Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

A. M. Pittman, A. J. Myers, P. Abou-Sleiman, H. C. Fung, M. Kaleem, L. Marlowe, J. Duckworth, D. Leung, D. Williams, L. Kilford, N. Thomas, C. M. Morris, D. Dickson, N. W. Wood, J. Hardy, Andrew J. Lees, R. De Silva

Research output: Contribution to journalArticle

183 Scopus citations

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-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's disease and other tauopathies, including Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)837-846
Number of pages10
JournalJournal of medical genetics
Volume42
Issue number11
DOIs
StatePublished - Nov 1 2005

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration'. Together they form a unique fingerprint.

  • Cite this

    Pittman, A. M., Myers, A. J., Abou-Sleiman, P., Fung, H. C., Kaleem, M., Marlowe, L., Duckworth, J., Leung, D., Williams, D., Kilford, L., Thomas, N., Morris, C. M., Dickson, D., Wood, N. W., Hardy, J., Lees, A. J., & De Silva, R. (2005). Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. Journal of medical genetics, 42(11), 837-846. https://doi.org/10.1136/jmg.2005.031377