Maraganore DM et al. (2006) Collaborative analysis of α-synuclein gene promoter variability and Parkinson disease. JAMA 296: 661–670

Several small studies have suggested that certain alleles of a dinucleotide repeat sequence (REP1) of the α-synuclein (SNCA) promoter might be associated with the risk of developing Parkinson's disease (PD). A large-scale collaborative study, involving 18 genetic consortium sites around the world, was set up to test this hypothesis.

Data on the three most common REP1 alleles (259 bp, 261 bp and 263 bp) were collected. Frequency data for the haplotypes defined by the REP1 loci, and for two single-nucleotide polymorphisms flanking the SNCA promoter at the −770 and −116 loci, were also gathered.

Complete data sets for 2,692 cases of PD and 2,652 unrelated controls were obtained from the 11 sites that met data bias and sensitivity standards. Genotypes defined by the 263 bp REP1 allele had a significantly increased risk of developing PD compared with genotypes lacking this allele (P <0.001). By contrast, genotypes including the 259 bp allele had a significantly reduced risk of developing PD (P = 0.002 for trend). Surprisingly, no association was found between any of the REP1 alleles and age at onset of PD. The frequencies of the REP1, −770 and −116 loci in individuals with PD were significantly different from those in individuals without PD (P <0.001); further analysis revealed that the REP1 locus was responsible for the association between haplotype and risk of PD. The authors conclude that in the general population, variability at the SNCA REP1 locus might account for approximately 3% of the risk of developing PD.