Genetic studies, including genome-wide association, have demonstrated the importance of both the inversion polymorphism and haplotype-specific polymorphisms in disease.
In fact, two distinct types of disease association have been demonstrated, of which the first is the association of the H1 haplotype with an increased risk of PD (odds ratio ∼1.7) (4–6), PSP (odds ratio 5.5) (1,2) and CBD (odds ratio ∼5) (3).
This sequence appears, in Europeans at least, to descend from a single founder (13,14).
The common haplotype clades marking the majority and inverted sequences are termed H1 and H2, respectively.
These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the (microtubule-associated protein tau) locus is one of the most remarkable in neurogenetics due not only to its involvement in multiple neurodegenerative disorders, including progressive supranuclear palsy (PSP) (1,2), corticobasal degeneration (CBD) (3), Parksinson's disease (PD) (4–6) and possibly Alzheimer's disease (AD) (7,8), but also its genetic evolution and complex alternative splicing—features which are to some extent linked and so all the more intriguing (9–11).