The Interplay of Genetics and Environment in Parkinson’s Disease

Key takeaways:
~ Parkinson’s disease is caused by a combination of genetic factors and environmental exposures.
~ Several different genetic pathways can contribute to the development of the disease.
~ This article discusses various genetic variants that increase the risk of Parkinson’s disease and how they interact with environmental and lifestyle factors.

Members will see their genotype report below, plus additional solutions in the Lifehacks section. Consider joining today.

Is Parkinson’s Disease Hereditary?

Parkinson’s disease (PD) is a neurological disorder caused by the degradation of dopamine-producing neurons in a part of the brain called the substantia nigra. PD affects up to 10 million people worldwide.

Symptoms of Parkinson’s include motor system related symptoms, such as tremors (usually in the hand), problems with balance and walking, problems with moving limbs, and also non-motor symptoms such as depression, sleep problems, and dementia. Loss of the sense of smell is often an early symptom that may happen several years before any of the motor symptoms.[ref]

The underlying causes of Parkinson’s disease (PD) are not yet completely understood, but researchers think it is caused by a combination of genetics and environmental factors for most people.

There are two categories used for Parkinson’s:

Early-onset Parkinson’s: Several genetic mutations are linked to greatly increasing the risk, however, this type of PD only affects about 10% of patients.
Late-onset Parkinson’s disease: It is often due to a combination of genetic variants that increase susceptibility combined with specific environmental causes.

Non-motor symptoms of Parkinson’s include sleep disorders, autonomic dysfunction, gastrointestinal problems, and emotional dysregulation.[ref]

Environmental Exposures Linked to Parkinson’s

Environmental causes linked to PD include exposure to specific toxicants.[ref] It is likely that these causes are also tied to genetic susceptibilities, such as the ability to detoxify the toxicants.

Paraquat is a herbicide linked to increasing the risk for PD.[ref] It is still in use in the US, but the EU banned it in 2007. The EPA explains that Paraquat is one of the most widely used herbicides in the US. It is used as a weed and grass killer both in commercial and residential settings.[ref]

Maneb is a fungicide linked to increasing the risk of PD.[ref] It is often used to create Parkinson’s in animal research. Mancozeb is another formulation of Maneb, and it is sold under a variety of brand names. It is used for potato blight, downy mildew on grapes, and other plant fungal diseases.

Trichloroethylene (aka trichlor) is another chemical that is linked to PD.[ref] It is an industrial solvent and is used in refrigerants. Initially, trichloroethylene was used as an anesthetic alternative to ether and chloroform. Better anesthetics have come along, and trichloroethylene is no longer used because it had a nasty side effect of cardiac arrhythmia and neurologic dysfunction. The EPA now lists it as having both carcinogenic and non-carcinogenic health effects. The main route of exposure is contaminated drinking water in areas near industrial spills or landfill leaks.

Twin studies help researchers determine whether a disease is genetic or caused by an environmental factor. The risk of solvent exposure was made clear in a study of 97 twin pairs where one twin had PD and the other didn’t. Exposure to trichloroethylene increased the risk of PD by 6-fold, and combined exposure to perchloroethylene and carbon tetrachloride was also found to increase the risk of PD significantly.[ref]

Organophosphate exposure is also linked to Parkinson’s risk. Chlorpyrifos and other organophosphates increase the risk of Parkinson’s disease, depending on the amount of exposure and the genetic variants the person carries.[ref][ref][ref]

Smoking and Parkinson’s Disease:

Cigarette smoking has long been linked in epidemiological studies to decreasing the risk of Parkinson’s disease. Of course, smoking is not a good preventative measure since it will likely cause heart disease or lung cancer.

Researchers have been dialing in on why smoking cigarettes seems to reduce the risk of Parkinson’s and have determined it is due to nicotine exposure.

