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A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity

Nature Genetics volume 11, pages 287–293 (1995)Cite this article

Abstract

In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24–22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non–parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.

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References

  1. Gottesman, I.I. & Shields, J. Schizophrenia: The Epigenetic Puzzle. (Cambridge University Press, New York, 1982).

    Google Scholar 

  2. Kendler, K.S. The genetics of schizophrenia: an overview. In Handbook of Schizophrenia: Vol. 3: Nosology, Epidemiology, and Genetics. (eds Tsuang, M.T. & Simpson, J.C.) 437 (Elsevier Science Publishers, Amsterdam, The Netherlands, 1988).

    Google Scholar 

  3. Kendler, K.S. & Diehl, S.R. The genetics of schizophrenia: A current, genetic-epidemtologic perspective. Schizophr. Bull. 19, 261–285 (1993).

    Article  CAS  PubMed  Google Scholar 

  4. O'Rourke, D.H., Gottesman, I.I., Suarez, B.K., Rice, J. & Reich, T. Refutation of the general single-locus model for the etiology of schizophrenia. Am. J. hum. Genet. 34, 630–649 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Prescott, C.A. & Gottesman, I.I. Genetically mediated vulnerability to schizophrenia. [Review]. Psych. Clin. N. Am. 16, 245–267 (1993).

    Article  CAS  Google Scholar 

  6. Cloninger, C.R. Turning point in the design of linkage studies of schizophrenia. Am. J. med. Genet. 54, 83–92 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. O'Donovan, M.C. & Owen, M.J. Advances and retreats in the molecular genetics of major mental illness. Ann. Med. 24, 171–177 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Elston, R.C. P Values, Power, and Pitfalls in the Linkage Analysis of Psychiatric Disorders. In Genetic Approaches to Mental Disorders (ed. Gershon, E.S. & Cloninger, C.R.) 3 (American Psychiatric Press, Inc. Washington, DC, 1994).

    Google Scholar 

  9. Risch, N.J. Mapping Genes for Psychiatric Disorders. In Genetic Approaches to Mental Disorders. (eds Gershon, E.S. & Cloninger, C.R.) 47 (American Psychiatric Press Inc., Washington, DC, 1994).

    Google Scholar 

  10. Suarez, B.K., Hampe, C.L. & Van Eerdewegh, P. Problems of Replicating Linkage Claims in Psychiatry. In Genetic Approaches to Mental Disorders. (eds Gershon, E.S. and Cloninger, C.R.) 23 (American Psychiatric Press, Washington, DC, 1994).

    Google Scholar 

  11. Ott, J. Cutting a Gordian knot in the linkage analysis of complex human traits. Am. J. hum. Genet. 46, 219–221 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Risch, N. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. hum. Genet. 46, 222–228 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Risch, N. Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet. Epidemiol. 7, 3–16 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Baron, M. Genetic linkage in mental illness. Nature 346, 618 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Martinez, M.M. & Goldin, L.R. The detection of linkage and heterogeneity in nuclear families for complex disorders: One versus two marker loci. Am. J. hum. Genet. 44, 552–559 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Martinez, M. & Goldin, L.R. Power of the linkage test for a heterogeneous disorder due to two independent inherited causes: a simulation study. Genet. Epidemiol. 7, 219–230 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Chen, W.J., Faraone, S.V. & Tsuang, M.T. Linkage studies of schizophrenia: a simulation study of statistical power. Genet. Epidemiol. 9, 123–139 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Davies, J.L. et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 371, 130–136 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Hashimoto, L. et al. Genetic mapping of a susceptibility locus for insulin-dependent diabetes mellitus on chromosome 11q. Nature 371, 161–164 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Tanzi, R. et al. Genetic heterogeneity of gene defects responsible for familial Alzheimer disease. Genetica 91, 255–263 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Easton, D.F. et al. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am. J. hum. Genet 52, 678–701 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315 (1993).

  23. Wang, S. et al. Evidence for a susceptibility locus for schizophrenia on chromosome 6pter–6p22. Nature Genet. 10, 41–46 (1995).

