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J Med Genet. 2005 November; 42(11): 837–846.
Published online 2005 March 25. doi:  10.1136/jmg.2005.031377
PMCID: PMC1735957

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


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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Selected References

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  • Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat. 2004 Oct;24(4):277–295. [PubMed]
  • Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702–705. [PubMed]
  • Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7737–7741. [PubMed]
  • Maher ER, Lees AJ. The clinical features and natural history of the Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1986 Jul;36(7):1005–1008. [PubMed]
  • Daniel SE, de Bruin VM, Lees AJ. The clinical and pathological spectrum of Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy): a reappraisal. Brain. 1995 Jun;118(Pt 3):759–770. [PubMed]
  • Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, Goetz CG, Golbe LI, Grafman J, Growdon JH, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology. 1996 Jul;47(1):1–9. [PubMed]
  • de Yébenes JG, Sarasa JL, Daniel SE, Lees AJ. Familial progressive supranuclear palsy. Description of a pedigree and review of the literature. Brain. 1995 Oct;118(Pt 5):1095–1103. [PubMed]
  • Rojo A, Pernaute RS, Fontán A, Ruíz PG, Honnorat J, Lynch T, Chin S, Gonzalo I, Rábano A, Martínez A, et al. Clinical genetics of familial progressive supranuclear palsy. Brain. 1999 Jul;122(Pt 7):1233–1245. [PubMed]
  • Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, Wiederholt W, Hansen L, Masliah E, Thal LJ, et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol. 1997 Feb;41(2):277–281. [PubMed]
  • Di Maria E, Tabaton M, Vigo T, Abbruzzese G, Bellone E, Donati C, Frasson E, Marchese R, Montagna P, Munoz DG, et al. Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol. 2000 Mar;47(3):374–377. [PubMed]
  • Houlden H, Baker M, Morris HR, MacDonald N, Pickering-Brown S, Adamson J, Lees AJ, Rossor MN, Quinn NP, Kertesz A, et al. Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology. 2001 Jun 26;56(12):1702–1706. [PubMed]
  • Poorkaj Parvoneh, Muma Nancy A, Zhukareva Victoria, Cochran Elizabeth J, Shannon Kathleen M, Hurtig Howard, Koller William C, Bird Thomas D, Trojanowski John Q, Lee Virginia M-Y, et al. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol. 2002 Oct;52(4):511–516. [PubMed]
  • Wszolek ZK, Tsuboi Y, Uitti RJ, Reed L, Hutton ML, Dickson DW. Progressive supranuclear palsy as a disease phenotype caused by the S305S tau gene mutation. Brain. 2001 Aug;124(Pt 8):1666–1670. [PubMed]
  • Morris HR, Osaki Y, Holton J, Lees AJ, Wood NW, Revesz T, Quinn N. Tau exon 10 +16 mutation FTDP-17 presenting clinically as sporadic young onset PSP. Neurology. 2003 Jul 8;61(1):102–104. [PubMed]
  • Morris HR, Katzenschlager R, Janssen JC, Brown JM, Ozansoy M, Quinn N, Revesz T, Rossor MN, Daniel SE, Wood NW, et al. Sequence analysis of tau in familial and sporadic progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 2002 Mar;72(3):388–390. [PMC free article] [PubMed]
  • Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M. Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet. 1999 Apr;8(4):711–715. [PubMed]
  • Ezquerra M, Pastor P, Valldeoriola F, Molinuevo JL, Blesa R, Tolosa E, Oliva R. Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans. Neurosci Lett. 1999 Nov 19;275(3):183–186. [PubMed]
  • de Silva R, Weiler M, Morris HR, Martin ER, Wood NW, Lees AJ. Strong association of a novel Tau promoter haplotype in progressive supranuclear palsy. Neurosci Lett. 2001 Oct 5;311(3):145–148. [PubMed]
