Genetics and Parkinson's Disease:
Genetics can directly influence the development of Parkinson's disease, increase the risk of developing Parkinson's disease or increase the susceptibility to a pathogen that leads to Parkinson's disease.
While genetic correlations have been found with Parkinson's, the linkage is weak except for with the LRRK2 gene (74% correlation!). Unlike Huntington's Disease which has a direct one-to-one correlation which determines whether one will get the disorder if they have a Huntington's gene (HTT), Parkinson's is less correlated. Only 15% of those with Parkinson's have a family history of it. It is thought that the majority of Parkinson's cases were derived from the environment. It is a prudent execrcise to find out if your version of Parkinson's disease is genetically inherited (familial) or environmental (idiopathic) as it will determine which actions to pursue in treating the disease. Genetic tests are widely available to the public with results which can easily be deciphered with the help of the tables below.
Genetics:
Our genome is defined by 23 chromosome pairs (total of 46 chromosome) in our cell nuclei defined by sequences of the following nucleic acids:The human genome contains about 3 billion DNA nucleic acid elements (A, C, T or G) which are grouped into about 20,000 genes within the genome. More than 98% of our human genome is identical to other humans. Research is focused on that which makes us different. These genetic variations among humans are called SNPs (pronounced “snips”) or Single Nucleotide Polymorphisms. There are 4 to 5 million SNPs in a person's genome.
An "allele" refers to one of the possible genotype codes (sequence of A, C, T or G) available for a particular SNP. Only certain pairings are valid for human life.
A human cell has 23 chromosome pairs (22 autosomal chromosomes plus one extra to determine the sex) for a total of 46 chromosomes. One chromosome in each pair is donated from the mother and the other from the father. Each chromosome strand is a DNA helix containing genes and their nucleic acid pairs, or alleles.
DNA forms a helix structure were the "steps" in the ladder hold the A, C, T or G nucleic acid pairs defining its properties and characteristics in an organisms.
The side rails of the ladder are always the same repeating pattern of a nucleotide made up of of Phosphate, Sugar (Deoxyribose) and a Nitrogeneous base which is rather irrelevant to the traits the DNA will define, as it is the "steps" of the ladder which define the traits of the DNA.
Genes refer to one or to a few A, C, T or G nucleic acid element pairs defining the ladder "steps" in the DNA. It is typically a group of nucleic acid pairs which define a trait. Traits can also be defined by a subset of the gene called an SNP.
Genes encode the generation of proteins so when something is wrong with a gene, there is an error in the proteins the cell will generate.
Parkinson's Genetic Markers:
Genetic testing companies like 23andMe test for the LRRK2 and GBA Parkinson's genetic markers. A download of your raw data can also be analyzed for additional markers identified by SNPs. The 23 & Me raw data file is a text file listing in tab separated fields the snip "rsid", chromasome number and position where it can be found and the genotype (A, C, T or G) pair found in that location. The notation references the Genome Reference Consortium Human Build 37 (GRCh37). This "raw" data file can be searched for some of the markers listed below.
The following are considered genetic markers for Parkinson's:| Gene | SNP ID | Influence | Chromosome | Position | Genotype | 23&Me | Description |
|---|---|---|---|---|---|---|---|
| LRRK2 PARK8 | rs34637584 | 5 | 12 | 40340400 (snpedia.com) 40734202 (23&Me) | AA: Parkinson's risk AG: Parkinson's risk GG: common | Y | Overall, the risk of Parkinson's disease for a person who inherits a rs34637584(A) allele is 28% at age 59, 51% at 69, and 74% at 79. High correlation.
LRRK2 stands for leucine-rich repeat kinase (kinases are enzymes that activate proteins in cells), also known as the G2019S mutation.
LRRK2 mutations are believed to be involved in lysosomal and trafficking pathways by inducing the over phosphorylation of RAB enzymes (over 14 types of RAB enzymes affected by LRRK2) which affects alpha-synuclein induced cytotoxicity.
The LRRK2 mutation is more common with those of Ashkenazi (Eastern European) Jewish and North African Berber descent.
Autosomal dominant: parent with LRRK2 mutation has a 50% chance of passing it on to their child. Also see The role of the LRRK2 gene in Parkinsonism Targeted by therapies in development by Denali Therapeutics. See Parkinson's drugs in trials |
| CORO1C | 12 | N | Considered a polygenetic risk factor for those with the LRRK2 gene mutation.
Variants in the gene CORO1C may heighten risk of Parkinson’s in people who also carry a LRRK2 mutation.