    Article  PubMed  Google Scholar 

  24. Kendler, K.K., O'Neill, F.A., Burke, J., Murphy, B., Duke, F., Straub, R.E., Shinkwin, R., NiNuallain, M., MacLean, C.J. & Walsh, D. Irish study of high©density schizophrenia families: field methods and power to detect linkage. Am. J. med. Genet. (in the press).

  25. Kendler, K.S., McGuire, M., Gruenberg, A.M. & Walsh, D. An epidemiologic, clinical, and family study of simple schizophrenia in County Roscommon, Ireland. Am. J. Psych. 151, 27–34 (1994).

    Article  CAS  Google Scholar 

  26. Kendler, K.S., McGuire, M., Gruenberg, A.M., O'Hare, A., Spellman, M. & Walsh, D. Roscommon family study: I. Methods, diagnosis of probands, and risk of schizophrenia in relatives. Archs. gen. Psychiatry 50, 527–540 (1993).

    Article  CAS  Google Scholar 

  27. Kendler, K.S., McGuire, M., Gruenberg, A.M., Spellman, M., O'Hare, A. & Walsh, D. The Roscommon family study: II. The risk of nonschizophrenic nonaffective psychoses in relatives. Archs. gen. Psychiatry 50, 645–652 (1993).

    Article  CAS  Google Scholar 

  28. Kendler, K.S., McGuire, M., Gruenberg, A.M., O'Hare, A., Spellman, M. & Walsh, D. The Roscommon family study: III. Schizophrenia-related personality disorders in relatives. Archs. gen. Psychiatry 50, 781–788 (1993).

    Article  CAS  Google Scholar 

  29. MacLean, C.J., Ploughman, L.M., Diehl, S.R. & Kendler, K.S. A new test for linkage in the presence of locus heterogeneity. Am. J. hum. Genet. 50, 1259–1266 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Volz, A., Boyle, J.M., Cann, H.M., Cottingham, R.W., Orr, H.T. & Ziegler, A. Report of the second international workshop on human chromosome 6. Genomics 21, 464–472 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Martin, M., Mann, D. & Carrington, M. Recombination rates across the HLA complex: use of microsatelHtes as a rapid screen for recombinant chromosomes. Hum. mol. Genet. 4, 423–428 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Smith, C.A.B. Testing for heterogeneity of recombination fraction values in human genetics. Ann. hum. Genet. 27, 175–182 (1963).

    Article  CAS  PubMed  Google Scholar 

  33. Lange, K., Weeks, D. & Boehnke, M. Programs for pedigree analysis: MENDEL, FISHER, and dGENE. Genet. Epidemiol. 5, 471–472 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Sandkuijl, L.A. Analysis of affected sib pairs using information from extended families. Prog. clin. Biol. Res. 329, 117–122 (1989).

    Google Scholar 

  35. Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Baron, M. et al. Genetic linkage between X-chromosome markers and bipolar affective illness. Nature 326, 289–292 (1987).

    Article  CAS  PubMed  Google Scholar 

  37. Sherrington, R. et al. Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 336, 164–167 (1988).

    Article  CAS  PubMed  Google Scholar 

  38. Clerget-Darpoux, F., Bonaiti-Pellie, C. & Hochez, J. Effects of misspecifying genetic parameters in lod score analysis. Biometrics 42, 393–399 (1986).

    Article  CAS  PubMed  Google Scholar 

  39. Weeks, D.E., Lehner, T., Squires-Wheeler, E., Kaufmann, C. & Ott, J. Measuring the inflation of the lod score due to its maximization over model parameter values in human linkage analysis. Genet. Epidemiol. 7, 237–243 (1990).

    Article  CAS  PubMed  Google Scholar 

  40. Clerget-Darpoux, F., Babron, M.-C. & Bonaïti-Pellié, C. Assessing the effect of multiple linkage tests in complex diseases. Genet. Epidemiol. 7, 245–253 (1990).

