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:

A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3

Nature Genetics volume 8, pages 291–296 (1994)Cite this article

Abstract

In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p<0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Egeland, J.A. et al. Bipolar affective disorder linked to DNA markers on chromosome 11. Nature 325, 783–787 (1987).

    Article  CAS  PubMed  Google Scholar 

  2. Baron, M. Is there a gene for manic-depressive illness on the long arm of the X-chromosome? in Genetic approaches to mental disorders(eds Gershon, E.S. & Cloninger, C.R.) 253–272 (American Psychiatric Press, Washington, DC, 1994).

    Google Scholar 

  3. Kelsoe, J.R. et al. Revaluation of the linkage relationship between chromosome 11 p loci and the gene for bipolar affective disorder in the Old Order Amish. Nature 342, 238–243 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Baron, M. et al. Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees. Nature Genet. 3, 49–65 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Baron, M., Endicott, J. & Ott, J. Genetic linkage in mental illness: Limitations and prospects. Brit. J. Psychiat. 157, 645–655 (1990).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Risch, N. Genetic linkage: interpreting lod scores. Science 255, 803–804 (1992).

    Article  CAS  PubMed  Google Scholar 

  8. Pauls, D.L. Behavioural disorders: lessons in linkage. Nature Genet. 3, 4–5 (1993).

    Article  CAS  PubMed  Google Scholar 

  9. St George-Hyslop, P.H. et al. Genetic linakge studies suggest that Alzheimer's disease is not a single homogeneous disorder. Nature 347, 194–197 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Pericak-Vance, M.A. et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. hum. Genet. 48, 1034–1050 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Schellenberg, G.D. et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258, 668–671 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Risch, N. Assessing the role of HLA-linked and unlinked determinants of disease. Am. J. hum. Genet. 40, 1–14 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Easton, D.F. Linkage analysis and genetic models for type I diabetes mellitus. Genet. Epidemiol. 6, 83–88 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Owerbach, D. & Gabbay, K.H. Linkage of the VNTR/Insulin-gene and type I diabetes mellitus: increased gene sharing in affected sibling pairs. Am. J. hum. Genet. 54, 909–912 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. Baron, M. et al. A pedigree series for mapping disease genes in bipolar affective disorder: sampling, assessment and analytic considerations. Psychiat Genet. 4, 43–56 (1994).

    Article  CAS  Google Scholar 

  17. Delabar, J.-M. et al. Report on the Fourth International Workshop on Human Chromosome 21. Genomics 18, 735–745 (1993).

    Article  CAS  PubMed  Google Scholar 

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

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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 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 

  21. 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 

  22. Babron, M.-C. et al. Linkage detection by the affected — pedigree — member method: what is really tested?. Genet. Epidemiol. 10, 389–394 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Chumakov, I. et al. Continuum of overlapping clones spanning the entire human chromosome 21 q. Nature 359, 380–387 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Petrukhin, K. et al. Physical mapping, cloning, and genetic characterization of the Wilson disease locus. Nature Genet. 5, 338–343 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Wicking, C. & Williamson, B. From linked marker to gene. Trends Genet. 7, 288–293 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Lander, E.S. Finding similarities and differences among genomes. Nature Genet. 4, 5–6 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Lovett, M., Kere, J. & Hinton, L.M. Direct selection: a method for the isolation of cDNAs encoded by large genomic regions. Proc. natn. Acad. Sci. USA 88, 9628–9632 (1991).

    Article  CAS  Google Scholar 

  30. Church, D.M. et al. Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).

    Article  CAS  PubMed  Google Scholar 

  31. Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorhisms of human DNA by gel electrophoresis as single-stranded conformation polymorphisms. Proc. natn. Acad. Sci. U.S.A. 86, 2766–2770 (1989).

    Article  CAS  Google Scholar 

  32. Sheffield, V.C. et al. Attachment of a 40 base-pair G+C-rich sequence (GC-clamp) to genomic DNA fragments by the polymerase chain reaction results in improved detection of single-base changes. Proc. natn. Acad. Sci. U.S.A. 86, 232–236 (1989).

    Article  CAS  Google Scholar 

  33. Endicott, J. & Spitzer, R.L. A diagnostic interview: the schedule for affective disorders and schizophrenia. Archs. Gen. Psychiat. 35, 837–862 (1978).

    Article  CAS  Google Scholar 

  34. Andreasen, N.C. et al. The family history method using diagnostic criteria: reliability and validity. Archs. Gen. Psychiat. 34, 129–135 (1977).

    Article  Google Scholar 

  35. Spitzer, R.L., Endicott, J. & Robins, E. Research diagnostic criteria: rationale and validity. Archs. Gen. Psychiat. 35, 773–779 (1978).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  37. Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. natn. Acad. Sci. U.S.A. 81, 3443–3446 (1984).

    Article  CAS  Google Scholar 

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

    Google Scholar 

  39. Weeks, D.E., Ott, J. & Lathrop, G.M. SLINK: a general simulation program for linkage analysis. Am. J. hum. Genet. 47, A204 (abstr) (1990).

    Google Scholar 

  40. Xie, X. & Ott, J. Determining the effect of a change in affective status on the lod score. Am. J. hum. Genet. 47, A205 (abstr) (1990).

    Google Scholar 

  41. 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 

  42. Sandkuyl, L.A. Analysis of affected sib pairs using information from extended families. Prog. Clin. Biol. Research. 329, 117–122 (1989).

    CAS  Google Scholar 

Download references

Author information

Author notes

  1. Richard E. Straub

    Present address: Department of Psychiatry, Medical College of Virginia, Box 980710, Richmond, Virginia, 23298, USA

  2. T. Conrad Gilliam and Miron Baron: Correspondence should be addressed to M.B. & T.C.G.

Authors and Affiliations

  1. Department of Medical Genetics, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA

    Richard E. Straub, Ying Luo, Wei Shao, Kamna Das, T. Conrad Gilliam & Miron Baron

  2. Department of Statistical Genetics, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA

    Thomas Lehner & Jurg Ott

  3. Department of Research Assessment and Training, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA

    Jo Ellen Loth, Lawrence Sharpe, Robert Simon & Jean Endicott

  4. Department of Lithium Studies, New York State Psychiatric Institute, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA

    Ronald R. Fieve

  5. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA

    Ronald R. Fieve, Jean Endicott & Miron Baron

  6. Department of Genetics and Development, Columbia University College of Physicians and Surgeons, New York, New York, 10032, USA

    Jurg Ott & T. Conrad Gilliam

  7. Department of Psychiatry, Hadassah–Hebrew University Medical Center, Jerusalem, 91120, Israel

    Joyce R. Alexander & Bernard Lerer

Authors
  1. Richard E. Straub
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Lehner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jo Ellen Loth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lawrence Sharpe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joyce R. Alexander
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kamna Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert Simon
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ronald R. Fieve
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bernard Lerer
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean Endicott
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jurg Ott
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. T. Conrad Gilliam
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Miron Baron
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Straub, R., Lehner, T., Luo, Y. et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nat Genet 8, 291–296 (1994). https://doi.org/10.1038/ng1194-291

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1194-291

Search

Advanced 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