Also see Genomewide Association Studies of LRRK2 Modifiers of Parkinson’s Disease (pdf) | ||||
| GBA GCase | i4000415 (23&Me) rs76763715 | 2 | 1 | 155205634 | TT: comon CT: Parkinson's risk CC: Gaucher's disease | Y | Every person carries two copies of the Glucocerebrosidase beta (GBA) gene, one inherited from each parent.
When mutations occur in both copies of GBA, they cause Gaucher disease.
When mutations occur in only one copy of GBA, it may increase a person’s risk (5x) of developing Parkinson's disease and at an early onset.
While there are over 300 possible GBA gene mutations, it is the one known as N370S that is linked to Parkinson's.
The GBA gene instructs production of the glucocerebrosidase (GCase) protein enzyme, and mutations are associated with not enough GCase activity impairing the ability of lysosomes to process alpha-synuclein.
Autosomal dominant: parent with GBA mutation has a 50% chance of passing it on to their child. Also see The link between the GBA gene and parkinsonism |
| GBA | rs35095275 | ? | 1 | 155205043 | AG: Parkinson's risk GG: common | N | Parkinson's and Gaucher disease risk
Autosomal dominant |
| GBA: L444P | rs421016 | 2 | 1 | 155235252 | AA common AG Parkinson's risk GG: Parkinson's risk | N | Parkinson's and Gaucher disease risk
Autosomal dominant |
| SNCA PARK1 | rs2736990 | 3 | 4 | 90678541 | CC: Parkinson's risk CT: risk GA: most common (61%) AA: less common GG: common | Y | The SNCA gene provides instructions for making a small protein called alpha-synuclein.
Associated with rapid progression and early onset. Often presents with dementia and cognitive decline.
Autosomal dominant |
| SNCA PARK1 | rs104893875 | ? | 4 | 89828170 | AG: Parkinson's risk GG: common | N | Considered "probably pathogenic" in the Movement Disorder Society Genetic mutation database
The SNCA gene provides instructions for making a small protein called alpha-synuclein.
Associated with rapid progression and early onset; often presents with dementia and cognitive decline.
Autosomal dominant Related SNCA/PARK1 SNP's:
|
| PARK2 PRKN (Parkin) | rs9347683 | 1 | 6 | 162728023 | AA: AC: CC | N | Mutations in the PARK2 gene have been linked to rare forms of Parkinson's. PARK2 is a protein involved in normal turnover of damaged or old proteins inside the cell.
A common genetic contributor to young-onset Parkinson’s (diagnosed before age 50). Scientists believe the parkin protein plays a role in recycling mitochondria.
Bradykinesia and tremor are the most common presenting signs. Dementia is rarely observed.
Autosomal recessive |
| PARK5 (UCHL-1) | ? | N | The PARK5 (UCHL-1) gene controls the generation of an enzyme called ubiquitin carboxyl-terminal esterase L1 which is found in nerve cells throughout the brain and serves the purpose of degrading unneeded, damaged or misshapen proteins. It is unclear whether this UCHL1 gene mutation is a true risk factor for Parkinson disease, because it has been identified in only one family. | ||||
| PARK6 (PINK1) | rs45478900 | 2 | N | The PARK6 protein, also known as PINK1, is a mitochondrial protein kinase. Typically quite rare, has been primarily associated with an early onset form of Parkinson's disease.
Bradykinesia and tremor are the most common presenting signs.
Autosomal recessive Also see: | |||
| PARK7 DJ-1 | rs17523802 | ? | 1 | 7961680 | GG: common AA: AG: | N | Also known as DJ1, on chromosome 1 encodes the Parkinsonism associated deglycase protein. Primarily associated with a recessive, early onset form of Parkinson's.
The main function of DJ-1 is to protect the cell from oxidative stress insult.
Low DJ-1 protein level caused by DJ-1 gene mutation leads to Parkinson’s disease due to impaired antioxidative activity.
This gene also works in parallel to Parkin and Pink1 genes; together they form a complex to control the abnormal functions of mitochondria under stressed condition.
Clinically similar to Parkin; slowly progressive parkinsonism, dystonia and psychiatric abnormalities.
Autosomal recessive |
| PARK9 ATP13A2 | rs3738815 | ? | 1 | 16988207 | AA: AG: GG: | N | Important for neuronal integrity. Mutation in the ATP13A2 gene is linked to a rare form of Parkinson’s known as Kufor-Rakeb syndrome.
It strikes people with disease signs at a young age.
Linked to manganese susceptibility/resistance and Parkinson's pathology.
Mutations in the ATP13A2 gene disrupt the lysosome transport process, so that polyamines build up in lysosomes, the lysosomes swells and eventually burst, causing the cells to die and resulting in Parkinson's.
