MAPT H1 haplotype is a risk factor for essential tremor and multiple system atrophy

Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17).¹ In addition, the major common MAPT-containing H1 haplotype is associated with increased risk for 2 parkinsonian disorders: progressive supranuclear palsy (PSP) characterized by 4-repeat tau pathology and Parkinson disease (PD) with α-synuclein pathology.^2,3 However, the role of MAPT variation in other disorders with similar pathology or disease phenotype is unclear. We investigated the frequency of the MAPT H1 haplotype in both essential tremor (ET) and multiple system atrophy (MSA).

ET is the most common movement disorder, and prior evidence has indicated a common link between ET and PD from clinical, epidemiologic, and pathologic studies as well as some reports of brainstem Lewy bodies at autopsy in patients with ET.⁴ MSA is a neurodegenerative disorder with α-synuclein pathology with a mixed clinical presentation combining autonomic dysfunction, parkinsonism, and cerebellar or pyramidal symptoms. The initial clinical signs of MSA with prominent parkinsonism can make it difficult to differentially diagnose it from early PD. In addition, up to 30% of patients with MSA with prominent parkinsonism may have a transient response to levodopa therapy.⁵

Methods.

Genotyping of the MAPT H1 discriminating SNP (rs1052553) and H1c subhaplotype SNP (rs242557) was performed on a Sequenom MassArray iPLEX platform (San Diego, CA) (primer sequences are available on request) and analyzed with Typer 4.0 software. The rate of genotype calls was ≥95% in each population. The series contained 356 patients with clinical ET, 61 patients with pathologically confirmed MSA, and 409 US control subjects; all samples are North American Caucasians. Numerical variables were summarized with the sample mean, SD, and range (table e-1 on the Neurology® Web site at www.neurology.org). Associations between ET and MSA with MAPT rs1052553 and rs242557 were measured by χ² statistics with Pearson probability estimates and corresponding odds ratios (ORs) with confidence intervals (CIs).

Standard protocol approvals, registrations, and patient consents.

The ethical review boards at each institution approved the study, and all participants provided informed consent.

Results.

We observed an uncorrected association of MAPT H1 genotype with both ET (p = 0.027) and MSA (p = 0.016) when compared to the frequency in controls (table 1). No significant association was observed with SNP rs242557. The observed OR for ET [1.32 (1.03–1.67)] and MSA [1.91 (1.13–3.23)] are similar to those observed for PD in the same population [1.47 (1.15–1.89)].⁶

Table 1.

Allele and genotype frequencies for MAPT rs1052553 and rs242557^a

Abbreviations: CI = confidence interval; ET = essential tremor; MSA = multiple system atrophy; SNP = single nucleotide polymorphism.

^aFor rs1052553 allele A corresponds to the H1 haplotype, and for rs242557 allele A corresponds to the H1c haplotype.

^bSignificant.

Discussion.

Given the relatively small sample size for both the ET and MSA series, and the possible clinical overlap with PD in the ET series, these results must be treated with caution and require independent replication. However, it is intriguing that while the extended haplotype containing MAPT has now shown association with a number of parkinsonian disorders, there is no evidence of association with AD, which displays abundant tau pathology. Given the presence of α-synuclein pathology in PD, MSA, and ET, these findings indicate a possible interplay between these proteins. It has been previously suggested that α-synuclein induces fibrillization of tau and that coincubation of tau and α-synuclein synergistically promotes fibrillization of both proteins.⁷

While we observed an association between the MAPT H1 haplotype and both ET and MSA, the functional variant remains to be identified. The expanded H1 haplotype contains MAPT, which is the best candidate gene to explain the observed association; however, other genes are present in this haplotype that cannot be excluded. It is postulated that the alternate MAPT haplotypes affect a differential expression of 3-repeat and 4-repeat tau protein in FTDP-17.² The SNP displaying the strongest association with risk of the tauopathy PSP (rs242557) does not show the same association with PD, MSA, or ET, suggesting different pathomechanisms for disease risk.^2,6

It is now crucial to determine the functional risk variants that are located on the backbone of the extended H1 haplotype containing MAPT. With the established genomic capture and next-generation sequencing approaches, this goal is within reach. Sequencing of the entire extended haplotype will identify the variants influencing risk of PSP, PD, MSA, or ET, and help elucidate the disease pathways involved.

AUTHOR CONTRIBUTIONS

Statistical analysis was conducted by Dr. Carles Vilariño-Güell.