How do genetic factors influence the risk of Parkinson’s disease?

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How do genetic factors influence the risk of Parkinson’s disease?

Genetic factors play an important role in influencing the risk of developing Parkinson’s disease (PD), although most cases are considered sporadic and not directly inherited. Approximately 10-15% of Parkinson’s cases are linked to specific genetic mutations, while the remaining cases result from a complex interplay of genetic predisposition and environmental factors. Here’s how genetic factors influence the risk of Parkinson’s disease:

1. Monogenic Forms of Parkinson’s Disease

Role of Genetic Mutations: A small percentage of Parkinson’s cases are caused by single-gene mutations (monogenic forms), where the inheritance pattern is more straightforward. These mutations can be inherited in an autosomal dominant or autosomal recessive manner.

a. Autosomal Dominant Mutations

LRRK2 (Leucine-rich repeat kinase 2): Mutations in the LRRK2 gene are the most common genetic cause of familial Parkinson’s disease, especially among certain populations (such as Ashkenazi Jews and North Africans). This mutation follows an autosomal dominant inheritance pattern, meaning that inheriting one mutated copy of the gene from a parent increases the risk of developing PD.
- Risk Influence: Not all individuals with the LRRK2 mutation develop Parkinson’s, suggesting that environmental factors and other genes may modify the risk.
SNCA (Alpha-synuclein): Mutations or duplications of the SNCA gene, which encodes the alpha-synuclein protein, are another autosomal dominant cause of Parkinson’s. This mutation is rare but plays a critical role in understanding the disease, as abnormal accumulation of alpha-synuclein is a hallmark of Parkinson’s pathology (forming Lewy bodies).
- Risk Influence: Individuals with SNCA mutations typically have an early onset of Parkinson’s, and the disease progresses more rapidly than sporadic forms.

b. Autosomal Recessive Mutations

PARK2 (Parkin): Mutations in the PARK2 gene, which encodes the parkin protein, are associated with autosomal recessive juvenile Parkinson’s. This form tends to occur earlier (before age 40) and progresses more slowly than idiopathic PD.
- Risk Influence: Both copies of the PARK2 gene must be mutated for the disease to develop. Individuals with only one mutated copy are carriers but generally do not develop symptoms.
PINK1 (PTEN-induced kinase 1): Mutations in the PINK1 gene, which plays a role in protecting cells from stress, also lead to autosomal recessive early-onset Parkinson’s disease.
- Risk Influence: Similar to PARK2 mutations, both copies of the PINK1 gene must be mutated for the disease to manifest.
DJ-1: Mutations in the DJ-1 gene are associated with autosomal recessive Parkinson’s and involve mitochondrial dysfunction and oxidative stress.
- Risk Influence: This mutation also typically results in early-onset Parkinson’s.

2. Genetic Risk Factors in Sporadic Parkinson’s Disease

Polygenic Risk: In most cases of Parkinson’s, which are considered sporadic, genetic factors still contribute to disease risk, but they do so through complex interactions between multiple genes. These genetic variants may not directly cause Parkinson’s but increase susceptibility to the disease in combination with environmental factors.
GWAS (Genome-Wide Association Studies): Genetic research through GWAS has identified over 90 genetic loci associated with an increased risk of Parkinson’s. These variants, known as risk alleles, individually contribute small effects but collectively can significantly increase a person’s susceptibility to developing Parkinson’s disease.
- Risk Influence: While none of these variants is sufficient to cause Parkinson’s on its own, their cumulative effect can predispose individuals to develop the disease, particularly when combined with environmental triggers such as toxins, pesticides, or head injuries.

Examples of Genetic Risk Factors Identified by GWAS:

GBA (Glucocerebrosidase): Mutations in the GBA gene, which is involved in breaking down fatty substances, are the most common genetic risk factor for sporadic Parkinson’s. Individuals with GBA mutations have an increased risk of developing Parkinson’s, though the exact mechanism remains unclear.
- Risk Influence: People with one GBA mutation are at higher risk of Parkinson’s, while those with two mutations develop Gaucher disease, a separate lysosomal storage disorder.
MAPT (Microtubule-associated protein tau): Variants in the MAPT gene, associated with tau protein formation, have been linked to an increased risk of Parkinson’s and other neurodegenerative diseases.
- Risk Influence: MAPT gene variants can influence neurodegenerative pathways that contribute to Parkinson’s, particularly in relation to tau protein aggregation, which is seen in other neurological conditions like Alzheimer’s disease.

3. Epigenetic Factors

What Are Epigenetic Factors? Epigenetics refers to changes in gene expression that do not involve alterations to the DNA sequence itself but are instead caused by environmental factors and lifestyle choices.
Role in Parkinson’s Disease: Epigenetic modifications, such as DNA methylation or histone modification, may play a role in influencing the risk of Parkinson’s by regulating genes involved in neurodegeneration, inflammation, or cellular stress responses.
- Risk Influence: Environmental exposures, including pesticide exposure, air pollution, and diet, may induce epigenetic changes that increase the risk of developing Parkinson’s in genetically predisposed individuals.

4. Interaction Between Genetics and Environmental Factors

Gene-Environment Interactions: Genetic predisposition to Parkinson’s may be amplified by environmental factors such as pesticide exposure (e.g., paraquat and rotenone), rural living, well-water drinking, and head injuries. In these cases, individuals with genetic susceptibility may develop Parkinson’s more readily when exposed to certain environmental triggers.
- Example: Individuals with mutations in the LRRK2 or GBA genes may have a higher risk of developing Parkinson’s when exposed to toxins, as their genetic makeup could make their neurons more vulnerable to damage from these substances.

5. Familial Parkinson’s Disease

Inheritance Patterns: In familial Parkinson’s, where the disease appears in multiple members of the same family, genetic factors play a more prominent role. However, even in familial cases, the inheritance pattern can vary, with some forms being autosomal dominant, while others are recessive.
- Risk Influence: In these cases, family members who carry specific gene mutations may be more likely to develop the disease, especially in families with a history of early-onset Parkinson’s.

6. Mitochondrial Dysfunction and Parkinson’s

Role of Mitochondria: Mitochondria are the energy-producing structures within cells, and dysfunction in mitochondrial pathways has been linked to Parkinson’s disease. Mutations in genes like PINK1 and DJ-1 directly affect mitochondrial function.
Risk Influence: Genetic mutations that impair mitochondrial function can lead to increased oxidative stress, which in turn damages dopaminergic neurons, the cells most affected in Parkinson’s.

Conclusion:

Genetic factors influence the risk of developing Parkinson’s disease through both rare monogenic mutations and more common polygenic risk variants. While most cases are sporadic, familial forms of the disease caused by specific gene mutations also exist. Understanding these genetic influences helps researchers and healthcare providers identify at-risk individuals and develop targeted interventions. However, genetic factors alone do not account for all cases, and interactions with environmental exposures play a crucial role in triggering the disease in genetically predisposed individuals.

Jodi Knapp