Human Molecular Genetics

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Human Molecular Genetics, 2001, Vol. 10, No. 17 1847-1851
© 2001 Oxford University Press

-synuclein gene haplotypes are associated with Parkinson’s disease

Matt Farrer, Demetrius M. Maraganore¹, Paul Lockhart, Andrew Singleton, T.G. Lesnick², Mariza de Andrade², Andrew West, Rohan de Silva³, John Hardy⁺ and Dena Hernandez

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA, ¹Department of Neurology and ²Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA and ³Reta Lila Weston Institute of Neurological Studies, 46 Cleveland Street, London W1T 4JF, UK

Received May 9, 2001; Revised and Accepted June 18, 2001.

	ABSTRACT

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We report haplotype analysis of the -synuclein gene in Parkinson’s disease (PD), extending earlier reports of an association with a polymorphism within the gene promoter. This analysis showed significant differences in haplotypes between PD cases and controls. Our analyses demonstrate that genetic variability in the -synuclein gene is a risk factor for the development of PD. These genetic findings are analogous to the tau haplotype over-represented in progressive supranuclear palsy and further extend the similarity in the etiologies and pathogeneses of the synucleinopathies and tauopathies.

	INTRODUCTION

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Parkinson’s disease (PD) consists of a clinical disorder characterized by a minimum of two of the three cardinal signs of bradykinesia, rigidity and tremor, with response to levodopa (1). Pathologically it is defined by the presence of Lewy bodies, intracellular neuronal inclusions in the substantia nigra and at other sites in the brain (1). These Lewy bodies are comprised at least in part of -synuclein (2) and mutations in -synuclein are the only, albeit rare, defined cause of this disorder (3). Most cases of PD occur sporadically and are of unknown etiology although, even in such ‘sporadic’ cases, a genetic etiology may be important (4,5). This led us to investigate whether genetic variability in the -synuclein gene could predispose to PD. Genetic variability has been reported in the -synuclein promoter (6) and this has been suggested to show an association with PD (7,8) although this has been disputed (9–11).

	RESULTS

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We started our analysis by examining the promoter polymorphism (6). Our data is shown in Table 1 and suggests an association between the promoter polymorphism and disease (P = 0.005) (Table 1). However, we were concerned because of the variability in allele frequencies between populations and the disparity in association findings between studies (some positive, some negative), and because the polymorphism (referred to as Rep1) is a mixed sequence repeat (6). With this in mind we chose to sequence 50 individuals homozygous for the commonest 261 bp -synuclein promoter allele. Sequence analysis demonstrated considerable variability in alleles of the same length. The majority of variability lies within (TC)_10–11TT(TC)_8–11(TA)_7–9(CA)_10–11, the numerical subscript being indicative of the possible number of dinucleotide repeats within the four classes, although the total number of 39 repeats is consistent with allele size (Fig. 1). However, even within non-repetitive regions single nucleotide polymorphisms (SNPs) were common (data not shown). This would confound conventional genotype association analysis, which relies on the assumption of allelic homogeneity and could lead to the masking of true allelic association by alleles of the same length.

View this table: [in this window] [in a new window]   Table 1. -synuclein promoter polymorphism (Rep1)

 

View larger version (33K): [in this window] [in a new window]   Figure 1. Sequence analysis of homozygous -synuclein promoter alleles. Shown are four variable dinucleotide repeat regions that contribute to the length of the commonest 261 bp Rep1 allele, sequenced from 50 individuals homozygous for that genotype. Forty-eight percent of sequences (24/50 persons) were truly homozygous; however, note that the underlying allelic architecture is different (shaded); 52% of sequences (26/50 persons) were heterozygous although the overall allele length is again 261 bp. Similar sequence variability exists for other alleles (data not shown).

 
Using PCR direct sequencing of the -synuclein promoter we were not able to distinguish specific alleles because of the complexity of the variability, in the absence of phase information. We therefore chose to try to dissect haplotypes by finding other genetic variability in the -synuclein gene and promoter (Materials and Methods).

Our search for additional polymorphic variability within the -synuclein gene and promoter (accession no. U46896) revealed 10 SNPs with which haplotypes might be estimated (Table 2). Two from the promoter, –770 and –116, and two from the intron 4 region (IVS4) were chosen as they were all informative (heterozygosities of 50%), easily and unequivocally scored and did not appear to be in excessive linkage disequilibrium with each other, despite their physical proximity (Materials and Methods). We then tested each of these polymorphisms for association with disease in our population sample (Table 3). The frequencies of alleles only differed significantly between PD cases and controls for the IVS4+78insG polymorphism (simulated P = 0.014). We then inferred haplotypes using the EM algorithm between the -synuclein promoter and the IVS4+78insG polymorphism and carried out an association study between these inferred haplotypes and disease (12,13). To simplify this analysis and reduce the number of sparse cells, we grouped the two shortest and two longest categories of alleles for Rep1 in the -synuclein promoter (–1 and 0 to ‘1’, 1 to ‘2’, and 2 and 3 to ‘3’). Since only six of the 48 possible five-locus haplotypes had estimated proportions >5% in this study (Table 4), selecting subsets of important loci was difficult. However, the global likelihood ratio tests for three-locus configurations in Table 5 showed that combinations including Rep1 and the flanking loci had significantly different haplotype frequencies between PD cases and controls, whereas combinations not including those loci did not. This pattern also appeared in the two- and four-locus configurations (data not shown).