ATPace enzyme.
Other related PARK9 SNPs: Also see: ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese (2012) |
| PARK13 HtrA2/Omi | rs10779958 | ? | ? | ? | N | Variants in the Omi/HtrA2 gene have been nominated as a cause of Parkinson’s disease.
Associated witih late onset Parkinson's.
Protease enzyme.
Also see: Genetic variation of Omi/HtrA2 and Parkinson’s disease | |
| PARK14 PLA2G6 | ? | ? | ? | N | Mutations of PLA2G6 gene have been lately proposed to be the causative gene for PARK14 in patients with autosomal recessive young-onset parkinsonism (YOPD). The role of PLA2G6 mutations as a risk factor for Parkinson's disease is not clear.
Associated witih early onset Parkinson's.
Metabolic enzyme.
Also see: PLA2G6 mutations in PARK14-linked young-onset parkinsonism and sporadic Parkinson's disease | ||
| PARK15 FBXO7 | ? | ? | ? | N | Mutations in the F-box domain containing protein Fbxo7 (PARK15) is thought to be associated with early onset autosomal recessive Parkinson’s disease by an unknown mechanism.
Cells with reduced Fbxo7 expression show deficiencies in Parkin mitochondrial translocation, ubiquitination of mitofusin 1 and mitophagy.
Associated witih early onset Parkinson's.
Also see: The Parkinson’s disease genes Fbxo7 and Parkin interact to mediate mitophagy | ||
| PARK16 Rab7L1/SLC41A1 | ? | ? | ? | N | Further analysis is required to determine the role of genes within the PARK16 locus in development of PD.
Associated with late onset Parkinson's.
Vesicle trafficking.
Also see: Genetic variants in the RAB7L1 and SLC41A1 genes of the PARK16 locus in Chinese Parkinson's disease patients | ||
| VPS35 PARK19 | rs188286943 | ? | 16 | 46662452 | CC: common CT: Parkinson's mutation | N | Various studies have shown that the VPS35 gene is associated with late-onset, familial Parkinson’s disease.
Autosomal dominant |
| PARK21 RAB39B | ? | ? | ? | N | Pathogenic variants in the gene encoding RAB39B, resulting in the loss of protein function, lead to the development of X-linked early-onset parkinsonism.
Vesicle trafficking.
Also see: Genetic Analysis of RAB39B in an Early-Onset Parkinson's Disease Cohort | ||
| PARK23 VPS13C | ? | ? | ? | N | VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease.
Associated with early onset Parkinson's.
Vesicle trafficking.
Also see: Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy | ||
| TMEM175 MGC4618 | ? | 4 | N | Transmembrane protein 175: associated with early onset of Parkinson's diseasei. Impairs lysosomal and mitochondrial function and increased α-synuclein aggregation.
Significant PD association.
Also see: TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation (Jinn, Sarah et al., 2017) | |||
| TMEM230 | ? | 20 | N | also known as C20orf30, considered causative for Parkinson's disease | |||
| SCH2 | ? | N | Gene marker for MSA (Multiple System Atrophy) | ||||
| GRIN2A | rs4998386 | 2 | 16 | 10070545 (23&Me) 9976688 (snpedia.com) | CC: common CT: TT: rare | Y | Marker for Parkinson's Disease in the Swedish Population. |
| ApoE | rs429358 | ? | 19 | 45411941 (23&Me) 44908684 (snpedia.com) | CC: CT: 3x risk Alzheimers E4 allele TT: common | Y | Apoplipoprotein E4 allele is a marker for Alzheimers dementia and Dementia with Lewy body (DLB). Only about half of DLB patients will have Parkinsonism symptoms. Dementia symptoms typically occur first in DLB patients unlike Parkinson's patients which develop Parkinsonism symptoms first. Also, the ApoE2 protein expresses the amino acid cysteine which allows for the extraction of mercury while ApoE4 expresses the amino acid tyrosine which does not (ref). Mercury in turn affects the health of neuron structures, inhibits the cleanup of beta-amyloid and disrupts the metabolism of iron. |
| NLRP3 | rs7525979 | 2 | 1 | 247587408 (23&Me) 247424106 (snpedia.com) | CC: common CT: TT: rare | Y | Marker for protection from NLRP3 inflammation and a decreased risk of Parkinson's Disease.
