Familial genes in sporadic disease: Common variants of α-synuclein gene associate with Parkinson's disease

Abstract

Genetic variation of the α-synuclein gene (SNCA) is known to cause familial parkinsonism, however the role of SNCA variants in sporadic Parkinson's disease (PD) remains elusive. The present study identifies an association of common SNCA polymorphisms with disease susceptibility in a series of Irish PD patients. There is evidence for association with alternate regions, of protection and risk which may act independently/synergistically, within the promoter region (Rep1; OR: 0.59, 95% CI: 0.37–0.84) and the 3′UTR of the gene (rs356165; OR: 1.67, 95% CI: 1.08–2.58). Given previous reports of association a collaborative effort is required which may exploit global linkage disequilibrium patterns for SNCA and standardise polymorphic markers used in each population. It is now crucial to identify the susceptibility allele and elucidate its functionality which may generate a therapeutic target for PD.

Introduction

Genomic variations at the α-synuclein locus (SNCA) are observed to cause familial forms of parkinsonism (Chartier-Harlin et al., 2004, Ibanez et al., 2004, Nishioka et al., 2006, Singleton et al., 2003). Monoallelic triplication of SNCA (four copies) was first described in one kindred with fulminant manifestation of early-onset parkinsonism with dementia (Muenter et al., 1998). Subsequently SNCA duplication patients (three copies) were identified who present with a less severe disease that is more reminiscent of typical Parkinson's disease (PD) (Chartier-Harlin et al., 2004, Ibanez et al., 2004). The symptoms appear to correlate with SNCA gene expression and the level of α-synuclein protein (Farrer et al., 2004). Familial forms of disease are rare and only a handful of SNCA multiplication kindreds have been reported, however the identification of familial genes has provided great insight into parkinsonism pathogenesis and generated mechanistic hypothesises for PD (Farrer, 2006).

PD is one of the most prevalent age-related neurodegenerative disorders, with approximately 2% of the population older than 65 years being affected. Neither SNCA multiplication nor the three identified pathogenic substitutions (A30P, E46K and A53T) are a cause of typical late-onset sporadic PD (Farrer, 2006). However, a modest over-expression of SNCA over the lifetime of an individual may increase risk of developing PD. This hypothesis is promoted by association of common polymorphic variants within the SNCA locus that may effect a differential transcriptional expression in vitro (Chiba-Falek and Nussbaum, 2001, Kobayashi et al., 2006, Maraganore et al., 2006, Mizuta et al., 2006, Mueller et al., 2005, Pals et al., 2004).

Herein we describe a study examining the association of a set of 14 polymorphic markers spanning the haplotypic structure of the SNCA locus within a group of Irish PD patients and healthy subjects.