Researchers discovered that variants in the synaptic-vesicle glycoprotein 2C (SV2C) impact the degree to which smoking is inversely associated with PD.[ref] Animal research also shows that knocking out the SV2C gene takes away the positive effects of nicotine on dopaminergic neurons.[ref]

Head trauma as a cause?

Head trauma has been suggested as a potential cause of Parkinson’s disease. While traumatic brain injury has been linked to an increased risk of developing the disease, the exact connection is still unclear.

A recent animal study attempted to determine how repetitive mild traumatic brain injury (mTBI) could cause Parkinson’s symptoms. The results showed that repetitive, mild TBI caused aggregation of phosphorylated Tau protein in the substantia nigra of the animals. However, the researchers found mild TBI did not cause fibrils or Lewy body-like alpha-synuclein. The conclusion was that repetitive, mild TBI might add to pre-existing problems with misfolded alpha-synuclein.[ref]

REM Sleep Disorders and PD:

REM Sleep Behavior Disorder (RBD) is a condition characterized by intense and frequent physical movements during sleep. People with RBD may act out their dreams, such as kicking, punching, or jumping out of bed. They may also experience sleep talking, sleepwalking, and other unusual behaviors while asleep.

Normally during REM sleep, muscles are paralyzed through the activation of two systems: one controlling the input to the spinal cord to prevent muscle movement and the other controlling motor cortex activation.

In people with RBD, researchers think there is an abnormal disinhibition in the pyramidal motor tract. Brain imaging studies show that changes are going on with multiple neurotransmitters, including the cholinergic, noradrenergic, and dopaminergic circuits.[ref]

REM sleep behavior disorder is strongly linked to eventually developing Parkinson’s disease. While initial research showed that about 40% of people with RBD would go on to be diagnosed with Parkinson’s, newer research puts that estimate even higher, with up to 90% eventually developing either Parkinson’s or Lewy-body dementia.[ref]

Importantly, people with RBD have options for treatment and should talk with their doctor and a sleep specialist about determining the cause of RBD and the best options.

Genetic research links mutations in the SCNA and GBA genes (below) to an increased risk of REM sleep behavior disorder.[ref] Notably, other Parkinson-related genes, such as LRRK2, were not linked to RBD, which may indicate more than one pathway is involved in PD.

Circadian Rhythm and Parkinson’s:

Circadian rhythm dysregulation is linked to many of the non-motor symptoms in PD. These issues often occur years before motor-related symptoms (tremors, gait issues) occur.

Your circadian rhythm – your 24-hour body clock – is set by the increasing and decreasing amounts of two pairs of genes. The CRY and PER genes control what is known as the ‘negative arm’ of the clock, and their levels rise at night. The BMAL1 and CLOCK genes make up the positive arm of the circadian clock, and they are maximized during the day.

These pairs of genes control the expression of thousands of different genes in the body. The sleep-wake cycle is an obvious example of circadian rhythm, but additionally, your hormones, body temperature, neurotransmitter levels, digestive enzymes, detoxification enzymes, and even heart rate are controlled by your circadian rhythm.[ref]

Researchers estimate that 45% of PD patients suffer from depression and anxiety. Sleep rhythm is often disrupted, and the decreased REM sleep is tied to the mood changes in Parkinson’s.[ref]

Animal models of PD show that the circadian rhythm in the substantia nigra is completely gone, and the NLRP3 inflammasome is activated. Significantly, drugs that target specific circadian genes can partly reverse the loss of dopaminergic neurons (in animals).[ref]

According to animal studies, circadian rhythm disruption directly exacerbates dopaminergic neuronal loss by triggering neuroinflammation.[ref]

Parkinson’s Genotype Report:

Members: Log in to see your data below.
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the member’s information in the Lifehacks sections.

Keep in mind:
The genetic variants do not cause Parkinson’s on their own. Rather, exposure to environmental factors and genetic susceptibility are thought to lead to PD.

