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Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype

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Abstract.

We and others have previously detected association of the Tau H1 haplotype on chromosome 17 with risk of idiopathic Parkinson disease (PD). The H1 haplotype appears to have a fundamental importance in neurodegeneration, as multiple studies have shown it is also associated with an increased risk for progressive supranuclear palsy, corticobasal degeneration, frontotemporal lobar degeneration syndromes, and primary progressive aphasia. Therefore, to divide the H1 haplotype into sub-haplotypes that could be more significantly associated with the risk of developing PD, and to delimit the genes lying in the H1 haplotype, we analyzed 34 single nucleotide polymorphisms (SNPs) spanning over 3.15 megabases in the region containing Tau. These SNPs are located in or flank the corticotropin-releasing hormone receptor 1, presenilin homolog 2, Tau, Saitohin, and KIAA1267 genes. Analysis of linkage disequilibrium (LD) using these 34 SNPs suggests that the H1 haplotype extends over about 1.3 megabases, making it the largest region of LD reported to date. Of the 29 SNPs lying in this region of LD, 5 were identified as “haplotype tagging” SNPs (htSNPs), capturing 96% of the sample’s haplotype diversity. Association analysis with these htSNPs revealed a new H1 sub-haplotype that is significantly associated with PD (P<0.02). These results define the genes and regulatory regions included in this region of LD, containing an important susceptibility allele contributing to increased risk of neurodegeneration.

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References

  1. Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, Pahwa R, Stern MB, Colcher A, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Goetz CG, Small GW, Masterman D, Mastaglia F, Laing NG, Stajich JM, Slotterbeck B, Booze MW, Ribble RC, Rampersaud E, West SG, Gibson RA, Middleton LT, Roses AD, Haines JL, Scott BL, Vance JM, Pericak-Vance MA (2001) Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA 286:2239–2244

    Article  CAS  PubMed  Google Scholar 

  2. Martin ER, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, Pahwa R, Stern MB, Colcher A, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Goetz CG, Small GW, Masterman D, Mastaglia F, Laing NG, Stajich JM, Ribble RC, Booze MW, Rogala A, Hauser MA, Zhang F, Gibson RA, Middleton LT, Roses AD, Haines JL, Scott BL, Pericak-Vance MA, Vance JM (2001) Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA 286:2245–2250

    Article  CAS  PubMed  Google Scholar 

  3. Maraganore DM, Hernandez DG, Singleton AB, Farrer MJ, McDonnell SK, Hutton ML, Hardy JA, Rocca WA (2001) Case-control study of the extended tau gene haplotype in Parkinson’s disease. Ann Neurol 50:658–661

    Article  CAS  PubMed  Google Scholar 

  4. Farrer M, Skipper L, Berg M, Bisceglio G, Hanson M, Hardy J, Adam A, Gwinn-Hardy K, Aasly J (2002) The tau H1 haplotype is associated with Parkinson’s disease in the Norwegian population. Neurosci Lett 322:83–86

    Article  CAS  PubMed  Google Scholar 

  5. Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, Wiederholt W, Hansen L, Masliah E, Thlal LJ, Katzman R, Xia Y, Saitoh T (1997) Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol 41:277–281

    CAS  PubMed  Google Scholar 

  6. Baker M, Litvan I, Houlden H, Adamson J, Dickson D, Perez-Tur J, Hardy J, Lynch T, Bigio E, Hutton M (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8:711–715

    Article  PubMed  Google Scholar 

  7. Higgins JJ, Golbe LI, De Biase A, Jankovic J, Factor SA, Adler RL (2000) An extended 5’-tau susceptibility haplotype in progressive supranuclear palsy. Neurology 55:1364–1367

    CAS  PubMed  Google Scholar 

  8. Houlden H, Baker M, Morris HR, MacDonald N, Pickering-Brown S, Adamson J, Lees AJ, Rossor MN, Quinn NP, Kertesz A, Khan MN, Hardy J, Lantos PL, George-Hyslop P, Munoz DG, Mann D, Lang AE, Bergeron C, Bigio EH, Litvan I, Bhatia KP, Dickson D, Wood NW, Hutton M (2001) Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56:1702–1706

    CAS  PubMed  Google Scholar 

  9. Verpillat P, Camuzat A, Hannequin D, Thomas-Anterion C, Puel M, Belliard S, Dubois B, Didic M, Michel BF, Lacomblez L, Moreaud O, Sellal F, Golfier V, Campion D, Clerget-Darpoux F, Brice A (2002) Association between the extended tau haplotype and frontotemporal dementia. Arch Neurol 59:935–939

    Article  PubMed  Google Scholar 

  10. Sobrido MJ, Abu-Khalil A, Weintraub S, Johnson N, Quinn B, Cummings JL, Mesulam MM, Geschwind DH (2003) Possible association of the tau H1/H1 genotype with primary progressive aphasia. Neurology 60:862–864