Reference: NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson's disease (2018) Also see: Inflammation and Parkinson's disease |
Terms:
- Autosomal dominant: inheritance pattern where the abnormal gene is a dominant gene located on one of the nonsex chromosomes. You need only one abnormal gene (one parent) to be affected by this type of disorder. One parent with an autosomal dominant disorder has a 50% chance of having an affected child with one abnormal gene and a 50% chance of having an unaffected child with two normal genes.
- Autosomal recessive: requires two copies (one from each parent) of an abnormal gene to be present in order for the disease or trait to develop.
See article Parkinson's Disease Genetic Markers
The Parkinson's Foundation conducted a genetic study which found that 16.8% of the PDGENEration study participants had a genetic form of Parkinson's. They released the following chart showing that the most common mutation was GBA.
Nearly 2,400 participants, 58.4% are males and 41.6% are females, average age of diagnosis: 61 yrs old
Parkinson's Treatment and Progression Influences:
The following are genetic markers to be aware of which may influence your condition, health and treatments to limit the effects and progression of Parkinson's:
| Gene | SNP ID | Influence | Chromosome | Position | Genotype | 23&Me | Description |
|---|---|---|---|---|---|---|---|
| Methylations SNPs | |||||||
| FUT2 | rs602662 | 3 | 19 | 49206985 | AA: likely to have higher B12 AG: moderate B12 levels GG: lower B12 | Y | risk of low vitamin B12 in Indian population and for lower intestinal microbial diversity.
Low levels of vitamin B12 have been associated with peripheral neuropathy, cognitive impairment, and more rapid rate of disease progression in PD.
Also see: Low Vitamin B12 and Parkinson Disease |
| FUT2 | rs492602 | 5 | 19 | 49206417 | AA: likely to have higher B12 AG: moderate B12 levels GG: lower B12 | Y | vitamin B12 levels |
| MTHFR | rs1801133 | 5 | 1 | 11856378 | GG: common AG: 30% reduced function AA: 70% reduced function TT: known to induce hyperhomocysteinemia | Y | C677T MTHFR polymorphism: associated with low folates, B12 and elevated homocysteine, inflammation.
Ability to activate folates to 5-MTHF which is critical for the remethylation of homocysteine to methionine.
If the methionine cycle is dysfunctional, methylation becomes inhibited and homocysteine (inflammation) levels may increase.
If the folate cycle is not functioning optimally, dysfunction in the areas of energy generation (ATP synthesis), DNA synthesis, DNA repair and methylation occurs (blocking the readability of specific genes turning them off).
Folic acid is a type of B vitamin that is normally found in beans, peas, lentils, oranges, whole-wheat products, liver, asparagus, beets, broccoli, brussels sprouts, and spinach.
Also see: |
| MTHFR | rs1801131 | 5 | 1 | 11854476 | TT: common GT: reduced function GG: greatly reduced function. | Y | This rs1801131 SNP has less effect on MTHFR than does rs1801133. Responsible for the creation and repair of DNA |
| MTR | rs1805087 | 2 | 1 | 237048500 | AA: common AG: GG: | Y | potential vitamin B12 depletion |
| CBS | rs5742905 | ? | 21 | 43063074 | TT: common CC: CT: | N | T833C CBS polymorphism: potential vitamin B6 depletion and elevated levels of homocysteine, recognized as a risk factor for coronary artery disease and Parkinson's.
Also see: |
| GC | rs2282679 | 3 | 4 | 72608383 | AA: common AC: somewhat lower vitamin D risk CC: lower vitamin D risk | Y | linked by several studies to vitamin D serum concentrations |
| TCN2 | rs1801198 | 1 | 22 | 30615623 | CC: common GG: neuropathy risk | N | higher risk of peripheral neuropathy, even with a normal vitamin B-12 status. A marker for intracellular B12 levels.
Also see: TCN2 polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake |
| Detox SNPs | |||||||
| GSTA1 | rs3957357 | 2 | 6 | 52668687 | AA: low enzyme activity GA: Normal GG: Normal | Y | The glutathione transferase (GST) polymorphisms will affect the ability to conjugate certain toxins with glutathione and the ability to clear mercury
Also see: GST Gene Variant Analysis |
| GSTP1 | rs1695 | 2 | 11 | 67352689 | AA: low enzyme activity GA: Normal GG: Normal | Y | The glutathione transferase (GST) polymorphisms will affect the ability to conjugate certain toxins with glutathione and the ability to clear mercury.
GST polymorphisms, interaction with smoking and pesticide use, and risk for Parkinson's disease in a Japanese population.
