|(A;A)||3||possible miscall in Ancestry V2.0 datasets; otherwise, 15 to 30% chance of Parkinson's disease, depending on age, family history, and ethnicity|
|(A;G)||3||possible miscall in Ancestry V2.0 datasets; otherwise, 15 to 30% chance of Parkinson's disease, depending on age, family history, and ethnicity|
First discovered in 2004, rs34637584 is a SNP indicating a position within the LRRK2 that encodes a variant protein. This SNP is commonly referred to as the G2019S variant (or, mutation) based on the potential change from glycine (encoded by rs34637584(G) allele) to serine (encoded by the rs34637584(A) allele) at position 2019 of the LRRK2 protein.[PMID 15680456][PMID 15680455]
Note: as of June 2016, we have noticed that this SNP is prone to being miscalled in AncestryDNA V2.0 datasets.
One copy of a rs34637584(A) allele is sufficient to greatly increase one's risk for Parkinson's disease. It is considered a disease causing mutation because it is rarely found in healthy, elderly people without Parkinson's disease, and it has been found in both familial and sporadic types of the disease. While there are many different SNPs that can influence one's risk for Parkinson's disease, rs34637584 is an especially common cause of the disease in Berber Arabs and Ashkenazi Jews. 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, according to the International LRRK2 Consortium.[PMID 18539534]
This SNP has been associated with disease at varying frequencies in Asian (<1%), European (1%–7%), North American (1%–3%), North African (34-41%), and Ashkenazi (10–25%) sporadic and familial Parkinson's disease patient populations [PMID 19283415].
The G2019S mutation is also common not only in Parkinson's disease patients but also in controls at a frequency of 2.2% in North African Berber-Arabs (13/597, [PMID 18666856]), 1.4% in Sephardic Jews (5/361, [PMID 18666856]) and 1.3% in Ashkenazic Jews (4/317, [PMID 16436782]) while it is found at a very low frequency of 0.06% in Europeans (1/1550, [PMID 18666856]) and not found in sub-Saharan Africans.
Individuals with G2019S who share the most common haplotype (mainly Europeans, Jews and North-Africans) very likely share a common ancestor estimated to have lived 1,525–1,830 years ago between the second and fifth centuries A.D.[PMID 19283415] either in the Middle East [PMID 16960813] or in North Africa [PMID 18666856]. In contrast, other authors hypothesized that LRRK2 G2019S might be of Phoenician origin, rather than Arabic-Berber or Jewish, dating from the founding of ancient Carthage in 814 B.C. [PMID 18702998]. G2019S has been observed on two additional background haplotypes (one in European–Americans and one in Japanese) distinct from the main one observed in Europeans, North-Africans and Jews. This suggests that G2019S has arisen independently on at least three separate occasions.[PMID 19283415] According to the most extensive and thorough study by Lesage et al. in 2010, estimations indicated that the LRRK2 mutation on the main haplotype initially arose among Near-Easterners at least 4,000 years ago, much earlier than in previous estimations. Because of a founder effect, the ancestors of present-day Ashkenazi Jews may have kept the low-frequency G2019S mutation through the different diasporas, whereas Near Eastern daughter populations lost the mutation. "The mutation might then have been reintroduced by recurrent gene flow from Ashkenazi populations to other Jewish, European and North-African populations. The present-day frequency of the mutation in control populations (0.05% in Europeans, 0.5% in North-African Arabs and 1% in Ashkenazi Jews) may support this scenario"[PMID 20197411]
Is a carrier of at least one rs34637584(A) allele definitely going to develop Parkinson's disease if they live long enough? No. Several studies have found that overall the odds of developing the disease for G2019S carriers depends on age, family history, and ethnicity. The odds for G2019S carriers were calculated to be 15% at 60 years, 21% at 70 years, and 32% at 80 years in a study of Italian patients [PMID 17215492], whereas in a Jewish population the age-specific odds were 24% at age 80.[PMID 17050822]
Having a family history of Parkinson's disease in addition to carrying a rs34637584(A) allele is also associated with increased risk for the disease.[PMID 15726496]
Do the odds differ between carriers of one and two rs34637584(A) alleles? Apparently not; a study of North Africans - one of the few populations likely to have sufficient numbers of homozygote rs34637584(A;A) individuals to study due to the rarity of the mutation - there was no clinical difference between Parkinson's disease patients carrying one or two copies, and, 3 individuals (ranging from 42-70 years old) who were rs34637584(A;A) and yet did not have the disease were also observed.[PMID 16966502]
In 2019, a study concluded that compared to Parkinson patients due to other causes, G2019S-associated Parkinson patients had a ~10-fold higher chance of developing leukemia and a 2-fold higher chance of developing colon cancer, perhaps thereby meriting additional screening for those conditions. However, it was not clear if higher odds would have been seen in G2019S-carriers compared to healthy individuals not carrying the G2019S mutation.[PMID 31348549]
This SNP was in the news  in 2008 as one of Google's founders, Sergey Brin, announced that he and his mother (who has Parkinson's disease) both carry the G2019S SNP. Mr. Brin was 35 years old at the time of the announcement, and in his blog, he comments that "I now have the opportunity to adjust my life to reduce those odds", which he states are "somewhere between 20% to 80% depending on the study and how you measure".
Helixgene discusses this extensively and concludes that people with G2019S have about a 25% chance of Parkinson's disease in their lifetime. This chance is greatly influenced by other factors including ethnicity and family history.
BMC in LRRK2 is not fully penetrant in familial Parkinson's Disease and commentary
gs248 is relevant
|Title||Web-based genome-wide association study identifies two novel Loci and a substantial genetic component for Parkinson's disease.|
|Odds Ratio||9.6200 [6.43-14.37]|
[PMID 21812969] Genome-Wide Association Study Identifies Candidate Genes for Parkinson's Disease in an Ashkenazi Jewish Population
|Disease||Parkinson disease 8 not provided|
|CLNDBN||Parkinson disease 8, autosomal dominant not provided|
|CLNSRC||OMIM Allelic Variant UniProtKB (protein)|
[PMID 20186690] Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.
[PMID 21850687] Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
[PMID 15680457] A common LRRK2 mutation in idiopathic Parkinson's disease.