  • Pittman Alan M, Myers Amanda J, Duckworth Jaime, Bryden Leslie, Hanson Melissa, Abou-Sleiman Patrick, Wood Nicholas W, Hardy John, Lees Andrew, de Silva Rohan. The structure of the tau haplotype in controls and in progressive supranuclear palsy. Hum Mol Genet. 2004 Jun 15;13(12):1267–1274. [PubMed]
  • Conrad Chris, Vianna Cintia, Freeman Melissa, Davies Peter. A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer's disease. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7751–7756. [PubMed]
  • de Silva R, Hope A, Pittman A, Weale ME, Morris HR, Wood NW, Lees AJ. Strong association of the Saitohin gene Q7 variant with progressive supranuclear palsy. Neurology. 2003 Aug 12;61(3):407–409. [PubMed]
  • Ponting Chris P, Hutton Mike, Nyborg Andrew, Baker Matthew, Jansen Karen, Golde Todd E. Identification of a novel family of presenilin homologues. Hum Mol Genet. 2002 May 1;11(9):1037–1044. [PubMed]
  • Healy DG, Abou-Sleiman PM, Lees AJ, Casas JP, Quinn N, Bhatia K, Hingorani AD, Wood NW. Tau gene and Parkinson's disease: a case-control study and meta-analysis. J Neurol Neurosurg Psychiatry. 2004 Jul;75(7):962–965. [PMC free article] [PubMed]
  • Skipper Lisa, Wilkes Kristen, Toft Mathias, Baker Matthew, Lincoln Sarah, Hulihan Mary, Ross Owen A, Hutton Mike, Aasly Jan, Farrer Matthew. Linkage disequilibrium and association of MAPT H1 in Parkinson disease. Am J Hum Genet. 2004 Oct;75(4):669–677. [PubMed]
  • Weale Mike E, Depondt Chantal, Macdonald Stuart J, Smith Alice, Lai Poh San, Shorvon Simon D, Wood Nicholas W, Goldstein David B. Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping. Am J Hum Genet. 2003 Sep;73(3):551–565. [PubMed]
  • Lewontin RC. The Interaction of Selection and Linkage. I. General Considerations; Heterotic Models. Genetics. 1964 Jan;49(1):49–67. [PubMed]
  • Morris HR, Janssen JC, Bandmann O, Daniel SE, Rossor MN, Lees AJ, Wood NW. The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 1999 May;66(5):665–667. [PMC free article] [PubMed]
  • Sham PC, Curtis D. Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet. 1995 Jan;59(Pt 1):97–105. [PubMed]
  • Evans Whitney, Fung Hon Chung, Steele John, Eerola Johanna, Tienari Pentti, Pittman Alan, Silva Rohan de, Myers Amanda, Vrieze Fabienne Wavrant-De, Singleton Andrew, et al. The tau H2 haplotype is almost exclusively Caucasian in origin. Neurosci Lett. 2004 Oct 21;369(3):183–185. [PubMed]
  • Golbe LI, Lazzarini AM, Spychala JR, Johnson WG, Stenroos ES, Mark MH, Sage JI. The tau A0 allele in Parkinson's disease. Mov Disord. 2001 May;16(3):442–447. [PubMed]
  • Oliveira Sofia A, Scott William K, Zhang Fengyu, Stajich Jeffrey M, Fujiwara Kenichiro, Hauser Michael, Scott Burton L, Pericak-Vance Margaret A, Vance Jeffery M, Martin Eden R. Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype. Neurogenetics. 2004 Sep;5(3):147–155. [PubMed]
  • Stefansson Hreinn, Helgason Agnar, Thorleifsson Gudmar, Steinthorsdottir Valgerdur, Masson Gisli, Barnard John, Baker Adam, Jonasdottir Aslaug, Ingason Andres, Gudnadottir Vala G, et al. A common inversion under selection in Europeans. Nat Genet. 2005 Feb;37(2):129–137. [PubMed]
  • Pastor Pau, Ezquerra Mario, Perez J Christian, Chakraverty Sumi, Norton Joanne, Racette Brad A, McKeel Dan, Perlmutter Joel S, Tolosa Eduardo, Goate Alison M. Novel haplotypes in 17q21 are associated with progressive supranuclear palsy. Ann Neurol. 2004 Aug;56(2):249–258. [PubMed]
  • Kwok John B J, Teber Erdahl T, Loy Clement, Hallupp Marianne, Nicholson Garth, Mellick George D, Buchanan Daniel D, Silburn Peter A, Schofield Peter R. Tau haplotypes regulate transcription and are associated with Parkinson's disease. Ann Neurol. 2004 Mar;55(3):329–334. [PubMed]
  • Buée L, Delacourte A. Comparative biochemistry of tau in progressive supranuclear palsy, corticobasal degeneration, FTDP-17 and Pick's disease. Brain Pathol. 1999 Oct;9(4):681–693. [PubMed]

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