As research continues to search for the cause of Parkinson’s disease (PD), one of the areas of study is genetics. All cells have coded instructions in their genes. Genes are inherited, and researchers study PD in families to find genes that might provide clues to the development of the disease. While only 10-15% of all cases of PD are thought to be directly linked to a genetic cause, researchers believe that understanding the genetic factors may lead to a greater understanding of how PD develops and possibly provide information on potential therapeutic strategies.1,2
Some genes are considered causal – these genes, without any additional influence such as environmental factors, guarantee that a person will develop PD. These causal genes are rare, occurring in only 1-2% of all people with PD. Other genes are considered associated genes and increase a person’s risk of developing PD without causing it directly. This variability in how genes affect an outcome is called penetrance. Penetrance refers to the percentage of people with a particular gene who have an observable characteristic. Genes that are 100% penetrant are causal genes, while genes with a lower penetrance are associated genes.3,4
Genes come in pairs, and each person’s genes are 50% from their mother and 50% from their father. A gene is considered autosomal dominant if only one abnormal gene from either parent causes the disease. If a gene is autosomal recessive, two abnormal copies, one from each parent, must be present for the disease or trait to develop.5
Autosomal dominant genes in Parkinson’s disease
- Alpha-synuclein – Researchers from the National Institutes of Health discovered mutations in a gene called SNCA, which provides coded instructions for the protein alpha-synuclein, were common in families with a high rate of PD. This gene is also referred to as “alpha-synuclein.” Mutations in this gene are extremely rare. However, the formation of clumps of alpha-synuclein in the nerve cells is one of the identifying characteristics of PD and abnormal clumps or aggregates of alpha-synuclein contribute to PD.1
- LRRK2 – LRRK2 was discovered in 2004 and seems to be the most common genetic contributor to PD, accounting for 1-2% of cases of the disease. Mutations in the LRRK2 gene are most common in people of North African, Basque, Portuguese, and Ashkenazi Jewish descent, although this mutation can occur in other ethnic groups. There is great variability in how PD develops among people with the LRRK2 mutation, with some developing the disease at a young age (30s or 40s), while others develop it later in life. Some people with the genetic mutation do not develop PD at all, making LRRK2 not fully penetrant (20-80% penetrance depending on a person’s ethnic background). Research continues to search for the reasons why some people with LRRK2 develop certain features of PD and others do not.1,3
- VPS35– VPS35 is an autosomal dominant genetic mutation that causes an adult-onset form of PD. It was discovered through researching a Swiss family who had a high prevalence of PD.2,6
- GBA – The GBA gene codes for an enzyme that aids cells in breaking down toxic substances. Heterozygosity (mutations in only one gene) for a mutation in GBA is one of the most common risk factors for developing PD. Mutations on the GBA gene may contribute to the accumulation of alpha-synuclein in the nerve cells.2 People homozygous for GBA mutations (mutations in GBA on both genes) develop a disease called Gaucher disease. Because there are already treatments for Gaucher’s disease, these treatments are now in clinical trials for PD.2
Autosomal recessive genes in Parkinson’s disease
- Parkin – Parkin is known as an ubiquitin ligase. It adds ubiquitin molecules to proteins that tag damaged proteins for degradation in the cell so the proteins get chopped up into their more basic form. More than 200 mutations in Parkin have been identified that can lead to PD. Some of the mutations cause a juvenile form of PD (appearing before age 20), while other mutations cause a later onset of the disease.2
- PINK1 – The PINK1 gene codes for a protein called PTEN induced putative kinase 1. More than 70 mutations in the PINK1 gene can cause PD, and mutations on PINK1 are associated with an early onset of the disease (prior to age 50). It is thought that both PINK1 and Parkin act together to target damaged mitochondria for destruction. Mitochondria are responsible for producing energy in the cell in the form of ATP. When they are damaged, they can produce what are called reactive oxygen species which can be toxic for proteins. Mutations in PINK1 and Parkin may prevent the cell from getting rid of damaged mitochondria, causing damage and possibly death of neurons.2
- ATP13A2 – Recessive mutations on the ATP13A2 gene are associated with Kufor-Rakeb syndrome, a rare form of juvenile (early onset) parkinsonism.2
Risk factors identified by genome-wide association studies
Genome-Wide Association (GWA) studies look at markers across complete sets of DNA (genomes) to find genetic variations associated with a particular disease. The goal in identifying genetic associations is to provide targets for additional research to detect, treat, and prevent diseases. Genetic variations that have been found in GWA studies that are associated with PD include:
- MAPT
- GAK
- RAB7L1
- PARK16
- BST1
- HLA-DRB5
- GCH1
These markers provide a starting point for future studies, and much research is needed to understand the mechanisms and potential therapeutic strategies of these genetic targets.7
