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.

  • Original Research Article
  • Published:

Identification of a potential Bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4

Molecular Psychiatry volume 10, pages 920–927 (2005)Cite this article

Abstract

The gene encoding the transcription factor RFX4 represents an excellent neurobiological and positional candidate gene for Bipolar disorder due to the potential involvement of RFX4 proteins in the regulation of circadian rhythms and the proximity of the locus to numerous linkage signals on chromosome 12q23. In this study we have sought to identify common variants within the gene, which might confer risk to the disease in our large UK Caucasian sample of Bipolar patients (676 DSMIV Bipolar I probands, 690 controls). RFX4 was screened for sequence variants and the LD block structure across the genomic region determined using 22 biallelic polymorphisms (minor allele frequency ≥0.1). Through analysis of 10 haplotype-tagging markers and using a two-stage approach (subset I: 347 cases, 374 controls; subset II: 329 cases, 316 controls), we identified a haplotype at rs10778502 and ss24735177, which showed nominally significant disease association in our full sample (haplotype-specific P=0.002, global P=0.017; subset I: haplotype-specific P=0.0002, global P=0.0008; subset II: haplotype-specific P=0.572, global P=0.109). Evidence for potential disease association with mutations across the RFX4 region came also from the analysis of the nearby microsatellite D12S2072 (empirical P=0.009 in our full sample). Investigation of RFX4 brain cDNA tagged by rs10778502 provided evidence for significant allelic differences in expression (P<0.001), where some of the variance was accounted for by the genotype at ss24735177. Our findings thus indicate the potential functional relevance of the associated haplotype and now require replication in independent samples.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Craddock N, Jones I . Genetics of bipolar disorder. J Med Genet 1999; 36: 585–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. McGuffin P, Owen MJ, O'Donovan MC, Thapar A, Gottesmann II . Seminars in psychiatric genetics. Gaskell: London, 1994.

    Google Scholar 

  3. Potash JB, DePaulo JR . Searching high and low: a review of the genetics of bipolar disorder. Bipolar Disord 2000; 2: 8–26.

    Article  CAS  PubMed  Google Scholar 

  4. Baron M . Manic-depression genes and the new millennium: poised for discovery. Mol Psychiatry 2002; 7: 342–358.

    Article  CAS  PubMed  Google Scholar 

  5. McGuffin P, Rijsdijk F, Andrew M, Sham P, Katz R, Cardno A . The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch Gen Psychiatry 2003; 60: 497–502.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Dawson E, Parfitt E, Roberts Q, Daniels J, Lim L, Sham P et al. Linkage studies of bipolar disorder in the region of the Dariers-disease gene on chromosome 12q23–24.1. Am J Med Genet 1995; 60: 94–102.

    Article  CAS  PubMed  Google Scholar 

  8. 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 Genet 1999; 88: 567–587.

    Article  CAS  PubMed  Google Scholar 

  9. Jones I, Jacobsen N, Green EK, Elvidge GP, Owen MJ, Craddock N . Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease. Mol Psychiatry 2002; 7: 424–427.

    Article  CAS  PubMed  Google Scholar 

  10. Ewald H, Flint T, Kruse TA, Mors O . A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22–21, 4p16, 6q14–22, 10q26 and 16p13.3. Mol Psychiatry 2002; 7: 734–744.

    Article  CAS  PubMed  Google Scholar 

  11. Curtis D, Kalsi G, Brynjolfsson J, McInnis M, O'Neill J, Smyth C et al. Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23–q24, and suggests the presence of additional loci on 1p and 1q. Psychiatr Genet 2003; 13: 77–84.

    PubMed  Google Scholar 

  12. Ekholm JM, Kieseppa T, Hiekkalinna T, Partonen T, Paunio T, Perola M et al. Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder. Hum Mol Genet 2003; 12: 1907–1915.

    Article  CAS  PubMed  Google Scholar 

  13. Abkevich V, Camp NJ, Hensel CH, Neff CD, Russell DL, Hughes DC et al. Predisposition locus for major depression at chromosome 12q22–12q23.2. Am J Hum Genet 2003; 73: 1271–1281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zubenko GS, Maher B, Hughes III HB, Zubenko WN, Stiffler JS, Kaplan BB et al. Genome-wide linkage survey for genetic loci that influence the development of depressive disorders in families with recurrent early-onset, major depression. Am J Med Genet 2003; 123B: 1–18.

    Article  PubMed  Google Scholar 

  15. Blacker D, Lavori PW, Faraone SV, Tsuang MT . Unipolar relatives in bipolar pedigrees: a search for indicators of underlying bipolarity. Am J Med Genet 1993; 48: 192–199.

    Article  CAS  PubMed  Google Scholar 

  16. Green E, Elvidge G, Jacobsen N, Glaser B, Jones I, O'Donovan MC et al. Localization of bipolar susceptibility locus by molecular genetic analysis of the chromosome 12q23–q24 region in two pedigrees with bipolar disorder and Darier's disease. Am J Psychiatry 2005; 162: 35–42.

    Article  PubMed  Google Scholar 

  17. Gajiwala KS, Chen H, Cornille F, Roques BP, Reith W, Mach B et al. Structure of the winged-helix protein hRFX1 reveals a new mode of DNA binding. Nature 2000; 403: 916–921.

