problems.

Current studies are examining how the reduction in DJ-1 triggers the death of nerve cells that produce dopamine. It is possible that PARK7 variants impair DJ-1’s ability to protect cells from a destructive process called oxidative stress that damages dopamine-producing nerve cells. The death of these cells weakens communication between the brain and muscles. Eventually, the brain becomes unable to control muscle movement.

Researchers are studying whether treatments focused on DJ-1 could suppress nerve cell death.

• For more information read the PARK7 Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

VPS35

Only discovered in 2011, this is a rare genetic mutation recently tied to Parkinson’s. The mutation is tied to the late onset of Parkinson’s, which begins after age 50. VPS35 interrupts the brain’s Retromer system, which helps brain proteins communicate. If you get this abnormal gene from only one parent, you can get the disease.

The Parkinson’s Foundation PD GENEration team is studying people with this mutation to better understand what VPS35-related Parkinson’s looks like. Understanding more about the gene can lead to the development of treatment strategies.

• For more information read the VPS35 Gene Information fact sheet developed by the PD GENEration genetic counseling team at Indiana University.

Parkinson's Disease Gene Curation Expert Panel (PD GCEP)

The Parkinson’s Foundation was appointed by the NIH to convene an international multidisciplinary expert panel of the world’s most esteemed molecular geneticists, clinicians with a general research focus, and PD-specific genetic counselors. The PD GCEP aims to support the expansion of high-quality and expert-driven variant curation for PD-relevant genes such as LRRK2, GBA, SNCA, PRKN, PINK1, PARK7, AND VPS35. 

You can read a recent paper published on behalf of PD GCEP, The Commercial Genetic Testing Landscape for Parkinson’s Disease.