    PubMed  Google Scholar 

  11. Heutink P, Stevens M, Rizzu P, Bakker E, Kros J, Tibben A, Niermeijer M, Duijn C van, Oostra B, Swieten J van (1997) Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families. Ann Neurol 41:150–159

    CAS  PubMed  Google Scholar 

  12. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, Graaff E de, Wauters E, Baren J van, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Heutink P (1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705

    CAS  PubMed  Google Scholar 

  13. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VMY (1998) Mutation-specific functional impairments in distinct Tau isoforms of hereditary FTDP-17. Science 282:1914–1917

    Article  CAS  PubMed  Google Scholar 

  14. Murrell JR, Spillantini MG, Zolo P, Guazzelli M, Smith MJ, Hasegawa M, Redi F, Crowther RA, Pietrini P, Ghetti B, Goedert M (1999) Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 58:1207–1226

    Google Scholar 

  15. Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Lantos PL, Rossor M, Iwatsubo T, Davies Y, Allsop D, Furlong R, Owen F, Hardy J, Mann D, Hutton M (2000) Pick’s disease is associated with mutations in the tau gene. Ann Neurol 48:859–867

    Article  CAS  PubMed  Google Scholar 

  16. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D’Souza I, Lee VMY, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC (1998) Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A 95:13103–13107

    CAS  PubMed  Google Scholar 

  17. Ishizawa T, Mattila P, Davies P, Wang DS, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397

    Google Scholar 

  18. Cappelletti G, Maggioni MG, Maci R (1999) Influence of MPP+ on the state of tubulin polymerisation in NGF-differentiated PC12 cells. J Neurosci Res 56:28–35

    Article  CAS  PubMed  Google Scholar 

  19. Cappelletti G, Pedrotti B, Maggioni MG, Maci R (2001) Microtubule assembly is directly affected by MPP(+)in vitro. Cell Biol Int 25:981–984

    Article  CAS  PubMed  Google Scholar 

  20. Brinkley BR, Barham SS, Barranco SC, Fuller GM (1974) Rotenone inhibition of spindle microtubule assembly in mammalian cells. Exp Cell Res 85:41–46

    CAS  PubMed  Google Scholar 

  21. Oliveira SA, Scott WK, Martin ER, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia F, Stajich JM, Zhang F, Booze MW, Winn MP, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM (2003) Parkin mutations and susceptibility alleles in late-onset Parkinson’s disease. Ann Neurol 53:624–629

    Article  CAS  PubMed  Google Scholar 

  22. Ren Y, Zhao J, Feng J (2003) Parkin binds to alpha/beta tubulin and increases their ubiquitination and degradation. J Neurosci 23:3316–3324

    CAS  PubMed  Google Scholar 

  23. Oliveira SA, Scott WK, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons KE, Pahwa R, Stern MB, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Scott BL, Goetz CG, Small GW, Mastaglia FL, Stajich JM, Zhang F, Booze MW, Reaves JA, Middleton LT, Haines JL, Pericak-Vance MA, Vance JM, Martin ER (2003) Association study of Parkin gene polymorphisms with idiopathic Parkinson disease. Arch Neurol 60:975–980

    Article  PubMed  Google Scholar 

  24. (2000) Genetic Data Analysis: computer program for analysis of allelic data version 1.0(d15)

    Google Scholar 

  25. Abecasis GR, Cookson WO (2000) GOLD--graphical overview of linkage disequilibrium. Bioinformatics 16:182–183

    CAS  PubMed  Google Scholar 

  26. Martin ER, Monks SA, Warren LL, Kaplan NL (2000) A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 67:146–154

    CAS  PubMed  Google Scholar 

  27. Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype--phenotype associations. Eur J Hum Genet 9:301–306

    Google Scholar 

  28. Martin ER, Bass MP, Gilbert JR, Pericak-Vance MA, Hauser ER (2003) Genotype-based association test for general pedigrees: the genotype-PDT. Genet Epidemiol 25:203–213

    Article  CAS  PubMed  Google Scholar 

  29. Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A 81:3443–3446

    CAS  PubMed  Google Scholar 

  30. Nielsen DM, Ehm MG, Weir BS (1998) Detecting marker-disease association by testing for Hardy-Weinberg disequilibrium at a marker locus. Am J Hum Genet 63:1531–1540

    Article  CAS  PubMed  Google Scholar 

  31. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229

    CAS  PubMed  Google Scholar 

  32. Johnson GCL, Esposito L, Barratt BJ, Smith AN, Heward J, Genova GD, Ueda H, Cordell HJ, Eaves IA, Twells RCJ, Payne F, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SCL, Clayton DG, Todd JA (2001) Haplotype tagging for the identification of common disease genes. Nature 29:233–237

