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Covariate analysis of late-onset Alzheimer disease refines the chromosome 12 locus

Molecular Psychiatry volume 11, pages 280–285 (2006)Cite this article

Abstract

Alzheimer disease (AD) is a progressive neurodegenerative disorder of later life with a complex etiology and a strong genetic component. Several genomic screens have suggested that a region between chromosome 12p13 and 12q22 contains at least one additional locus underlying the susceptibility of AD. However, localization of this locus has been difficult. We performed a 5 cM microsatellite marker screen across 74 cM on chromosome 12 with 15 markers in 585 multiplex families consisting of 994 affected sibpairs and 213 other affected relative pairs. Analyses across the entire data set did not reveal significant evidence of linkage. However, suggestive linkage was observed in several subsets. In the 91 families where no affected individuals carry an ApoE ɛ4 allele, an HLOD score of 1.55 was generated at D12S1042. We further examined the linkage data considering the proposed linkages to chromosome 9 (D9S741) and chromosome 10 (α-catenin gene). There was a modest (P=0.20) increase in the LOD score for D12S368 (MLOD=1.70) when using the D9S741 LOD scores as a covariate and a highly significant (P<0.001) increase in the MLOD score (4.19) for D12S1701 in autopsy-confirmed families (n=228) when using α-catenin LOD scores as a covariate. In both cases, families with no evidence of linkage to D9S741 or α-catenin demonstrated most of the evidence of linkage to chromosome 12, suggesting locus heterogeneity. Taken together, our data suggest that the 16 cM region between D12S1042 and D12S368 should be the subject of further detailed genomic efforts for the disease.

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References

  1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA . Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 2003; 60: 1119–1122.

    Article  Google Scholar 

  2. Guttman R, Altman RD, Nielsen NH . Alzheimer disease. Report of the council on scientific affairs. Arch Fam Med 1999; 8: 347–353.

    Article  CAS  Google Scholar 

  3. Myers AJ, Goate AM . The genetics of late-onset Alzheimer's disease. Curr Opin Neurol 2001; 14: 433–440.

    Article  CAS  Google Scholar 

  4. Sherrington R, Rogaev E, Liang Y, Rogaeva EA, Levesque G, Ikeda M et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995; 375: 754–760.

    Article  CAS  Google Scholar 

  5. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995; 269: 973–977.

    Article  CAS  Google Scholar 

  6. Goate AM, Chartier-Harlin MC, Mullan MC, Brown J, Crawford F, Fidani L et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991; 33: 53–56.

    Google Scholar 

  7. Rocchi A, Pellegrini S, Siciliano G, Murri L . Causative and susceptibility genes for Alzheimer's disease: a review. Brain Res Bull 2003; 61: 1–24.

    Article  CAS  Google Scholar 

  8. Pericak-Vance MA, Bebout JL, Gaskell PC, Yamaoka LH, Hung W-Y, Alberts MJ et al. Linkage studies in familial Alzheimer's disease: evidence for chromosome 19 linkage. Am J Hum Genet 1991; 48: 1034–1050.

    PubMed  PubMed Central  CAS  Google Scholar 

  9. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921–923.

    Article  CAS  Google Scholar 

  10. Cheng CY, Hong CJ, Liu HC, Liu TY, Tsai SJ . Study of the association between Alzheimer's disease and angiotensin-converting enzyme gene polymorphism using DNA from lymphocytes. Eur Neurol 2002; 47: 26–29.

    Article  CAS  Google Scholar 

  11. Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA et al. Complete genomic screen in late-onset familial Alzheimer disease: evidence for a new locus on chromosome 12. JAMA 1997; 278: 1237–1241.

    Article  CAS  Google Scholar 

  12. Kehoe P, Wavrant-De VF, Crook R, Wu WS, Holmans P, Fenton I et al. A full genome scan for late onset Alzheimer's disease. Hum Mol Genet 1999; 8: 237–245.

    Article  CAS  Google Scholar 

  13. Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small GW, Roses AD et al. Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. Am J Hum Genet 2003; 73: 1041–1051.

    Article  CAS  Google Scholar 

  14. Pericak-Vance MA, Haines JL . Genetic susceptilbility to Alzheimer disease. Trends Genet 1995; 11: 504–508.

    Article  CAS  Google Scholar 

  15. Pericak-Vance MA, Bass ML, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA et al. Complete genomic screen in late-onset familial Alzheimer's disease. Neurobiol Aging 1998; 19: S39–S42.

