The tau A0 allele in Parkinson's disease

Abstract

Parkinson's disease (PD) is primarily an alpha-synucleinopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis.

The<i> Tau</i> Gene Haplotype H1 Confers a Susceptibility to Parkinson’s Disease

“…Furthermore, a family-based association analysis of the same study population found that both the tau H1 haplotype and the A0 allele were significantly overtransmitted to affected individuals with late-onset PD [16]. However, the results from previous case-control studies appeared to be inconsistent, a significant association between tau polymorphisms and PD risk was shown in some [14,17,18,19,20] but not all studies [12, 13,21,22,23,24,25]. One study reported a reverse association.…”

“…Differences were reconciled through group discussion. Twelve published articles met the searching criteria [12,13,14,17,18,19,20,21,22,23,24,25] and included five studies specifically on the A0 allele and PD risk [17, 18, 21, 22, 25], four on H1 haplotype and PD risk [14, 19, 23, 24], and three studies on the Q7R polymorphism of the STH and PD risk [12, 13, 20]. One study, which reported the data for three ethnic groups respectively, was counted as three separate studies in the meta-analysis [12].…”

Genome-wide association study confirms extant PD risk loci among the Dutch

“…9,18 To determine which of the associated alleles in the MAPT locus were present in H1 (previously associated with PD [19][20][21][22][23][24] ) a two-locus haplotype association analysis of rs1981997 and SNPs in the MAPT region was carried out using PLINK. 15 Although we are aware that the sample size of this cohort has a limited power and a GWAS would probably fail to find any associated locus after correcting for 514 799 independent tests, we decided to carry out this analysis to look for specific PD risk loci in the Dutch population.…”

Rare genetic mutations shed light on the pathogenesis of Parkinson disease

“…Thus, the association of PD with the haplotype of tau and the evidence for linkage to that region of chromosome 17q suggest that tau, or a gene in linkage disequilibrium with tau, is a genetic risk factor for PD. Three large case-series studies also established a significant association between polymorphism of the tau gene and PD (24)(25)(26). Frontotemporal dementia with parkinsonism (FTDP) is caused, in part, by mutations in tau (27).…”