PdCure.org

  Providing resources and ideas for cures for Parkinson's disease:

 

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.

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.

DNA Helix

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 file can be searched for some of the markers listed below.

The following are considered genetic markers for Parkinson's:
GeneSNP IDInfluenceChromosomePositionGenotype23&MeDescription
LRRK2rs3463758451240340400 (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. The LRRK2 mutation is more common with those of Ashkenazi (Eastern European) Jewish and North African Berber descent.
Autosomal dominant
Also see The role of the LRRK2 gene in Parkinsonism
Targeted by therapies in development by Denali Therapeutics. See Parkinson's drugs in trials
GBA
GCase
i4000415 (23&Me)
rs76763715
21155205634TT: 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. The GBA gene instructs production of the glucocerebrosidase (GCase) protein, and mutations are associated with not enough GCase activity.
Autosomal dominant
Also see The link between the GBA gene and parkinsonism
GBArs35095275?1155205043AG: Parkinson's risk
GG: common
N Parkinson's and Gaucher disease risk
Autosomal dominant
GBA: L444Prs42101621155235252AA common
AG Parkinson's risk
GG: Parkinson's risk
N Parkinson's and Gaucher disease risk
Autosomal dominant
VPS35rs188286943?1646662452CC: 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
SCNA
PARK1
rs27369903490678541CC: 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. Rapid progression; often presents with dementia and cognitive decline.
Autosomal dominant
SCNA
PARK1
rs104893875?489828170AG: 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. Rapid progression; often presents with dementia and cognitive decline.
Autosomal dominant
Related SCNA/PARK1 SNP's:
  • rs104893875: 4:89828170 AG: Parkinson's risk, GG: most common
    23andme: N
  • rs104893877: 4:89828149 AG: Parkinson's risk, GG: most common
    23andme: N
  • rs104893878: 4:89835580 CG: Parkinson's risk, GG: most common
    23andme: N
  • rs431905511: 4:89828154 AG: Parkinson's risk, GG: most common
    23andme: N
PARK2
PRKN (Parkin)
rs934768316162728023AA:
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?17961680 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?116988207AA:
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.
Other related PARK9 SNPs:
Also see: ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese (2012)
TMEM230 ?20 N also known as C20orf30, considered causative for Parkinson's disease
SCH2 ? N Gene marker for MSA (Multiple System Atrophy)
GRIN2Ars499838621610070545 (23&Me)
9976688 (snpedia.com)
CC: common
CT:
TT: rare
Y Marker for Parkinson's Disease in the Swedish Population.
ApoErs429358?1945411941 (23&Me)
44908684 (snpedia.com)
CC:
CT: 3x risk Alzheimers E4 allele
TT: common
Y Apoplipoprotein E4 allele is a marker for 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.
NLRP3rs752597921247587408 (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

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:

GeneSNP IDInfluenceChromosomePositionGenotype23&MeDescription
Methylations SNPs
FUT2rs60266231949206985AA: 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
FUT2rs49260251949206417AA: likely to have higher B12
AG: moderate B12 levels
GG: lower B12
Y vitamin B12 levels
MTHFRrs18011335111856378GG: 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. 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:
MTHFRrs18011315111854476TT: 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
MTRrs180508721237048500AA: common
AG:
GG:
Y potential vitamin B12 depletion
CBSrs5742905?2143063074TT: 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:
GCrs22826793472608383AA: common
AC: somewhat lower vitamin D risk
CC: lower vitamin D risk
Y linked by several studies to vitamin D serum concentrations
TCN2rs180119812230615623CC: 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
GSTA1rs3957357 2652668687AA: 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
GSTP1rs1695 21167352689AA: 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
NQO1rs180056651669745145CC: 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.
PON1-55rs8545605795316772AA: 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:
SOD2rs488056160113872CC:
CT:
TT:
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
BDNFrs6265
Val66Met
G196A
11127679916CC: 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
NBPF3rs46547482121459575CC: 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:


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.