Dr. Burke's genotype is CT for the SNP rs6812193. A genotype of CC has been linked to increase odds, while TT has been linked to decreased odds of developing disease. For the SNP rs10513789, Dr. Burke's genotype is TT. Having genotypes of GT and GG for this allele have been linked to lower and moderately lower odds of developing Parkinson's respectively. Thus, both SNP genotypes suggest typical odds.
Importantly, 23andMe is careful to mention that this preliminary report needs to be verified by the scientific community with many more peer-reviewed articles. Here, we will discuss the genetic details and SNPs used in defining the typical risk and how these genes may contribute to Parkinson's Disease.
Parkinson's Disease (PD) is a disease of the central nervous system in which the neurotransmitter dopamine is not released and motor functions begin to fail. The decrease in dopamine is due to the death of dopamine producing neurons in the midbrain (substantia nigra) (1). This neuronal death is seen in Figure 1, where a patient without Parkinson's (A) was compared to a patient exhibiting signs of Parkinson's disease (B) using positron emission tomography (2) and radio-labeled fallypride and fluorodeoxyglucose (18F), an antagonist of dopamine receptors. Panel C of Figure 1 shows the statistical decrease in dopamine receptors in yellow and where those difficiencies are located (3).
PD was originally described by Dr. James Parkinson in 1817. He characterized the usual symptoms of the disease including: shaking tremors, trouble moving quickly, changes in posture, trouble walking, general impaired muscle movement and at later onset memory loss, dementia, and depression. The disease progesses slowly and affects many people over the age of 70. Upon autopsy, the single best confirmation of PD is the formation of Lewy bodies, or abnormal deposits of protein in the brain. Treatments for Parkinson's include Levodopa, which helps to increase the amount of dopamine produced, as well as physical and speech therapies for the decline in motor functions (3,4).
Genetic Basis for Parkinson'sEdit
The question of whether PD is inherited or if certain populations are susceptible to the disease is still under scrutinization. 23andMe researchers asked just the question on whether certain genes are associated with PD. Do et al performed a GWAS study in order to answer this question. The authors compared 3,426 people who had PD participating in 23andMe research surveys to 29,624 people without disease. All of the participants were of European decent.(5)
The results of the study produced two SNPs associated with genes that showed an association with PD. These were rs6812193 associated with the SCARB2 gene and rs10513787 associated with the MCCC1/LAMP3 gene. SCARB2 codes for lysosome integral membrane 2 (LIMP-2) protein. LIMP-2 is thought to traffic B-glucocerebrosidase to the lysosome where it cleaves glucosylceramide. Deficiencies in this enzyme therefore lead to high levels of this glycoprotein to be stored causing the lysosomal storage disease Gaucher syndrome. The authors of this paper point out that mutations in this enzyme have been identified in patients with PD in a separate GWAS study (Aharon-Peretz et al ) (6). Do et al show that a CT allele genotype corresponds to a typical risk, meaning neither higher or lower association. The paper found many associations previously reported, confirming association of at least 6 SNPs. The SCARB2 SNP was the only novel significant association, while many other associations the authors discuss were below the significance level in this study. (5,6)
Although not new, but confirmed in this study, Do et al confirmed association of the MCCC1/LAMP3 gene locus with PD. This association was orgininally described by Nalls et al. (7) in a meta-analysis study. The MCCC1 codes for 3-methylcrotonyl-CoA-carboxylase, an important enzyme in leucine catabolism (8 ) while LAMP3 codes for lysosomal-associated membrane protein 3 (9 ). It is still unclear how these genes and proteins could be involved in disease and progression of Parkinson's.
1. Wikipedia. Parkinson's Disease. http://en.wikipedia.org/wiki/Parkinson's_disease
2. Wikipedia. Positron Emission Tomography. http://en.wikipedia.org/wiki/Positron_emission_tomography
3. Obesco, Jose et al. Missing pieces in the Parkinson's disease puzzle. (2010) Nature Medicine. 16(6), 653-661 PMID: 20495568
4. Parkinson's Disease Health Center. http://www.webmd.com/parkinsons-disease/default.htm
5. Do, Chuong et al. Web-Based Genome Wide Association Study Identifies Two Novel Loci and a Substantial Genetic Component for Parkinson's Disease. PLoS Genetics. (2011) Jun7 (6) PMID: 21738487
6. Aharon-Perez et al. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. (2004); 351 (19): 1972-7
7. Nalls et al. Imputation of sequence variants for identification of genetic risk for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet. (2011) 19Feb; 377(9766):641-9
8. MCCC1. http://www.ncbi.nlm.nih.gov/gene/56922
9. LAMP3. http://www.ncbi.nlm.nih.gov/gene/27074