An association of the H1 haplotype and subhaplotypes in the microtubule-associated protein Tau (MAPT) gene with Parkinson's disease (PD) has been reported. To further evaluate their role in PD, we genotyped a sample set of 765 cases and controls consisting of two large European subgroups of German (n ¼ 418) and Serbian (n ¼ 347) origin for the MAPT haplotypes H1 and H2. The H1/H1 carriers were tested for three additional MAPT polymorphisms. In the Serbian sample, there was significant evidence (P ¼ 0.0108) of an association of the H1/H1 genotype and PD. Surprisingly, in the German sample, we did not find significant differences in genotype or haplotype frequencies between patients and controls. These results suggest that the role of H1 haplotypes in the etiology of PD may be ethnically dependent.
IntroductionAlthough in the past decade several monogenic forms of Parkinson's disease (PD) have been identified, the cause of the disease in the majority of cases remains unknown, and a combination of (multiple) susceptibility genes and environmental factors is discussed. 1 Many association studies of various polymorphisms within different candidate genes have been described, often yielding conflicting results and thus precluding definite conclusions.A specific haplotype of the microtubule-associated protein Tau (MAPT) gene, denominated the H1 haplotype, has consistently been reported to be overrepresented in patients with progressive supranuclear palsy, a form of atypical parkinsonism. 2 Furthermore, an association with the H1 haplotype and idiopathic PD has also been demonstrated in most but not all studies. 3 -10 Interestingly, a biological effect of this haplotype was shown in two different cell lines in vitro; the H1 haplotype was more efficient at driving gene expression than the H2 haplotype, suggesting increased MAPT expression as the H1-mediated susceptibility factor in idiopathic PD. 6 Recently, the H1 haplotype of the MAPT gene has been partitioned into several H1-specific subhaplotypes, six of which were exclusively found in Norwegian PD patients, but not in matched controls. 11 The frequency of H1 subhaplotypes tagged with the specific single-nucleotide polymorphism (SNP) markers rs242562 (G/A), rs3785883 (G/A), rs2435207 (G/A) (corresponding to SNPs 1, 13, and 2 in Skipper et al 11 (Figure 1)) was strikingly different between the 81 studied cases and 81 controls. Especially the 'A-A' haplotype, denoted by H1-SNPs 1 and 2, was the most significantly associated one with the disease. Linkage disequilibrium (LD) among these SNPs was significant in cases but not in controls. 11 However, these findings seem to differ between ethnic groups. In a study of 133 Greek patients, the at-risk subhaplotype was the 'G-A' haplotype, represented by the same SNPs. 12 Here, we tested a larger sample set of PD patients and matched controls from two different European populations for an association with the H1 haplotype and these specific SNP markers. The German subgroup represents a Northern European population and should be...