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, Dennis W Dickson, N. W. Wood, J. Hardy, Andrew J. Lees, R. De Silva

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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 2005

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Progressive Supranuclear Palsy
Linkage Disequilibrium
Haplotypes
Genes
Single Nucleotide Polymorphism
Genotype
Tauopathies
HapMap Project
Introns
Parkinson Disease
Exons
Alzheimer Disease

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. / 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, Dennis W; Wood, N. W.; Hardy, J.; Lees, Andrew J.; De Silva, R.

In: Journal of Medical Genetics, Vol. 42, No. 11, 11.2005, p. 837-846.

Research output: Contribution to journalArticle

Pittman, AM, Myers, AJ, Abou-Sleiman, P, Fung, HC, Kaleem, M, Marlowe, L, Duckworth, J, Leung, D, Williams, D, Kilford, L, Thomas, N, Morris, CM, Dickson, DW, Wood, NW, Hardy, J, Lees, AJ & 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, vol. 42, no. 11, pp. 837-846. https://doi.org/10.1136/jmg.2005.031377
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, Dennis W ; Wood, N. W. ; Hardy, J. ; Lees, Andrew J. ; De Silva, R. / Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. In: Journal of Medical Genetics. 2005 ; Vol. 42, No. 11. pp. 837-846.
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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.",
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T1 - Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

AU - Pittman, A. M.

AU - Myers, A. J.

AU - Abou-Sleiman, P.

AU - Fung, H. C.

AU - Kaleem, M.

AU - Marlowe, L.

AU - Duckworth, J.

AU - Leung, D.

AU - Williams, D.

AU - Kilford, L.

AU - Thomas, N.

AU - Morris, C. M.

AU - Dickson, Dennis W

AU - Wood, N. W.

AU - Hardy, J.

AU - Lees, Andrew J.

AU - De Silva, R.

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N2 - 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.

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