The rare mutations in LRRK2 and GBA are not guaranteed to be clinically accurate from AncestryDNA or other data. If your data shows a rare mutation, you should talk with your doctor and consider family history to see if a second test to confirm is warranted.

LRRK2 gene: Mutations in this gene are linked to a higher risk of Parkinson’s disease. There are rare mutations that lead to early-onset disease. Of the LRRK2 variants listed below, the G2019S variant listed first causes the most significant increase in risk, and it may be one that you should talk to your doctor about getting a second genetic test to confirm.

Check your genetic data for rs34637584 G2019S (23andMe v4, v5):

G/G: typical
A/G: significantly increased risk of Parkinson’s[ref]
A/A: significantly increased risk of Parkinson’s[ref]

Note: This genetic variant may be misreported on AncestryDNA v2 data.

Members: Your genotype for rs34637584 is —.

Check your genetic data for rs34778348 G2385R (23andMe v4, v5; AncestryDNA):

G/G: typical
A/G: increased risk of Parkinson’s
A/A: increased risk of Parkinson’s[ref][ref]

Members: Your genotype for rs34778348 is —.

Check your genetic data for rs33995883 N2081D (23andMe v4, v5; AncestryDNA):

A/A: typical
A/G: increased risk of Crohn’s disease, slight increased risk for Parkinson’s depending on the study[ref][ref]
G/G: increased risk of Crohn’s disease, slight increased risk for Parkinson’s depending on the study[ref][ref]

Members: Your genotype for rs33995883 is —.

SNCA gene: alpha-synuclein is found in the terminal of neurons.

Check your genetic data for rs2736990 (23andMe v4, v5; AncestryDNA):

A/A: typical risk of Parkinson’s
A/G: slightly increased risk of Parkinson’s (really common variant)
G/G: increased risk for Parkinson’s[ref]

Members: Your genotype for rs2736990 is —.

Check your genetic data for rs356218 (AncestryDNA only):

A/A: typical risk of Parkinson’s
A/G: slight increased risk of Parkinson’s (really common variant)
G/G: slight increased risk of Parkinson’s[ref]

Members: Your genotype for rs356218 is —.

PER1 gene: A core circadian clock gene.

Check your genetic data for rs2253820 (23andMe v4 only; AncestryDNA):

T/T: typical risk of Parkinson’s
C/T: slightly increased risk of Parkinson’s
C/C: increased risk of Parkinson’s[ref]

Members: Your genotype for rs2253820 is —.

SLC2A13 gene: encodes a protein that facilitates glucose transport

Check your genetic data for rs1994090 (23andMe v4, v5; AncestryDNA):

G/G: increased risk of Parkinson’s disease[ref]
G/T: slightly increased risk of Parkinson’s disease
T/T: typical

Members: Your genotype for rs1994090 is —.

ALDH gene: Aldehyde dehydrogenase gene, important in the metabolism of alcohol and certain pesticides

Check your genetic data for rs671 (23andMe v4, v5; AncestryDNA):

G/G: typical
A/G: increased risk of PD with pesticide exposure, inc. dementia
A/A: increased risk of PD with pesticide exposure, inc. dementia[ref][ref][ref]

Members: Your genotype for rs671 is —.

BCHE gene: encodes butylcholine esterase (see full article on BChE)

Check your genetic data for rs1803274 (23andMe v4, v5):

C/C: typical
C/T: one copy of the K-variant, decreased BChE, possibly more sensitive to nightshades; increased risk of Parkinson’s with organophosphate exposure, slightly impacts anesthesia[ref]
TT: two copies of the K-variant, 30% decrease in BChE, possibly sensitive to nightshades; increased risk of Parkinson’s with organophosphate exposure; possibly increased risk of breast cancer[ref][ref][ref][ref][ref]

Members: Your genotype for rs1803274 is —.

Check your genetic data for rs1126680 (AncestryDNA):

C/C: typical
C/T: reduced risk of Parkinson’s regardless of pesticide exposure[ref]
T/T: reduced risk of Parkinson’s regardless of pesticide exposure[ref]

Members: Your genotype for rs1126680 is —.