    Article  CAS  Google Scholar 

  33. Pastor P, Ezquerra M, Tolosa E, Munoz E, Marti MJ, Valldeoriola F, Molinuevo JL, Calopa M, Oliva R (2002) Further extension of the H1 haplotype associated with progressive supranuclear palsy. Mov Disord 17:550–556

    Article  PubMed  Google Scholar 

  34. Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI, Anderson GG, Zhang Y, Lench NJ, Carey A, Cardon LR, Moffatt MF, Cookson WO (2001) Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 68:191–197

    PubMed  Google Scholar 

  35. Dawson E, Abecasis GR, Bumpstead S, Chen Y, Hunt S, Beare DM, Pabial J, Dibling T, Tinsley E, Kirby S, Carter D, Papaspyridonos M, Livingstone S, Ganske R, Lohmmussaar E, Zernant J, Tonisson N, Remm M, Magi R, Puurand T, Vilo J, Kurg A, Rice K, Deloukas P, Mott R, Metspalu A, Bentley DR, Cardon LR, Dunham I (2002) A first-generation linkage disequilibrium map of human chromosome 22. Nature 418:544–548

    CAS  PubMed  Google Scholar 

  36. Desouza EB (1995) Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 20:789–819

    PubMed  Google Scholar 

  37. Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE (2002) Identification of a novel family of presenilin homologues. Hum Mol Genet 11:1037–1044

    Article  CAS  PubMed  Google Scholar 

  38. Conrad C, Vianna C, Freeman M, Davies P (2002) A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer’s disease. Proc Natl Acad Sci U S A 99:7751–7756

    Article  CAS  PubMed  Google Scholar 

  39. Oliveira SA, Martin ER, Scott WK, Nicodemus KK, Small GW, Schmechel DE, Doraiswamy PM, Roses AD, Saunders AM, Gilbert JR, Haines JL, Vance JM, Pericak-Vance MA (2003) The Q7R Saitohin gene polymorphism is not associated with Alzheimer disease. Neurosci Lett 347:143–146

    Article  CAS  PubMed  Google Scholar 

  40. Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O (1999) Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res 6:337–345

    CAS  PubMed  Google Scholar 

  41. Poorkaj P, Kas A, D’Souza I, Zhou Y, Pham Q, Stone M, Olson MV, Schellenberg GD (2001) A genomic sequence analysis of the mouse and human microtubule-associated protein tau. Mamm Genome 12:700–712

    Article  CAS  PubMed  Google Scholar 

  42. Devlin B, Risch N (1995) A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics 29:311–322

    PubMed  Google Scholar 

  43. Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J, Finch KL, Stevens JF, Livak KJ, Slotterbeck BD, Slifer SH, Warren LL, Conneally PM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM (2000) SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am J Hum Genet 67:383–394

    Article  CAS  PubMed  Google Scholar 

  44. Hauser MA, Li YJ, Takeuchi S, Walters R, Noureddine M, Maready M, Darden T, Hulette C, Martin E, Hauser E, Xu H, Schmechel D, Stenger JE, Dietrich F, Vance J (2003) Genomic convergence: identifying candidate genes for Parkinson’s disease by combining serial analysis of gene expression and genetic linkage. Hum Mol Genet 12:671–677

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements.

We are grateful to all of the families whose participation made this project possible. We thank the members of the PD Genetics Collaboration Martha A. Nance, Ray L. Watts, Jean P. Hubble, William C. Koller, Kelly Lyons, Rajesh Pahwa, Matthew B. Stern, Amy Colcher, Bradley C. Hiner, Joseph Jankovic, William G. Ondo, Fred H. Allen Jr, Christopher G. Goetz, Gary W. Small, Donna Masterman, Frank Mastaglia, and Jonathan L. Haines who contributed families to the study. We also thank Drs. Richard Morris and Norman Kaplan for their review of this manuscript and helpful comments, and the personnel at the Center for Human Genetics, Duke University Medical Center. This research was supported in part by the Morris K. Udall Parkinson’s Disease Research Center of Excellence grant 5 P50 NS39764. Additional funding was received from the National Institute on Aging (1R01-AG-20135–01) and GlaxoSmithKline. S.A.O. receives funding from a post-doctoral fellowship (BPD/5733/2001) granted by the Portuguese Science and Technology Foundation (FCT).

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Correspondence to Eden R. Martin.

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Oliveira, S.A., Scott, W.K., Zhang, F. et al. Linkage disequilibrium and haplotype tagging polymorphisms in the Tau H1 haplotype. Neurogenetics 5, 147–155 (2004). https://doi.org/10.1007/s10048-004-0180-5

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