Parkinson’s disease (PD) is a complex neurological disorder influenced by a mix of genetic, environmental, and lifestyle factors. When it comes to the **genetic risks** of Parkinson’s, the picture is intricate and involves several genes that can increase the likelihood of developing the disease, though genetics alone rarely tell the whole story.
A small but significant portion of Parkinson’s cases—about 4%—are directly caused by differences in a single gene. These cases are often referred to as monogenic Parkinson’s, meaning one gene mutation can be enough to cause the disease. The most common gene linked to Parkinson’s is called **LRRK2**. Variations in this gene are found in roughly 1 in 100 people with Parkinson’s, and it is especially prevalent in certain populations, such as North African and Ashkenazi Jewish groups. People with LRRK2 mutations tend to develop Parkinson’s later in life, and about half of those with the most common mutation in this gene will develop the disease by age 80. Interestingly, Parkinson’s symptoms in these individuals may be milder compared to other forms.
Other gene mutations are much rarer but can cause Parkinson’s, especially in people who develop symptoms at a younger age, often before 50. One such gene is **PRKN** (also known as Parkin). Differences in PRKN are more common among younger patients, with estimates suggesting that between 2% and 15% of early-onset Parkinson’s cases involve this gene. The inheritance pattern here is usually recessive, meaning a person typically needs to inherit the mutated gene from both parents to develop the disease, which makes it quite rare.
Beyond these, there are several other genes implicated in Parkinson’s, such as **GBA**, **PINK1**, and **SNCA**. These genes affect critical cellular processes like mitochondrial function, lysosomal degradation, and vesicular trafficking. For example, mutations in GBA impair lysosomal function, which is important for breaking down and recycling cellular waste. When this process is disrupted, harmful proteins like alpha-synuclein can accumulate, contributing to the death of nerve cells. Similarly, PINK1 and Parkin mutations interfere with the removal of damaged mitochondria, leading to increased oxidative stress and cell damage.
Alpha-synuclein, a protein that clumps abnormally in Parkinson’s brains, is central to the disease’s progression. Genetic mutations can worsen the handling of alpha-synuclein by cells, leading to its buildup and triggering a cascade of cellular dysfunction. This includes stress on the endoplasmic reticulum (a cell structure involved in protein folding), impaired transport of vesicles (small sacs that move molecules within cells), and mitochondrial damage. These disruptions contribute to the death of dopamine-producing neurons, which is the hallmark of Parkinson’s.
It’s important to note that **most Parkinson’s cases do not have a clear genetic cause**. Around 75% of people with Parkinson’s do not carry known genetic mutations linked to the disease. Instead, their risk likely arises from a combination of multiple small genetic factors interacting with environmental exposures and lifestyle choices.
Environmental factors such as exposure to pesticides (like rotenone and paraquat), industrial solvents (such as trichloroethylene), and other toxins have been linked to increased Parkinson’s risk. These exposures may interact with genetic susceptibilities to trigger or accelerate the disease. For example, someone with a genetic mutation in LRRK2 or GBA might never develop Parkinson’s unless they also encounter certain environmental risks.
Another layer of complexity involves **metabolic health**. Conditions grouped under metabolic syndrome—such as abdominal obesity, high blood pressure, elevated blood sugar, high triglycerides, and low HDL cholesterol—have been associated with a roughly 40% increased risk of developing Parkinson’s. This risk is even higher in people who have both metabolic syndrome and genetic susceptibility. This suggests that managing metabolic health coul