Rs34637584

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.

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.

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.

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, ), 1.4% in Sephardic Jews (5/361, ) and 1.3% in Ashkenazic Jews (4/317, ) while it is found at a very low frequency of 0.06% in Europeans (1/1550, ) 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. either in the Middle East or in  North Africa. 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. . 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. 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"

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, whereas in a Jewish population the age-specific odds were 24% at age 80.

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.

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.

Recently (2008), this SNP was in the news 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