Alpha-synuclein and familial Parkinson's disease

Abstract

Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3' region of SNCA. The four SNPs were in high LD (r(2) > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3' haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3' haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3' region of SNCA convey an increased risk for PD.

FIG. 1

Linkage disequilibrium between Rep1 and the 3′ SNPs. The gene structure of SNCA is based on transcript NM_000345, isoform NACP140. The direction of transcription is indicated by an arrow, which explains why the promoter is on the right side and the 3′ end of the gene is on the left side. The size of the gene is indicated by the ruler at the top of the figure. The pairwise linkage disequilibrium (D′ on the left side; r² on the right side) estimates for the genotyped SNPs are represented by the boxes. Darkly shaded boxes have strong evidence of LD, whereas lightly shaded boxes have lower evidence of LD. Boxes without numbers are in complete LD (100%). Note that the 263 and 259 alleles have been separated as two distinct alleles for the purpose of this diagram. Similarly, the two major haplotypes were incorporated as a two-allele system (which means that the information from these SNPs is presented twice – once individually and once collectively as a haplotype).