Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Evidence for a susceptibility locus for schizophrenia on chromosome 6pter–p22

Abstract

We have performed linkage analysis in 186 multiplex families to search for genes that predispose to schizophrenia. Under a model with partially dominant inheritance, moderately broad disease definition and assuming locus homogeneity, a lod score of 3.2 was obtained for D6S260 on chromosome 6p23. A multipoint lod score of 3.9 (P=2.3 × 10−5) was achieved when the F13A1 and D6S260 loci were analysed, allowing for locus heterogeneity. Adjusted for testing of multiple models, the multipoint lod score of 3.9 under heterogeneity has a genome wide significance of between 5–8%. The non–parametric affected pedigree member test provided results (P=3 × 10−4) also supporting this finding. Our findings provide supportive evidence for a susceptibility locus for schizophrenia orr distal chromosome 6p, and support a model of locus heterogeneity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Gottesman, I., SchizophreniaGenesis:TheOrigins of Madness (W.H.Freeman, New York, 1991).

    Google Scholar 

  2. Kendler, K.S. & Diehl, S.R. The genetics of schizophrenia: a current, genetic-epidemiologic perspective. Schizophrenia Bull. 19, 261–285 (1993).

    Article  CAS  Google Scholar 

  3. Baron, M., Endicott, J. & Ott, J. Genetic linkage in mental illness: limitations and prospects. Br. J. Psychiatry 157, 645–655 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Weeks, D.E. et al. Report of a workshop on genetic linkage studies in schizophrenia. Schizophrenia Bull. 16, 673–686 (1990).

    Article  CAS  Google Scholar 

  5. 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 

  6. Coon, H. et al. Genomic scan for genes predisposing to schizophrenia. Am. J. med. Genet. 54, 59–71 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Barr, C.L. et al. Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred. Am. J. med. Genet 54, 51–58 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Kendler, K.S. & Diehl, S.R. Strategies for linkage studies of schizophrenia: pedigrees, DMA markers, and statistical analyses. Schizophrenia Bull. 15, 403–419 (1989).

    Article  Google Scholar 

  9. Su, Y. et al. Exclusion of linkage between schizophrenia and the D2 dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families. Arch. Gen. Psych. 50, 205–211 (1993).

    Article  CAS  Google Scholar 

  10. Diehl, S.R., Ziegie, J., Buck, G.A., Reynolds, T.R. & Weber, J.L. Automated genotyping of human DMA polymorphisms. Am. J. hum. Genet. 47, A177 (1990).

    Google Scholar 

  11. Ziegie, J.S. et al. Application of automated DMA sizing technology for genotyping microsatellite loci. Genomics 14, 1026–1031 (1992).

    Article  Google Scholar 

  12. Reed, P.W. et al. Chromosome-specific microsatellite sets for fluorescence-based, semi-automated genome mapping. Nature Genet. 7, 390–395 (1994).

    Article  CAS  PubMed  Google Scholar 

  13. Kendler, K.S. et al. The Roscommon Family Study. II. The risk of nonschizophrenic nonaffective psychoses in relatives. Arch. Gen. Psych. 50, 645–652 (1993).

    Article  CAS  Google Scholar 

  14. 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 

  15. Kendler, K.S. et al. The Roscommon Family Study III. Schizophrenia-related personality disorders in relatives. Arch. Gen. Psych. 50, 781–788 (1993).

    Article  CAS  Google Scholar 

  16. Kostyu, D.D. The HLA gene complex and genetic susceptibility to disease. Curr. Op. Genet. Develop. 1, 40–47.

    Article  CAS  Google Scholar 

  17. NIH/CEPH Collaborative Mapping GroupA comprehensive genetic linkage map of the human genome. Science 258, 67–86 (1992).

  18. Gyapay, G. et al. The 1993–94 Généthon human genetic linkage map. Nature Genetics 7, 246–339 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Faraway, J.J. Distribution of the admixture test for the detection of linkage under heterogeneity. Genet. Epidemiol. 10, 75–83 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Blackwelder, W.C. & Elston, R.C. A comparison of sib-pair linkage tests for disease susceptibility loci.Genef. Epidemiol. 2, 85–97 (1985).