    Article  CAS  PubMed  Google Scholar 

  41. Risch, N. A note on multiple testing procedures in linkage analysis. Am. J. hum. Genet. 48, 1058–1064 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hodge, S.E. & Greenberg, D.A. Sensitivity of lod scores to changes in diagnostic status. Am. J. hum. Genet. 50, 1053–1066 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Goldin, L.R., DeLisi, L.E. & Gershon, E.S. Relationship of HLA to schizophrenia in 10 nuclear families. Psychiatry. Res. 20, 69–77 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. Wright, P., Gill, M. & Murray, R.M. Schizophrenia: genetics and the maternal immune response to viral infection. Am. J. med. Genet. 48, 40–46 (1993).

    Article  CAS  PubMed  Google Scholar 

  45. Risch, N. & Giuffra, L. Model misspecification and multipoint linkage analysis. Hum. Hered. 42, 77–92 (1992).

    Article  CAS  PubMed  Google Scholar 

  46. Vieland, V.J., Hodge, S.E. & Greenberg, D.A. Adequacy of single-locus approximations for linkage analysis of oligogenic traits. Genet. Epidemiol. 9, 45–59 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. Antonarakis, S.E. et al. Follow-up of potential vulnerability locus for schizophrenia on chromosome 6p24-p22. Nature. Genet. 11, 235–236 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Schwab, S.G. et al. Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nature Genet. 11, 325–327 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Moises, H.W. et al. An international Two-stage genome wide search for schizophrenia susceptibility genes. Nature Genet. 11, 321–324 (1995).

    Article  CAS  PubMed  Google Scholar 

  50. Mowry, B.J. et al. Lack of support for a schizophrenia susceptibility locus on chromosome 6p24-22 Nature Genet. 11, 233–234 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Gurling, H. et al. Negative linkage results for schizophrenia with D6S296 and D6S285. Nature Genet. 11, 234–235 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised, (The American Psychiatric Association, USA, 1987).

  53. Kendler, K.S., McGuire, M., Gruenberg, A.M. & Waish, D. Examining the validity of DSM-III-R schizoaffective disorder and its putative subtypes in the Roscommon family study. Am. J. Psychiatry 152, 755–764 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Spitzer, R.L., Williams, J.B.W., Gibbon, M. & First, M.B. The structured clinical interview for DSM-III-R(SCID): I: History, rationale, and description. Arch. Gen. Psychiatry 49, 624–629 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Kendler, K.S., Lieberman, J.A. & Walsh, D. The structured interview for schizotypy (SIS): a preliminary report. Schizophr. Bull. 15, 559–571 (1989).

    Article  CAS  PubMed  Google Scholar 

  56. Straub, R.E. et al. A microsatellite genetic linkage map of human chromosome 18. Genomics 15, 48–56 (1993).

    Article  CAS  PubMed  Google Scholar 

  57. Kendler, K.S. and Walsh, D. Gender and schizophrenia: results of an epidemiologically based family study. Br. J. Psych. 167, 184–192 (1995).

    Article  CAS  Google Scholar 

  58. MacLean, C.J., Sham, P.C., Ploughman, L.M., Diehl, S.R. & Kendler, K.S. Testing for linkage under heterogeneity: A test versus C test. Am. J. hum. Genet. 54, 564–567 (1994).

    PubMed Central  Google Scholar 

  59. Donis-Keller, H. et al. A genetic linkage map of the human genome. Cell 51, 319–337 (1987).

    Article  CAS  PubMed  Google Scholar 

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Author information

Author notes

  1. John Burke

    Present address: Department of Psychiatry, University of Leicester, UK

Authors and Affiliations

  1. Department of Psychiatry, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, 23298, USA

    Richard E. Straub, Charles J. MacLean, Bradley T. Webb, Jie Zhang & Kenneth S. Kendler

  2. Department of Human Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, 23298, USA

    Charles J. MacLean & Kenneth S. Kendler

  3. The Department of Psychiatry, The Queens University, Belfast, Northern Ireland, UK

    F. Anthony O'Neill & Fiona Duke

  4. The Health Research Board, Dublin, Ireland

    John Burke, Bernadette Murphy, Rosemarie Shinkwin & Dermot Walsh

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Straub, R., MacLean, C., O'Neill, F. et al. A potential vulnerability locus for schizophrenia on chromosome 6p24–22: evidence for genetic heterogeneity. Nat Genet 11, 287–293 (1995). https://doi.org/10.1038/ng1195-287

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