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


METHODS
Genomewide association study.


METHODS
University research laboratory.


METHODS
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.


METHODS
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.
Webb
Amy
A
Department of Biomedical Engineering, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264, USA.
Miller
Bruce
B
Bonasera
Stephen
S
Boxer
Adam
A
Karydas
Anna
A
Wilhelmsen
Kirk C
KC
D000368:Aged; D001479:Basal Ganglia; D002540:Cerebral Cortex; D007446:Chromosome Inversion; D002886:Chromosomes, Human, Pair 17; D003704:Dementia / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D013494:Supranuclear Palsy, Progressive / Q000235:genetics*; D024801:Tauopathies / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
C054369:MAPT protein, human; D016875:tau Proteins