@article {Pittman837, author = {A M Pittman and A J Myers and P Abou-Sleiman and H C Fung and M Kaleem and L Marlowe and J Duckworth and D Leung and D Williams and L Kilford and N Thomas and C M Morris and D Dickson and N W Wood and J Hardy and A J Lees and R de Silva}, title = {Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration}, volume = {42}, number = {11}, pages = {837--846}, year = {2005}, doi = {10.1136/jmg.2005.031377}, publisher = {BMJ Publishing Group Ltd}, abstract = {Background: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Objective: To investigate the pathogenic basis of this association. Methods: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. Results: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95\% of the common haplotype diversity were used to genotype well characterised PSP and CBD case{\textendash}control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least \~{}56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. Conclusions: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson{\textquoteright}s disease and other tauopathies, including Alzheimer{\textquoteright}s disease.}, issn = {0022-2593}, URL = {https://jmg.bmj.com/content/42/11/837}, eprint = {https://jmg.bmj.com/content/42/11/837.full.pdf}, journal = {Journal of Medical Genetics} }