Role of ethnicity on the association of MAPT H1 haplotypes and subhaplotypes in Parkinson's disease

Abstract

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...

MAPT rs242562 and GSK3B rs334558 are associated with Parkinson’s Disease in central China

“…The frequency of rs242562 GG genotype is higher in controls compared to that in cases, indicating it may play a protective role. These data are different from a previous study which showed that MAPT polymorphism rs242562 revealed no significant difference between PD patients and controls in Germany, Serbia and Greece [6,18,19]. The sample size, ethnic groups and environment may contribute to the different results.…”

Caffeine Interaction with Glutamate Receptor Gene GRIN2A: Parkinson's Disease in Swedish Population

“…In the population with European ancestry, the H2 haplotype has a 20% prevalence whereas it is nearly absent in East Asians [17]. Even among European populations, MAPT ethnic variations were found [16]. While there was a significant association of the H1/H1 genotype and PD in the Serbian population, the same study failed to find such association in a German population.…”

“…For example, it is known that there are ethnic variations in MAPT . Caucasians display two distinctive haplotypes; H1 and H2, a 900-kb inversion polymorphism on chromosome 17 that contains several genes including MAPT [16]. In the population with European ancestry, the H2 haplotype has a 20% prevalence whereas it is nearly absent in East Asians [17].…”

H1 tau haplotype-related genomic variation at 17q21.3 as an Asian heritage of the European Gypsy population

“…Exposure to different (European) environmental factors means differences in epigenetic effects on gene expression (Spielman et al, 2007). For instance, a recent study (Winkler et al, 2007) indicated H1/H1 genotype as an ethnically dependent risk factor of Parkinson's disease, and another one raised remarkable suggestions on this field . An early work also observed association regarding tau variants and Asian versus Caucasian populations in progressive supranuclear palsy (Conrad et al, 1998).…”