    CAS  Google Scholar 

  21. Weeks, D.E. & Lange, K. The affected-pedigree-member method of linkage analysis. Am. J. hum. Genet. 42, 315–326 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Weeks, D.E. & Lange, K. A multilocus extension of the affected-pedigree-member method of linkage analysis. Am. J. hum. Genet. 50, 859–868 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Schellenberg, G.D. et al. Chromosome 14 and late-onset familial Alzheimer disease (FAD). Am. J. hum. Genet. 53, 619–628 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Rutter, M. Psychiatric genetics: research challenges and pathways forward. Am. J. med. Genet. 54, 185–198 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Thomson, G. Identifying complex disease genes: progress and paradigms. Nature Genet. 8, 108–110 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Diehl, S.R. & MacLean, C. J. Reply to Hodge et al. al.Am. J. hum. Genet. 53, 776–777 (1993).

    Google Scholar 

  28. 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 

  29. Straub, R.E. et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nature Genet. 8, 291–296 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Babron, M.C., Martinez, M., Bonaiti-Pellie, C. & Clerget-Darpoux, F. Linkage detection by the affected-pedigree-member method: what is really tested? Genet.Epidemiol. 10, 389–394 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Ott, J. Strategies for characterizing highly polymorphic markers in human gene mapping. Am. J. hum. Genet. 51, 283–290 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Suarez, B.K., Hampe, C.L. & Van Eerdewegh, P. Problems of replicating linkage claims in psychiatry. In New Genetic Approaches to Mental Disorders (eds Gershon, E.S. & Cloninger, C.R.) 23–46 (Am. Psychiatric Press, Washington D.C., 1994).

    Google Scholar 

  33. Polymeropolous, M.H., Rath, D.S., Xiao, H. & Merril, C.R. Tetranucleotide repeat polymorphism at the human coagulation factor XIII A subunit gene (F13A1). Nucl. Acids Res. 19, 4306 (1991).

    Google Scholar 

  34. Nedospasov, S.A., Udalova, I.A., Kuprash, D.V. & Turetskaya, R.L. DMA sequence polymorphism at the human tumor necrosis factor (TNF) locus. J. Immunol. 147, 1053–1059 (1991).

    CAS  PubMed  Google Scholar 

  35. Pulver, A.E. et al. Follow-upof a report of a potential linkage for schizophrenia on chromosome 22q12–q13.1: Part 2. Am. J. med. Genet. 54, 44–50 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Boehnke, M. Allele frequency estimation from data on relatives. Am. J. hum. Genef. 48, 22–25 (1991).

    CAS  Google Scholar 

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

    Article  Google Scholar 

  38. 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 

  39. Lathrop, G.M. et al. Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. U.S.A. 81, 3443–3446 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cottingham, R.W. Jr., Idury, R.M., Schaffer, A.A. Faster sequential genetic linkage computations. Am. J. hum. Genet. 53, 252–263 (1993).

    PubMed  PubMed Central  Google Scholar 

  41. Schaffer, A.A., Gupta, S.K., Shriram, K., Cottingham, R.W. Jr., Avoiding recomputation in genetic linkage analysis. Hum. Hered. 44, 225–237 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Ott, J. Analysis of Human Genetic Linkage. (Johns Hopkins University Press, Baltimore, 1991).

    Google Scholar 

  43. Tran, L.D., Elston, R.C., Keats, B.J.B. & Wilson, A.F. Sib-pair linkage program. (ed R.C. Elston, New Orleans), Ver. 2.5.

  44. Suarez, B.K. & Van Eerdewegh, P. A comparison of three affected-sib-pair scoring methods to detect HLA-linked disease susceptibility genes. Am. J. med. Genet. 18, 135–146 (1984).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, S., Sun, Ce., Walczak, C. et al. Evidence for a susceptibility locus for schizophrenia on chromosome 6pter–p22. Nat Genet 10, 41–46 (1995). https://doi.org/10.1038/ng0595-41

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0595-41

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing