Association of α-synuclein gene haplotypes with Parkinson's disease

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Abstract

In a previous study, we detected an association between a dinucleotide repeat (Rep1) in the α-Synuclein (SNCA) gene and sporadic Parkinson's disease (PD). To extend our previous finding in a larger sample and further determine the role of SNCA in the development of PD, we screened a sample of 194 familial PD (FPD), 327 sporadic PD (SPD), and 215 controls with the Rep1 marker and 2 single nucleotide polymorphisms (SNPs) (770 and int4) in the SNCA gene. There was significant difference in allele frequency between African American and American Indian groups for Rep1 marker (p=0.03). These two samples were excluded from further analysis because of sample size. Comparison of allele frequency differences between PD and controls for the single-locus was significant only for Rep1 and SPD (p=0.017). The global case control association was highly significant for the three loci haplotypes comparisons. Our results indicate that Rep1 locus may be in linkage disequilibrium (LD) with a mutation in the gene or itself could be a risk factor for SPD.

Introduction

Idiopathic Parkinson's disease (PD) is an age dependent, neurodegenerative disease that affects almost one million people in North America. The report of a mutation within the α-synuclein gene (SNCA) on chromosome 4, that segregates with PD in an Italian kindred [1], drew attention to genetic causes of idiopathic PD. Sequence analysis of exon four revealed a single base pair change at position 209 from G to A (G209A) that causes an Ala to Thr substitution at position 53 of the protein (Ala53Thr) and creates a Tsp45I restriction site. This mutation, also found in five Greek families with early onset PD [1], [2], has not been replicated in other samples [3], [4], [5], [6]. Two other distinct mutations in this gene have been found to cause PD; a G–C transversion at position 88 of the coding sequence (Ala30Pro) in a German family [7] and an E46K mutation in a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucination [8]. Triplication of the SNCA gene has also been associated with autosomal dominant PD with dementia [9]. Pathologically, both sporadic and SNCA associated PD brains include α-synuclein containing inclusions (lewy bodies), suggesting a pathophysiologic link between sporadic and hereditary PD syndromes.

In a previous study, we detected an association between a dinucleotide repeat (Rep1) in the SNCA gene and sporadic PD (SPD) [3] that has been confirmed by others [10], [11], [12], [13]. One study reported a strong association between single nucleotide polymorphisms (SNPs) in SNCA and SPD in a Japanese population [13]. Meta-analysis also revealed a highly significant association of SNCA Rep1 with risk of PD [14]. However, others did not find an association between Rep1 alleles or other polymorphisms in SNCA and PD in European populations [15], [16]. To extend our previous finding in a larger sample and further determine the role of SNCA in the development of PD, we collected a much larger sample of people with PD. This sample is well characterized (regular follow up and systematic evaluation), categorized based on family history (FPD and SPD), and age at onset. The PD and control samples were screened with the Rep1 marker and 2 SNPs (770 and int4) in the gene.

Section snippets

Patients

This study was approved by the Washington University and University of Arkansas for Medical Sciences Human Studies Committees. PD subjects were recruited from the Washington University Movement Disorder Center. After obtaining written informed consent, all subjects had a history and physical examination performed by a movement disorders expert. Each subject provided a detailed family history of all first-degree relatives including name, age (or age at death), medical problems, cause of death

Results

The distribution of alleles in the PD groups of diagnostic certainty is shown in Table 1. Every group contained a few missing data point (genotype) due to poor PCR amplification. Observed allele frequencies for Rep1 were significantly different between SPD and controls (p=0.017) but not FPD and controls. Comparison of allele frequencies between FPD, SPD and controls with SNPs (770 and int4) was negative. The genotype distribution in PD groups is presented in Table 2. Hardy–Weinberg equilibria

Discussion

The major findings of this study are the association of SNCA Rep1 with SPD, a highly significant association of SNCA haplotypes with the total PD sample (FPD and SPD), and haplotypes associated with increased risk of PD. This study of a larger sample of patients with PD from the same Movement Disorders Center that has been categorized by family history and age of onset confirms our previous publication [3]. Since the publication of our first report of an association between Rep1 in SNCA gene

Acknowledgement

Support has been provided in part by the Arkansas Biosciences Institute, the major research component of the Tobacco Settlement Proceeds Act of 2000.

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