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:

Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22

Molecular Psychiatry volume 10, pages 831–841 (2005)Cite this article

A Corrigendum to this article was published on 28 November 2006

Abstract

Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16–q21 (MLS=2.61) and 4q12–q21 (MLS=2.38). 6q16–q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male–male pairs. Our scan also provides support for linkage (MLS≥1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14–p12 and 18q22.

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

Similar content being viewed by others

References

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

    Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baron M . Linkage mapping of bipolar affective disorder. Am J Med Genet 2000; 96: 881–883.

    Article  CAS  PubMed  Google Scholar 

  4. Craddock N, Khodel V, Van Eerdewegh P, Reich T . Mathematical limits of multilocus models: the genetic transmission of bipolar disorder. Am J Hum Genet 1995; 57: 690–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Badner JA, Gershon ES . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.

    Article  CAS  PubMed  Google Scholar 

  6. Segurado R, Detera-Wadleigh SD, Levinson DF, Lewis CM, Gill M, Nurnberger Jr JI et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part III: bipolar disorder. Am J Hum Genet 2003; 73: 49–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Craddock N, O'Donovan MC, Owen MJ . Genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42: 288–299.

    Article  Google Scholar 

  9. Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL et al. Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet 2003; 73: 107–114, (Erratum 73: 979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Holmans P, Craddock N . Efficient strategies for genome scanning using maximum-likelihood affected-sib-pair analysis. Am J Hum Genet 1997; 60: 657–666.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Bennett P, Segurado R, Jones I, Bort S, McCandless F, Lambert D et al. The Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: first stage report. Mol Psychiatry 2002; 7: 189–200.

    Article  CAS  PubMed  Google Scholar 

  12. APA. Diagnostic and Statistical Manual for Mental Disorders Fourth Edition (DSM-IV), 4th ed. American Psychiatric Press, Inc.: Washington, DC, USA, 1994.

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

    Article  CAS  PubMed  Google Scholar 

  14. Cohen J . Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychol Bull 1968; 70: 213–220.

    Article  CAS  PubMed  Google Scholar 

  15. Ott J . Analysis of Human Genetic Linkage, Revised Edition. Johns Hopkins University Press: Baltimore, 1991.

    Google Scholar 

  16. Lander ES, Green P . Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci USA 1987; 84: 2363–2367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Matise TC, Gitlin JA . MAP-O-MAT: marker-based linkage mapping on the World Wide Web. Am J Hum Genet 1999; 65: A435.

    Google Scholar 

  18. Fenton I, Sandkuijl LA . MEGABASE/PKD: a genetic database for polycystic kidney disease. Contrib Nephrol 1992; 97: 118–127.

    Article  CAS  PubMed  Google Scholar 

  19. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Göring HH, Ott J . Relationship estimation in affected sib pair analysis of late-onset diseases. Eur J Hum Genet 1997; 5: 69–77.

    PubMed  Google Scholar 

  21. Boehnke M, Cox NJ . Accurate inference of relationships in sib-pair linkage studies. Am J Hum Genet 1997; 61: 423–429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Broman KW, Weber JL . Estimation of pairwise relationships in the presence of genotyping errors. Am J Hum Genet 1998; 63: 1563–1564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. McPeek MS, Sun L . Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet 2000; 66: 1076–1094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . GRR: graphical representation of relationship errors. Bioinformatics 2001; 17: 742–743.

    Article  CAS  PubMed  Google Scholar 

  25. Holmans P . Asymptotic properties of affected-sib-pair linkage analysis. Am J Hum Genet 1993; 52: 362–374.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Holmans P, Clayton D . Efficiency of typing unaffected relatives in an affected-sib-pair linkage study with single-locus and multiple tightly linked markers. Am J Hum Genet 1995; 57: 1221–1232.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet 1995; 57: 439–454.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. Rice JP, Rochberg N, Neuman RJ, Saccone NL, Liu KY, Zhang X et al. Covariates in linkage analysis. Genet Epidemiol 1999; 17 (Suppl 1): S691–S695.

    Article  PubMed  Google Scholar 

  30. Holmans P . Detecting gene–gene interactions using affected sib pair analysis with covariates. Hum Hered 2002; 53: 92–102.

    Article  PubMed  Google Scholar 

  31. 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 

  32. Risch N . Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 1990; 46: 222–228.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Middleton FA, Pato MT, Gentile KL, Morley CP, Zhao X, Eisener AF et al. Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. Am J Hum Genet 2004; 74: 886–897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schulze TG, Buervenich S, Badner JA, Steele CJ, Detera-Wadleigh SD, Dick D et al. Loci on chromosomes 6q and 6p interact to increase susceptibility to bipolar affective disorder in the national institute of mental health genetics initiative pedigrees. Biol Psychiatry 2004; 56: 18–23.

    Article  CAS  PubMed  Google Scholar 

  35. Pato CN, Pato MT, Kirby A, Petryshen TL, Medeiros H, Carvalho C et al. Genome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11. Am J Med Genet 2004; 127B: 30–34.

    Article  PubMed  Google Scholar 

  36. 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 

  37. McInnis MG, Dick DM, Willour VL, Avramopoulos D, MacKinnon DF, Simpson SG et al. Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees. Biol Psychiatry 2003; 54: 1265–1273.