    Article  CAS  Google Scholar 

  16. Myers A, Wavrant De-Vrieze F, Holmans P, Hamshere M, Crook R, Compton D et al. Full genome screen for Alzheimer disease: stage II analysis. Am J Med Genet 2002; 114: 235–244.

    Article  Google Scholar 

  17. Mayeux R, Lee JH, Romas SN, Mayo D, Santana V, Williamson J et al. Chromosome-12 mapping of late-onset Alzheimer disease among Caribbean Hispanics. Am J Hum Genet 2002; 70: 237–243.

    Article  CAS  Google Scholar 

  18. McKhann G, Drachman G, Folstein M . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of the department of health and human services task force on Alzheimer's disease. Neurology 1984; 34: 939–944.

    Article  CAS  Google Scholar 

  19. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B et al. A high-resolution recombination map of the human genome. Nat Genet 2002; 31: 241–247.

    Article  CAS  Google Scholar 

  20. Rimmler J, McDowell JG, Slotterbeck BD, Haynes CS, Menold MM, Rogala A et al. Development of a data coordinating center (DCC): data quality control for complex disease studies. Am J Hum Genet 1998; 63: A240.

    Google Scholar 

  21. O'Connell JR, Weeks DE . The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recording and fuzzy inheritance. Nat Genet 1995; 11: 402–408.

    Article  CAS  Google Scholar 

  22. Schaffer AA, Gupta SK, Shriram K, Cottingham RW . Avoiding recomputation in linkage analysis. Hum Hered 1994; 44: 225–237.

    Article  CAS  Google Scholar 

  23. Ott J . Analysis of Human Genetic Linkage. Johns Hopkins University Press: Baltimore, 1999.

    Google Scholar 

  24. Cottingham Jr RW, Idury RM, Schaffer AA . Faster sequential genetic linkage computations. Am J Hum Genet 1993; 53: 252–263.

    PubMed  PubMed Central  Google Scholar 

  25. Gudbjartsson DF, Jonasson K, Frigge ML, Kong A . Allegro, a new computer program for multipoint linkage analysis. Nat Genet 2000; 25: 12–13.

    Article  CAS  Google Scholar 

  26. McPeek MS . Optimal allele-sharing statistics for genetic mapping using affected relatives. Genet Epidemiol 1999; 16: 225–249.

    Article  CAS  Google Scholar 

  27. Hauser ER, Watanabe RM, Duren WL, Bass MP, Langefeld CD, Boehnke M . Ordered subset analysis in genetic linkage mapping of complex traits. Genet Epidemiol 2004; 27: 53–63.

    Article  Google Scholar 

  28. Ertekin-Taner N, Ronald J, Asahara H, Younkin L, Hella M, Jain S et al. Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Hum Mol Genet 2003; 12: 3133–3143.

    Article  CAS  Google Scholar 

  29. Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J et al. Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science 2000; 290: 2303–2304.

    Article  CAS  Google Scholar 

  30. Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L et al. Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol 2000; 35: 1343–1352.

    Article  CAS  Google Scholar 

  31. Scott WK, Grubber JM, Conneally PM, Small GW, Hulette CM, Rosenberg CK et al. Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity. Am J Hum Genet 2000; 66: 922–932.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all of the families who participated in this study. This study was supported by NIH Grants AG019757, AG021547, AG20135, and U24 AG21886 and a grant from the Alzheimer Association (IIRG-00-2006). This work used the core resources of the GCRC (MO1 RR-00095) and the CHGR at VUMC, and the CHG at DUMC.

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Authors and Affiliations

  1. Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA

    X Liang, N Schnetz-Boutaud, S J Kenealy, L Jiang, J Bartlett, B Lynch, P C Gaskell, H Gwirtsman, L McFarland & J L Haines

  2. Center for Human Genetics and Department of Medicine, Duke University Medical Center, Durham, NC, USA

    M L Bembe, P Bronson, J R Gilbert, E R Martin & M A Pericak-Vance

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  1. X Liang
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Correspondence to J L Haines.

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Liang, X., Schnetz-Boutaud, N., Kenealy, S. et al. Covariate analysis of late-onset Alzheimer disease refines the chromosome 12 locus. Mol Psychiatry 11, 280–285 (2006). https://doi.org/10.1038/sj.mp.4001766

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