Variability in α-Synuclein Gene Promoter Variability and Parkinson Disease

Harvey Checkoway, Ph.D., University of Washington and
Demetrius M. Maraganore, MD, Mayo Clinic College of Medicine
P42ES04696, R01ES10751, and R01ES10750

Variability in the α-synuclein (SNCA) gene is linked with a greater susceptibility for Parkinson disease, according to a study in the August 9 issue of the Journal of the American Medical Association. Previous research has shown that the origins of Parkinson's can be both genetic and environmental. One of the most promising leads in the genetics of Parkinson disease is the potential role of the SNCA gene. Some evidence suggests that SNCA may be associated with risk of Parkinson disease, but studies from different populations have yielded conflicting results. Large-scale studies have been lacking.

NIEHS grantees Demetrius M. Maraganore and Harvey Checkoway and colleagues with the Genetic Epidemiology of Parkinson Disease Consortium, conducted a study to examine several issues, including whether allele-length variabilitin the dinucleotide repeat sequence (REP1) of the SNCA gene is associated with Parkinson disease susceptibility. The researchers performed a collaborative analysis of individual-level data on SNCA REP1 and markers in patients with Parkinson disease and controls. Eleven participating sites in the genetics consortium provided clinical data for 2,692 cases and 2,652 controls. The researchers found that genotypes defined by the 263 base-pair gene were associated with Parkinson disease.

"Our study demonstrates that the SNCA gene is not only a rare cause of autosomal dominant Parkinson disease in some families, but also a susceptibility gene for Parkinson disease at the population level. Based on our results, we estimate that REP1 locus variability may explain approximately 3 percent of the risk in the general population. This is in the same range as the population effect of other common variants implicated in Parkinson disease. The additive effects of these and other common gene variants may ultimately account for a substantial fraction of the susceptibility to Parkinson disease," the authors write.

Citation: Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C; Genetic Epidemiology of Parkinson's Disease (GEO-PD) Consortium. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA. 2006 Aug 9;296(6):661-70.