    Article  CAS  PubMed  Google Scholar 

  38. Maes M, Goossens F, Scharpe S, Meltzer HY, D'Hondt P, Cosyns P . Lower serum prolyl endopeptidase enzyme activity in major depression: further evidence that peptidases play a role in the pathophysiology of depression. Biol Psychiatry 1994; 35: 545–552.

    Article  CAS  PubMed  Google Scholar 

  39. Maes M, Goossens F, Scharpe S, Calabrese J, Desnyder R, Meltzer HY . Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. Psychiatry Res 1995; 58: 217–225.

    Article  CAS  PubMed  Google Scholar 

  40. Williams RS, Cheng L, Mudge AW, Harwood AJ . A common mechanism of action for three mood-stabilizing drugs. Nature 2002; 417: 292–295.

    Article  CAS  PubMed  Google Scholar 

  41. Williams RS, Eames M, Ryves WJ, Viggars J, Harwood AJ . Loss of a prolyl oligopeptidase confers resistance to lithium by elevation of inositol (1,4,5) trisphosphate. EMBO J 1999; 18: 2734–2745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Murai KK, Pasquale EB . Can Eph receptors stimulate the mind? Neuron 2002; 33: 159–162.

    Article  CAS  PubMed  Google Scholar 

  43. Gerlai R, McNamara A . Anesthesia induced retrograde amnesia is ameliorated by ephrinA5-IgG in mice: EphA receptor tyrosine kinases are involved in mammalian memory. Behav Brain Res 2000; 108: 133–143.

    Article  CAS  PubMed  Google Scholar 

  44. Murai KK, Pasquale EB . Eph receptors, ephrins, and synaptic function. Neuroscientist 2004; 10: 1–11.

    Article  Google Scholar 

  45. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 1999; 96: 5604–5609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kelsoe JR, Spence MA, Loetscher E, Foguet M, Sadovnick AD, Remick RA et al. A genome survey indicates a possible susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci USA 2001; 98: 585–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen KR, Rosso A et al. A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q. Mol Psychiatry 2001; 6: 396–403.

    Article  CAS  PubMed  Google Scholar 

  48. Liu J, Juo SH, Dewan A, Grunn A, Tong X, Brito M et al. Evidence for a putative bipolar disorder locus on 2p13–16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21–24, 13q32, 14q21 and 17q11–12. Mol Psychiatry 2003; 8: 333–342.

    Article  CAS  PubMed  Google Scholar 

  49. Shaw SH, Mroczkowski-Parker Z, Shekhtman T, Alexander M, Remick RA, Sadovnick AD et al. Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series. Mol Psychiatry 2003; 8: 558–564.

    Article  CAS  PubMed  Google Scholar 

  50. Potash JB, Zandi PP, Willour VL, Lan TH, Huo Y, Avramopoulos D et al. Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder. Am J Psychiatry 2003; 160: 680–686.

    Article  PubMed  Google Scholar 

  51. Liu C, Badner JA, Christian SL, Guroff JJ, Detera-Wadleigh SD, Gershon ES . Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32. Am J Med Genet 2001; 105: 375–380.

    Article  CAS  PubMed  Google Scholar 

  52. Berrettini W . Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet 2003; 123C: 59–64.

    Article  PubMed  Google Scholar 

  53. Evans DM, Cardon LR . Guidelines for genotyping in genomewide linkage studies: single-nucleotide-polymorphism maps versus microsatellite maps. Am J Hum Genet 2004; 75: 687–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was funded by grants from the Wellcome Trust. We are grateful to all the professionals and researchers who have helped in the recruitment of family members. We are indebted to the willingness and enthusiasm of all the participants who agreed to help with this work.

Author information

Authors and Affiliations

  1. Department of Genetics, Trinity College Dublin, Dublin, 2, Republic of Ireland

    D Lambert, R Segurado, A Corvin, E O'Mahony, T Mulcahy, S Bort & M Gill

  2. Department of Psychiatry, Trinity College Dublin, Dublin, 2, Republic of Ireland

    D Lambert, R Segurado, A Corvin, E O'Mahony, T Mulcahy, S Bort & M Gill

  3. Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, UK

    F Middle, S Haque, P Bennett, C Lendon & L Jones

  4. Department of Psychological Medicine, The Henry Wellcome Building for Biomedical Research in Wales, Wales School of Medicine, Cardiff University, Heath Park, Cardiff, UK

    M L Hamshere, R Raybould, E Green, I Nikolov, N Norton, M J Owen, G Kirov, I Jones, P Holmans & N Craddock

  5. Biostatistics and Bioinformatics Unit, Wales School of Medicine, Cardiff University, Heath Park, Cardiff, UK

    M L Hamshere, I Nikolov & P Holmans

Authors
  1. D Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Middle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M L Hamshere
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R Segurado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R Raybould
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Corvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E O'Mahony
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. I Nikolov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. T Mulcahy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S Bort
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. N Norton
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. G Kirov
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. C Lendon
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. L Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. I Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. P Holmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. M Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. N Craddock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N Craddock.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lambert, D., Middle, F., Hamshere, M. et al. Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22. Mol Psychiatry 10, 831–841 (2005). https://doi.org/10.1038/sj.mp.4001684

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001684

Keywords

This article is cited by

Search

Advanced search

Quick links