Gaucher’s disease and Parkinson’s:

Gaucher’s disease is a liposomal storage disease, usually caused by two copies of a mutated GBA gene.

The GBA gene codes for an enzyme called β-Glucocerebrosidase, which is part of the lysosome. People with Gaucher’s disease are at an increased risk for Parkinson’s disease — and people who carry one mutation are also at an increased risk for Parkinson’s disease. One study showed that GBA mutations led to a 28-fold increase in the relative risk for Parkinson’s.[ref] Please note that not everyone with GBA mutations will get Parkinson’s, so another gene mutation is likely needed or an environmental factor.[ref]

GBA gene: encodes β-Glucocerebrosidase

Check your genetic data for rs421016 L444P (23andMe v4):

A/A: typical
A/G: significantly increased risk for Parkinson’s
G/G: significantly increased risk for Parkinson’s and Gaucher’s disease[ref][ref]

Members: Your genotype for rs421016 is —.

Check your genetic data for rs387906315 (23andMe i4000417 v4, v5):

DD (or –): typical
DI (or -C): increased risk for Parkinson’s (carrier for Goucher’s)
II (or C/C): increased risk for Parkinson’s and Goucher’s disease[ref]

Members: Your genotype for i4000417 is — or for rs387906315 is —.

Check your genetic data for rs2230288 (23andMe v4, v5):

C/C: typical
C/T: increased risk for PD
T/T: 2x increased risk for PD, Goucher’s[ref]

Members: Your genotype for rs2230288 is —.

Check your genetic data for i4000415 N370S (23andMe v4, v5, rs76763715 other data sets):

C/C: type 1 Goucher’s[ref]; increased risk of PD[ref]
C/T: carrier for Goucher’s, increased risk for PD
T/T: typical

Members: Your genotype for i4000415 is — or for rs76763715 is —.

Lifehacks for Preventing Parkinson’s:

First, let me make it clear that you should always talk with your doctor if you suspect you are in the early stages of Parkinson’s disease. Healthcare providers can prescribe many medications to delay the progression of the disease. The lifehacks listed here are things to consider – along with whatever treatment course you’ve decided on with your doctor.

Get Your Circadian Rhythm In Sync:

One of my biggest takeaways from reading the research on Parkinson’s disease is that circadian rhythm is both crucial and also a lifestyle factor that can be optimized.

This article on circadian disruption in Parkinson’s explains that dopamine plays a vital role in circadian rhythms. Parkinson’s disease patients are likely to exhibit quite a few circadian rhythm disorder symptoms, including sleep disorders, body temperature decreases, and autonomic system disruptions such as blood pressure disturbances.

Here is another good review of circadian disruption in Parkinson’s disease. The thought is that while circadian disruption doesn’t cause Parkinson’s, the disturbance to the dopaminergic neurons possibly causes the circadian disruption, which may exacerbate or add to the neurodegenerative process.[ref]

So if circadian rhythm dysfunction is integral to PD, it makes sense to do everything you can to keep your circadian rhythm in sync. This includes:

maintaining a regular sleep/wake schedule – go to bed at the same time on the weekdays and weekends, as much as possible
exposure to sunlight during the morning to stop melatonin during the day
blocking blue light at night to increase melatonin
eating on a regular schedule (not too late at night)

Let me further explain the reason for blocking blue light at night:
Light in the blue wavelengths (~480nm) signals through photoreceptors in the retina that it is daytime. It blocks melatonin production and resets your circadian rhythm for the day. Beyond melatonin, there is a circadian rhythm to dopamine as its levels rise and fall over the course of a day. Animal studies show that constant light exposure disrupts the rhythm of dopamine production.[ref]

The rest of this article is for Genetic Lifehacks members only. Consider joining today to see the rest of this article.