Also see: GST Gene Variant Analysis |
| GSTP1 | rs1138272 | 2 | 11 | 67586108 | CC: Common CT: TT: | Y | The enzyme plays a neuroprotective role in Parkinson's disease. Facilitates the antioxidative system and inflammatory response in allergy. The glutathione transferase (GST) polymorphisms plays a rile in detoxifying carcinogens and cancer risk. |
| NQO1 | rs1800566 | 5 | 16 | 69745145 | CC: common CT: somewhat lower lung cancer risk TT: Benzene toxicity cancer risk | Y | Leads from xenobiotic metabolism genes for Parkinson's disease among north Indians.
Also see: Pharmacogenetics and Genomics article Detox: Cruciferous Vegetables: broccoli, Brussels sprouts, arugula, kale and cauliflower. |
| PON1-55 | rs854560 | 5 | 7 | 95316772 | AA: high risk heart disease, etc. Low paraoxonase AT: high risk heart disease, etc. Low paraoxonase TT: elevated levels of paraoxonase (good) | N | Carriers of PON1-55 genotype exposed to organophosphates (parathion, chlorpyrifos) exhibited a greater than 2-fold increase in Parkinson disease risk. Paraoxonase-1 polymorphisms in Alzheimer's disease, Parkinson's disease.
Also see:
|
| SOD2 | rs4880 | 5 | 6 | 160113872 | GG: lower enzyme activity, increased likelihood to get prostate cancer GA: better oxidative stress handling AA: better oxidative stress handling | Y | Increased risk of colon cancer, pancreatic cancer, heat attack. Associated with antioxidant defense and DNA repair genes.
Also see:
Detox: consumption of foods rich in lycopene and other antioxidants. Cruciferous Vegetables: broccoli, Brussels sprouts, arugula, kale and cauliflower. |
| Cognitive Health and Memory SNPs | |||||||
| BDNF | rs6265 Val66Met G196A | 1 | 11 | 27679916 | CC: common CT: similar to CC TT: anxiety, schizophrenia risk GG: | Y | Associated with Brain-derived neurotrophic factor (BDNF) levels.
BDNF is associated with neuron health, repair and regeneration - the opposite of Parkinson's disease which destroys neurons in the substantia nigra.
Also see: effect of exercise on BDNF Reference: Physical exercise improves peripheral BDNF levels and cognitive functions in mild cognitive impairment elderly with different BDNF Val66Met genotypes |
| Foundation Vitamin SNPs | |||||||
| NBPF3 | rs4654748 | 2 | 1 | 21459575 | CC: low B6 CT: somewhat lower B6 risk TT: normal | Y | Associated with vitamin B6 levels.
Also see: The Parkinson’s disease death rate: carbidopa and vitamin B6 Vitamin B6 found in beans, whole grains, meat, eggs and fish. |
Genetic Testing Companies:
- 23andMe
- Download your raw data here: https://you.23andme.com/tools/data/download/ and check the box to accept their conditions and hit the "Submit request" button. They will email you when the file has been generated.
- Athena Diagnnostics Inc: genetic testing of movement disorders and neurological diseases. Parkinson's: Parkin, PINK1, LRRK2, DJ1, SNCA
- Fulgent Genetics: lab contracted by PdGeneration study. Tested for GBA, LRRK2, SNCA, PRKN, PARK7, VPS35, PINK1 mutations
- GX Sciences: Neurological genetic panel
- Genova Diagnostics: (GDX)
- Nebula: whole genome for 100% sequencing of your DNA. Generates 100 Gb of raw data
- Parkinsons.org: PD GENEration study: FREE! if you qualify, tests for GBA, LRRK2, SNCA, PINK1, PARK7, PRKN, VPS35
Genetic Interpretation and Analysis:
- PureGenomics: upload 23andMe raw data for further analysis
- StrateGene.org: upload 23andMe raw data for further analysis
- Genetic Genie: genetics research tool. Upload 23andMe or Ancestry DNA file or a whole genome (WGS or WES) VCF format file.
Parkinson's Genetic Web Links:
- Parkinson's Disease Gene Curation Expert Panel (GCEP) - group assessing genetic correlation to disease development and setting genetic testing guidelines for Parkinson's disease.
- The genetic architecture of Parkinson’s disease (Blauwendraat, Cornelis et al, 2019)
- IPDGC: International Parkinson Disease Genomics Consortium
Pros:
- Knowing if one has the LRRK2 gene may one day be helpful for therapeutics in development which are specifically targeting those with LRRK2.
- Many of the genes tested by 23 and Me relate to the influence of genes which influence Parkinson's directly or the nutritional and vitamin influences, the degree of which is also genetic.
Cons:
- You can't change your genetics but one's predisposition to the effects of nutrition and vitamins can be used to optimize one's diet and behavior.