Pittman, AM and Myers, AJ and Abou-Sleiman, P and Fung, HC and Kaleem, M and Marlowe, L and Duckworth, J and Leung, D and Williams, D and Kilford, L and Thomas, N and Morris, CM and Dickson, D and Wood, NW and Hardy, J and Lees, AJ and de Silva, R (2005) Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J MED GENET , 42 (11) 837 - 846. 10.1136/jmg.2005.031377.
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-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 similar to 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's disease and other tauopathies, including Alzheimer's disease.
|Title:||Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration|
|Open access status:||An open access publication|
|Publisher version:||http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1735957/?tool=pubmed|
|Keywords:||RICHARDSON-OLSZEWSKI-SYNDROME, PARKINSONS-DISEASE, DEMENTIA, SELECTION, FTDP-17, IDENTIFICATION, POLYMORPHISM, PHENOTYPE, MUTATION, MAPT|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Molecular Neuroscience|
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > RLW Institute of Neurological Sciences
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