Role of the tau gene region chromosome inversion in progressive supranuclear palsy, corticobasal degeneration, and related disorders

Abstract

Background: An inverted region on chromosome 17 has been previously linked to many Pick complex diseases. Due to the inversion, an exact causal locus has been difficult to identify, but the microtubule-associated protein tau gene is a likely candidate gene for its involvement in these diseases with tau inclusion.

Objective: To search for variants that confer susceptibility to 4 tauopathies and clinically related disorders.

Design: Genomewide association study.

Setting: University research laboratory.

Participants: A total of 231 samples were genotyped from an unrelated white population of patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia, and frontotemporal dementia with amyotrophy. Unaffected individuals from the same population were used as controls.

Main outcome measures: The results from an inverted region of chromosome 17 that contains the MAPT gene. Genotypes of cases and controls were compared using a Fisher exact test on a marker-by-marker basis. Haplotypes were determined by visually inspecting genotypes.

Results: Comparing any particular disease and controls, the association was constant across the inverted chromosome segment. Significant associations were seen for PSP and PSP combined with CBD. Of the 2 haplotypes seen in the region, H1 was overrepresented in PSP and CBD cases compared with controls.

Conclusions: As expected, the markers are highly correlated and the association is seen across the entire region, which makes it difficult to narrow down a disease-causing variant or even a possible candidate gene. However, considering the pathologic abnormalities of these diseases and the involvement of tau mutations seen in familial forms, the MAPT gene represents the most likely cause driving the association.

Figure 1

The structure of the tau gene, indicating the locations of the microtubule-binding domains (asterisks) and the flanking low-copy repeats (LCRs).

Figure 2

Association and haplotypes across the interval. A, A plot of the negative log of the P value from the comparisons between cases and controls. Known genes are represented as lines at the top of the figure. B, The genotypes for all samples across the region of interest. Each row corresponds to a sample. The samples were sorted based on diagnosis and haplotype similarity. Samples with mostly blue, or major, alleles have the H1 haplotype, and samples with mostly yellow, or minor, alleles have the H2 haplotype. Samples with mostly red, or heterozygote, alleles are H1/H2. CBD indicates corticobasal degeneration; FTD, frontotemporal dementia; MND, motor neuron disease; and PSP, progressive supranuclear palsy. The figure was created using the National Institute of Environmental Health Sciences SNPs Visual Genotypes program.