View this table: [in this window] [in a new window]   Table 2. Polymorphic variants identified within the -synuclein promoter and gene

 

View this table: [in this window] [in a new window]   Table 3. -synuclein gene polymorphisms

 

View this table: [in this window] [in a new window]   Table 4. Pooled haplotype analyses for PD cases versus controls

 

View this table: [in this window] [in a new window]   Table 5. Global Likelihood Ratio and P-values for three-locus haplotypes

 

	DISCUSSION

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Our findings may be considered analogous to the over-representation of H1 haplotypes about the tau locus in PSP. In both PSP and PD, non-coding genetic variability contributes to the sporadic form of the disease entity (14 and this study). The precise mechanism by which non-coding variability in the -synuclein gene predisposes to disease is not clear: however, recent analysis of the -synuclein promoter suggests that the region of the promoter in which the polymorphism is found participates in the control of gene expression (15). Thus, it is possible that this polymorphism is itself biologically relevant, although the possibility that some other control element may be in linkage disequilibrium cannot be discounted.

	MATERIALS AND METHODS

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Subjects
The study from which these cases and controls were derived has been previously described (16). After informed consent, blood samples were drawn for DNA extraction from 319 cases and 196 controls. Cases and controls are Caucasian residents of Minnesota or the surrounding four states (Wisconsin, Iowa, South Dakota and North Dakota) with parents of European extraction. The median age at onset of cases was 64 years (range 31–91 years) and the median age at sampling of controls was 72 years (range 37–94 years).

Molecular analysis of the promoter polymorphism
Xia et al. (6) first reported a polymorphic dinucleotide repeat polymorphism in the -synuclein gene. However, when we analyzed this polymorphism by sequencing, we noted that it was a mixed repeat and that alleles of similar sizes had different sequences. Forward and fluorescently tagged reverse primers were designed to the -synuclein promoter locus (accession no. U46895), Fam5'-CCT GGC ATA TTT GAT TGC AA-3' and 5'-GAC TGG CCC AAG ATT AAC CA-3'.

Defining other variability with the -synuclein gene
Single nucleotide variants within the -synuclein promoter (accession no. U46896) were identified by sequencing overlapping PCR products derived from amplification of an equimolar pool of five samples, the products being sequenced in both directions using dRhodamine terminators. Fluorescent genotyping and sequencing were performed on an ABI377, the former analyzed using Genescan and Genotyper^® software, chromatograms aligned and base calls assessed using PolyPhredPhrap (17). This software is sufficiently sensitive to call a base mismatch in 1/5 sequences (less common variants would not have been informative for further genotyping analysis). Single base variants identified were confirmed by restriction digest, using an appropriate enzyme (New England Biolabs). Initially, a subset of 20 control samples was typed to assess heterozygosity and whether neighboring markers were in disequilibrium (whether samples homo- or heterozygous for one marker were invariably homo- or heterozygous for an adjacent marker). Larger sized alleles were denoted ‘1’, smaller alleles, ‘2’. Promoter variants –770 and –116 were assayed using PCR primers 5'-AAG AGT GCT CGT GAC CCT AAAC-3', 5'-TTG AAG GCA AGG CGT GAG-3', and 5'-CCG GTA GGC TAA ATC ACGC-3', 5'-CCA CCA AGG GCA GAG CTA TC-3', respectively, products digested with either CfoI or Cac81, according to the manufacturer’s conditions. The intron 4 (accession no. U46899) IVS4+66AG polymorphism was assayed using primers NACP 4F 5'-TCG ATG GCT AGT GGA AGT GG-3' and NACP 4R 5'-CCC ACA GTA AGT ATC TTG CTCC-3', followed by digestion with HaeIII. The IVS4+78insG polymorphism was additionally confirmed by sequencing this region in 10 control cases. A restriction digest assay was designed using the mismatch primers NACP 4F 5'-TCG ATG GCT AGT GGA AGT GG-3' and NACP 4R mismatch 5'-CCC ACA GTA AGT ATC TTG CTGC-3' and digesting with Cac81.

Statistical analysis
Model-free statistics were used to test for allelic association between PD cases and polymorphisms. To overcome the problem of inaccuracy of the asymptotic ² distribution due to sparse genotypes in contingency tables, permutation tests for allelic association and estimation of haplotypes were performed (12,13). All reported P-values for haplotype analysis were simulated using Monte Carlo methods. All analyses were performed using SAS and S-Plus software packages.

	ACKNOWLEDGEMENTS

 
We are indebted to the patients and their spouses who made this work feasible. We thank Daniel J. Schaid, PhD and Shannon K. McDonnell, MS for additional statistical assistance. M.F. and A.S. were supported in part by ADRC grant 1JA 1A3171; D.M.M. M.d.A. and T.G.L. by NIH grants NS33978, ES10751 and the Mayo Foundation; and M.F., D.M.M. and J.H. by an NIH/NINDS Udall Center grant.

	FOOTNOTES

 
⁺ To whom correspondence should be addressed. Tel: +1 904 953 7356; Fax: +1 904 953 7370; Email: hardy@mayo.edu

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