Lack of reproducibility in re-evaluating associations between GCH1 polymorphisms and Parkinson's disease and isolated dystonia in an Australian case-control group

Dystonia is a group of debilitating movement disorders characterized by the sustained or intermittent involuntary co-contraction of agonist and antagonist muscles. While the cause of the major of cases is not known (termed ‘idiopathic isolated dystonia’), mutations in at least 12 genes (‘DYT genes’) are known to cause hereditary dystonia syndromes [1]. We have previously investigated common single nucleotide polymorphisms (SNPs) in eight DYT genes as susceptibility factors for idiopathic isolated dystonia and reported modest associations between SNPs in the GCH1 gene and idiopathic isolated dystonia [2]. An additional supplementary analysis using a Parkinson's disease (PD) case group also demonstrated associations with the same GCH1 SNPs [2]. Two of these SNPs are in high linkage disequilibrium with SNPs that constitute a so-called “pain-protective” haplotype [3]. Because this haplotype is associated with reduced GCH1 expression and function [3], our initial findings suggested that there may be a shared functional genetic contribution to the pathogenesis of both dystonia and PD in the form of common GCH1 SNPs [2]. However, the similar odds ratios observed in both PD and dystonia association analyses for each SNP also suggested an unintentional bias in the selection of control subjects. We therefore decided to genotype these SNPs in a larger sample to reinvestigate our initial reported findings.