    Article  CAS  PubMed  Google Scholar 

  18. Emery P, Durand B, Mach B, Reith W . RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom. Nucl Acids Res 1996; 24: 803–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Morotami-Yano K, Yano K, Saito H, Sun Z, Iwama A, Miki Y . Human regulatory factor X 4 (RFX4) is a testis-specific dimeric DNA-binding protein that cooperates with other human RFX members. J Biol Chem 2002; 277: 836–842.

    Article  Google Scholar 

  20. Araki R, Takahashi H, Fukumura R, Sun F, Umeda N, Sujino M et al. Restricted expression and photic induction of a novel mouse regulatory factor X4 transcript in the suprachiasmatic nucleus. J Biol Chem 2004; 279: 10237–10242.

    Article  CAS  PubMed  Google Scholar 

  21. Dotzlaw H, Alkhalaf M, Murphy LC . Characterization of estrogen receptor variant mRNAs from human breast cancers. Mol Endocrinol 1992; 6: 773–785.

    CAS  PubMed  Google Scholar 

  22. Blackshear PJ, Graves JP, Stumpo DJ, Cobos I, Rubenstein JL, Zeldin DC . Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4. Development 2003; 130: 4539–4552.

    Article  CAS  PubMed  Google Scholar 

  23. Klein D, Moore R, Reppert S (eds). Suprachiasmatic Nucleus. The Mind's Clock. Oxford University Press: Oxford, 1991.

    Google Scholar 

  24. Wehr TA, Sack D, Rosenthal N, Duncan W, Gillin JC . Circadian rhythm disturbances in manic-depressive illness. Fed Proc 1983; 42: 2809–2814.

    CAS  PubMed  Google Scholar 

  25. Klemfuss H . Rhythms and the pharmacology of lithium. Pharmacol Ther 1992; 56: 53–78.

    Article  CAS  PubMed  Google Scholar 

  26. Abe M, Herzog ED, Block GD . Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport 2000; 11: 3261–3264.

    Article  CAS  PubMed  Google Scholar 

  27. APA. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association: Washington, DC, 1994.

  28. Endicott J, Spitzer RL . A diagnostic interview. The schedule for affective disorder and schizophrenia. Arch Gen Psychiatr 1978; 35: 837–844.

    Article  CAS  PubMed  Google Scholar 

  29. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R et al. SCAN. Schedules for clinical assessment in neuropsychiatry. Arch Gen Psychiatr 1990; 47: 589–593.

    Article  CAS  PubMed  Google Scholar 

  30. Owen MJ, Holmans P, McGuffin P . Association studies in psychiatric genetics. Mol Psychiatr 1997; 2: 270–273.

    Article  CAS  Google Scholar 

  31. Jacobsen NJO, Elvidge G, Franks EKE, O'Donovan MC, Craddock N, Owen MJ . CUX2, a potential regulator of NCAM expression: genomic characterization and analysis as a positional candidate susceptibility gene for bipolar disorder. Am J Med Genet 2001; 105: 295–300.

    Article  CAS  PubMed  Google Scholar 

  32. Abecasis GR, Cookson WOC . GOLD—graphical overview of linkage disequilibrium. Bioinformatics 2000; 16: 182–183.

    Article  CAS  PubMed  Google Scholar 

  33. Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.

    Article  PubMed  Google Scholar 

  34. Bray NJ, Buckland PR, Owen MJ, O'Donovan MC . Cis-acting variation in the expression of a high proportion of genes in human brain. Hum Genet 2003; 113: 149–153.

    PubMed  Google Scholar 

  35. Sham P, Curtis D . Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995; 59: 97–105.

    Article  CAS  PubMed  Google Scholar 

  36. Green EK, Elvidge GP, Owen MJ, Craddock N . Mutational analysis of two positional candidate susceptibility genes for bipolar disorder on chromosome 12q23–q24: phenylalanine hydroxylase and human LIM-homeobox LHX5. Psychiatr Genet 2003; 13: 97–101.

    PubMed  Google Scholar 

  37. Glaser B, Kirov G, Green E, Craddock N, Owen MJ . Linkage disequilibrium mapping of bipolar affective disorder at 12q23–q24 provides evidence for association at CUX2 and FLJ32356. Am J Med Genet B Neuropsychiatr Genet 2005; 132: 38–45.

    Article  Google Scholar 

  38. Jacobsen NJO, Lyons I, Hoogendoorn B, Burge S, Kwok PY, O'Donovan MC et al. ATP2A2 mutations in Darier's disease and their relationship to neuropsychiatric phenotypes. Hum Mol Genet 1999; 8: 1631–1636.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by the Wellcome Trust (Grant Ref: 054305/B/98) and the Medical Research Council, London, UK.

Author information

Authors and Affiliations

  1. Department of Psychological Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff, Wales, UK

    B Glaser, G Kirov, N J Bray, E Green, M C O'Donovan, N Craddock & M J Owen

Authors
  1. B Glaser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Kirov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N J Bray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M C O'Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N Craddock
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to N Craddock or M J Owen.

Additional information

Supplementary Information accompanies the paper on Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Glaser, B., Kirov, G., Bray, N. et al. Identification of a potential Bipolar risk haplotype in the gene encoding the winged-helix transcription factor RFX4. Mol Psychiatry 10, 920–927 (2005). https://doi.org/10.1038/sj.mp.4001689

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001689

Keywords

This article is cited by

Search

Advanced search

Quick links