Parkinson's disease
Wikipedia has general information about Parkinson's disease (PD), including a genetics section. Many SNPs have been reported to be associated with risk, but few have shown significant odds or have been robustly replicated. And as a 2016 editorial succinctly puts it, as for many other disorders, the genetic risk factors for Parkinson's disease can be roughly divided into three categories as follows:
- Mutations that lead to Parkinson's in nearly everyone who carries one. This is the smallest group, and people with these mutations usually have either a strong family history and/or a very early onset of the disease, i.e. in their twenties or thirties. At this time, only certain mutations in the LRRK2, SNCA, and TMEM230 genes appear to be causative for clinically typical and Lewy body–confirmed Parkinson's disease.
- Risk factors that significantly increase the risk of Parkinson’s (e.g., by 10-fold compared to the general population). However, note that many, if not most, of the carriers of these risk factors will never develop the disease.
- Variants that slightly increase Parkinson’s risk (up to two-fold in most cases). These variants are very common world-wide, with many of them present in 20-40% of the healthy population and none of whom will ever develop the disease. Only some abnormally high accumulation of such variants, and/or interaction with particular environmental factors, would actually lead to to Parkinson's.
Generally, Parkinson's disease that begins after age 50 is called late-onset disease. The condition is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 are sometimes referred to as juvenile-onset Parkinson's disease. Parkinson's disease is the second most common neurodegenerative disorder, after Alzheimer disease, affecting more than 1 million people in North America (1% of 55-year-olds and more than 3% of those over age 75) and more than 4 million people worldwide. In the United States, Parkinson's disease occurs in approximately 13 per 100,000 people, with a higher prevalence among males (19:100,000) than females (9.9:100,000), and about 60,000 new cases are identified each year.GHR
Most (~85%) cases of Parkinson's disease occur in people with no apparent family history of the disorder. These sporadic cases may not be inherited, or they may have an inheritance pattern that is unknown. For the minority (~15%) of familial (inherited) cases of Parkinson's disease, if the LRRK2, SNCA or VPS35 gene is involved, the disorder is inherited in an autosomal dominant pattern, whereas if the PARK2 (aka PRKN), PARK7, PINK1, ATP13A2, FBX07, or SLC6A3 gene is involved, the disease is inherited in an autosomal recessive manner.GHR
Keeping all of this in mind, the following genes are reported to varying degrees to affect risk of Parkinson's:
- TMEM230
- certain mutations in the gene encoding this synaptic vesicle transmembrane protein appear highly penetrant
- EIF4G1
- rs112176450, also known as Arg1205His, is one of several rare mutations in this gene which are associated with autosomally dominant forms of familial Parkinson's disease
- GBA
- rs35095275, also known as L444P, appears to increase the odds of developing Parkinson's disease by at least 5 fold, lowering the age of onset by about 4 years, across all ethnicities studied. [PMID 19846850]
- GRIN2A, a glutamate receptor gene
- GSTP1, a detoxification enzyme
- Variations have been linked to earlier onset of Parkinson's disease, especially in patients exposed to herbicides. [PMID 17190945]
- TNF-alpha promoter [PMID 17192953]
- LRRK2 [2]
- rs34778348
- rs34637584, also known as G2019S
- Two studies have concluded that the risk of developing Parkinson's disease upon exposure to pesticides is increased from 3 to 8 fold among carriers of CYP2D6*4 (rs3892097(A)) alleles. The risk appears proportional to the degree of pesticide exposure, with no additional risk for CYP2D6*4 carriers with no pesticide exposure, and the highest increased risk of developing Parkinson's seen for CYP2D6*4 carriers with frequent exposure to pesticides. [PMID 14991823, PMID 15174030]
- SLC6A3, encoding a dopanine transporter
- With pesticide exposure, the risk associated with these alleles is 6X higher. [PMID 16963468]
- rs287235 and rs838552 have been linked to Parkinson's disease [PMID 16917932] Having two copies of the risk variant does not lead to a more severe form [3]
- rs356219 a tagging SNP for a Parkinson's disease haplotype the "protective" genotype 259/259 of the repeat NACP-Rep1 is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263 [PMID 18162487]
- Various SNPs in the NOS1 and NOS2A genes were somewhat associated with sporadic Parkinson's disease and/or age of onset, with a subset also interacting with either smoking or pesticides. [PMID 18663495]
- The SREBF1 and SREBF2 genes, which are involved in lipid metabolism, have been implicated in type-2 diabetes [PMID 18192539], Parkinson's disease [PMID 21738487]], and schizophrenia [PMID 18936756].
- COMT
- SNPs in this gene may influence levodopa dosage used to treat Parkinson's disease patients. [PMID 18698234]
- A significant association was seen between caffeine intake and the onset of PD (P=2.01×10(-5)), with the odds ratio for moderate and high drinkers at 0.71 [95% confidence interval (CI): 0.50-1.00] and 0.47 (95% CI: 0.34-0.65), respectively against the low drinkers. [PMID 18075470] (P=0.08).
- CAST
- rs1559085 and other SNPs [PMID 20127884]
In 2011 23andMe published a paper in plos on Parkinson's disease which implicated rs6812193 and rs11868035 while confirming many old associations.
In Parkinson's disease patients some variants may be associated with how fast the disease progresses or with which symptoms develop. An example of this is the association of heterozygous mutations in the GBA gene. Parkinson's patients who were carriers of a neuropathic GBA mutation were ~3 times more likely to develop global cognitive impairment (hazard ratio 3.17, CI: 1.60–6.25) compared to noncarriers (p = 0.0009). At 10 years from their initial Parkinson's diagnosis, 79.5% (CI: 76.4–82.8) of noncarriers were free of global cognitive impairment compared to 52.2% (CI: 33.9–80.5) of neuropathic GD mutation carriers. The GBA mutations considered neuropathic in this study were L444P, R463C, R257Q, 84dupG, R120W, R359X, P266L, A456P, L444R, G377S, H255Q, and G195E.[PMID 27717005
]
Note that a 2006 survey of many common genetic variations that may be related to PD
[4] has been publicly released; the conclusion at that time was that no single SNP (from 400,00 on Illumina microarrays) was statistically significant enough to indicate (by itself) increased risk of Parkinson's. [PMID 17052657]
A 2007 report indicates that models built up from combinations of variations (i.e., SNPs) in "axon guidance pathway" genes can robustly score Parkinson's susceptibility (including age of onset). [PMID 17571925] A follow-up study published in January 2008 presents a model combining ~50 SNPs from genes in axon guidance pathways said to predict susceptibility to Parkinson's disease, survival free of Parkinson's, and age of onset. 10.1371/journal.pone.0001449; Medpage news article However, an independent 2008 study to replicate this not only did not, but reported that SNPs from randomly chosen genes fit to a model using similar methods seemed to give just as significant results as SNPs from axon guidance genes. In other words, the model was deemed highly "overfitted," calling all the results into question. [PMID 18628988]
The following list of additional genes that may affect risk of Parkinson's appeared in an article in The Lancet in February 2011. doi:10.1016/S0140-6736(10)62345-8
- MCCC1
- rs10513789 Each G allele is associated with 0.8 times lower odds of Parkinson's disease, according to research published by 23andMe [PMID 21738487]
