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.

  • Immediate Communication
  • Published:

Bipolar disorder susceptibility region on Xq24–q27.1 in Finnish families

Abstract

Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24–q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24–q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Goodwin FK, Jamison KR . Manic-Depressive Illness Oxford University Press: New York 1990

    Google Scholar 

  2. Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3 Nat Genet 1994 8: 291–296

    Article  CAS  PubMed  Google Scholar 

  3. Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nat Genet 1996 12: 427–430

    Article  CAS  PubMed  Google Scholar 

  4. McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S et al. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees Proc Natl Acad Sci 1996 93: 13060–13065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rice JP, Goate A, Williams JT, Bierut L, Dorr D, Wu W et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12 Am J Med Genet 1997 74: 247–253

    Article  CAS  PubMed  Google Scholar 

  6. Ginns EI, St Jean P, Philibert RA, Galdzicka M, Damschroder-Williams P et al. A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish Proc Natl Acad Sci 1998 95: 15531–15536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B et al. Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogeneous population in Quebec points to a locus of major effect on chromosome 12q23–q24 Am J Med Gen 1999 88: 567–587

    Article  CAS  Google Scholar 

  8. Peltonen L, Palotie A, Lange K . Use of population isolates for mapping complex traits Nat Rev Genet 2000 1: 182–190

    Article  CAS  PubMed  Google Scholar 

  9. Kuokkanen S, Sundvall M, Terwilliger JD, Tienari PJ, Wikstrom J, Holmdahl R et al. A putative vulnerability locus to multiple sclerosis maps to 5p14–p12 in a region syntenic to the murine locus Eae2 Nat Genet 1996 13: 477–480

    Article  CAS  PubMed  Google Scholar 

  10. Pajukanta P, Nuotio I, Terwilliger JD, Porkka KV, Ylitalo K, Pihlajamaki J et al. Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23 Nat Genet 1998 18: 369–373

    Article  CAS  PubMed  Google Scholar 

  11. Mahtani MM, Widen E, Lehto M, Thomas J, McCarthy M, Brayer J et al. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families Nat Genet 1996 14: 90–94

    Article  CAS  PubMed  Google Scholar 

  12. Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R et al. A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci Am J Hum Genet 1999 65: 1114–1124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pekkarinen P, Terwilliger J, Bredbacka PE, Lonnqvist J, Peltonen L . Evidence of a predisposing locus to bipolar disorder on Xq24–q27.1 in an extended Finnish pedigree Genome Res 1995 5: 105–115

    Article  CAS  PubMed  Google Scholar 

  14. Kuoppasalmi KLJ, Pylkkanen K, Huttunen M . Classification of mental disorders in Finland: a comparison of the Finnish classification of mental disorders 1987 with DSM-III-R Psychiatria Fennica 1989 20: 65–81

    Google Scholar 

  15. Kessing LV . Validity of diagnoses and other clinical register data in patients with affective disorder Eur Psychiatry 1998 13: 392–398

    Article  CAS  PubMed  Google Scholar 

  16. Kieseppä T, Partonen T, Kaprio J, Lönnqvist J . Accurancy of register- and record-based bipolar I disorder diagnoses in Finland; a study of twins Acta Neuropsychiatrica 2000 13: 106–109

    Article  Google Scholar 

  17. Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G et al. Blot hybridisation analysis of genomic DNA J Med Genet 1984 21: 164–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cox DR, Burmeister M, Price ER, Kim S, Myers RM . Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes Science 1990 250: 245–250

    Article  CAS  PubMed  Google Scholar 

  19. Gyapay G, Schmitt K, Fizames C, Jones H, Vega-Czarny N, Spillett D et al. A radiation hybrid map of the human genome Hum Mol Genet 1996 5: 339–346

    Article  CAS  PubMed  Google Scholar 

  20. Terwilliger JD, Goring HH . Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design Hum Biol 2000 72: 63–132

    CAS  PubMed  Google Scholar 

  21. Ott J . Analysis of Human Genetic Linkage, rev edn John Hopkins University Press: Baltimore 1991 p 223

    Google Scholar 

  22. Terwilliger JD, Ott J . A haplotype-based ‘haplotype relative risk’ approach to detecting allelic associations Hum Hered 1992 42: 337–346

    Article  CAS  PubMed  Google Scholar 

  23. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993 52: 506–516

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ott J . Computer-simulation methods in human linkage analysis Proc Natl Acad Sci 1989 86: 4175–4178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247

    Article  CAS  PubMed  Google Scholar 

  27. Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nat Genet 1996 12: 427–430

    Article  CAS  PubMed  Google Scholar 

  28. Ewald H, Degn B, Mors O, Kruse TA . Significant linkage between bipolar affective disorder and chromosome 12q24 Psychiatr Genet 1998 8: 131–140

    Article  CAS  PubMed  Google Scholar 

  29. Craddock N, Owen M, Burge S, Kurian B, Thomas P, McGuffin P . Familial cosegregation of major affective disorder and Darier's disease (keratosis follicularis) Br J Psychiatry 1994 164: 355–358

    Article  CAS  PubMed  Google Scholar 

  30. Freimer NB, Reus VI, Escamilla M, Spesny M, Smith L, Service S et al. An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees Am J Med Genet 1996 67: 254–263

    Article  CAS  PubMed  Google Scholar 

  31. Blackwood D, Muir W . Molecular genetics and the epidemiology of bipolar disorder Ann Med 2001 33: 242–247

    Article  CAS  PubMed  Google Scholar 

  32. Craddock N, Owen M . Christmas disease and major affective disorder Br J Psychiatry 1992 160: 715

    Article  CAS  PubMed  Google Scholar 

  33. Reich T, Clayton PJ, Winokur G . Family history studies: V. The genetics of mania Am J Psychiatry 1969 125: 1358–1369

    Article  CAS  PubMed  Google Scholar 

  34. Lucotte G, Landoulsi A, Berriche S, David F, Babron MC . Manic depressive illness is linked to factor IX in a French pedigree Ann Genet 1992 35: 93–95

    CAS  PubMed  Google Scholar 

  35. Gill M, Castle D, Duggan C . Cosegregation of Christmas disease and major affective disorder in a pedigree Br J Psychiatry 1992 160: 112–114

    Article  CAS  PubMed  Google Scholar 

  36. Jeffries FM, Reiss AL, Brown WT, Meyers DA, Glicksman AC, Bandyopadhyay S . Bipolar spectrum disorder and fragile X syndrome: a family study Biol Psychiatry 1993 33: 213–216

    Article  CAS  PubMed  Google Scholar 

  37. Baron M . X-linkage and manic-depressive illness: a reassessment Soc Biol 1991 38: 179–188

    CAS  PubMed  Google Scholar 

  38. Liu J, Aita VM, Wang Z, Knowles JA, Terwilliger J, Matis TC et al. Progress in a genome-wide search for genetic factors for bipolar disorder Am J Med Genet 1997 74: 590 (abstract)

    Google Scholar 

  39. Stine OC, McMahon FJ, Chen L, Xu J, Meyers DA, MacKinnon DF et al. Initial genome screen for bipolar disorder in the NIMH genetics initiative pedigrees: chromosomes 2, 11, 13, 14, and X Am J Med Genet 1997 74: 263–269

    Article  CAS  PubMed  Google Scholar 

  40. Gecz J, Barnett S, Liu J, Hollway G, Donnelly A, Eyre H et al. Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation Genomics 1999 62: 356–368

    Article  CAS  PubMed  Google Scholar 

  41. Saito T, Parsia S, Papolos DF, Lachman HM . Analysis of the pseudoautosomal X-linked gene SYBL1 in bipolar affective disorder: description of a new candidate allele for psychiatric disorders Am J Med Genet 2000 96: 317–323

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are very grateful to the participation of the members of the families involved in the study. We also want to thank Mari Sipila for the excellent technical assistance. In addition, the contribution of Drs Jesper Ekelund, Iiris Hovatta, Tero Hiekkalinna, Per-Erik Bredbacka, Lea Muhonen and Jari Seppälä have been invaluable.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to L Peltonen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ekholm, J., Pekkarinen, P., Pajukanta, P. et al. Bipolar disorder susceptibility region on Xq24–q27.1 in Finnish families. Mol Psychiatry 7, 453–459 (2002). https://doi.org/10.1038/sj.mp.4001104

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001104

Keywords

This article is cited by

Search

Quick links