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:

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

Abstract

The present study reports a genomewide scan using linkage analysis for risk genes involved in bipolar disorder with 613 microsatellite markers including additional testing of promising regions. As previously published significant linkage was obtained at chromosome 12q24.3 with a two-point parametric lod score of 3.42 at D12S1639 including all members in both families (empirical P-value 0.00004, genome-wide P-value 0.0417). The multipoint parametric lod score at D12S1639 was 3.63 (genome-wide P-value 0.0265). At chromosome 1p22–p21 a parametric, affecteds-only two-point lod score of 2.75 at marker D1S216 was found (empirical P-value 0.0002, genome-wide P-value 0.1622). A three-point lod score of 2.98 (genome-wide P-value 0.1022) at D1S216, and a multipoint non-parametric analysis with a maximum NPL-all score of 17.60 (P-value 0.00079) at D1S216 further supported this finding. A number of additional loci on chromosomes 4p16, 6q14–q22, 10q26 and 16p13.3 yielded parametric lod scores around or above 2.

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

Similar content being viewed by others

References

  1. Marneros AAJ . Bipolar disorders: roots and evolution In: Marneros AAJ (ed) Bipolar Disorders—1000 Years After Manic-depressive Insanity Kluwer Academic Publishers: Dordrecht 2000; pp 1–35

    Google Scholar 

  2. Parker JB, Theilie A, Spielberger CD . Frequency of blood types in a homogenous group of manic-depressive patients J Mental Sci 1961; 107: 936

    Article  CAS  Google Scholar 

  3. 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 

  4. Winokur G, Tanna VL . Possible role of X-linked dominant factor in manic depressive disease Dis Nerv Syst 1969; 30: 89–94

    CAS  PubMed  Google Scholar 

  5. 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 

  6. Ginns EI, St Jean P, Philibert RA, Galdzicka M, Damschroder-Williams P, Thiel B 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 USA 1998; 95: 15531–15536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Asherson P, Mant R, Williams N, Cardno A, Jones L, Murphy K et al. A study of chromosome 4p markers and dopamine D5 receptor gene in schizophrenia and bipolar disorder Mol Psychiatry 1998; 3: 310–320

    Article  CAS  PubMed  Google Scholar 

  8. Ewald H, Degn B, Mors O, Kruse TA . Support for the possible locus on chromosome 4p 16 for bipolar affective disorder Mol Psychiatry 1998; 3: 442–448

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. 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 

  11. 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 

  12. Degn B, Lundorf MD, Wang A, Vang M, Mors O, Kruse TA et al. Further evidence for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing and allelic association in patients from the Faroe Islands Mol Psychiatry 2001; 6: 450–455

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. 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 

  15. Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr et al. Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene Proc Natl Acad Sci USA 1994; 91: 5918–5921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Berrettini WH, Ferraro TN, Goldin LR, Detera-Wadleigh SD, Choi H, Muniec D et al. A linkage study of bipolar illness Arch Gen Psychiatry 1997; 54: 27–35

    Article  CAS  PubMed  Google Scholar 

  17. Nothen MM, Cichon S, Rohleder H, Hemmer S, Franzek E, Fritze J et al. Evaluation of linkage of bipolar affective disorder to chromosome 18 in a sample of 57 German families Mol Psychiatry 1999; 4: 76–84

    Article  CAS  PubMed  Google Scholar 

  18. Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect Am J Hum Genet 1995; 57: 1384–1394

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Coon H, Hoff M, Holik J, Hadley D, Fang N, Reimherr F et al. Analysis of chromosome 18 DNA markers in multiplex pedigrees with manic depression Biol Psychiatry 1996; 39: 689–696

    Article  CAS  PubMed  Google Scholar 

  20. De Bruyn A, Souery D, Mendelbaum K, Mendlewicz J, Van Broeckhoven C . Linkage analysis of families with bipolar illness and chromosome 18 markers Biol Psychiatry 1996; 39: 679–688

    Article  CAS  PubMed  Google Scholar 

  21. Ewald H, Wang AG, Vang M, Mors O, Nyegaard M, Kruse TA . A haplotype-based study of lithium responding patients with bipolar affective disorder on the Faroe Islands Psychiatr Genet 1999; 9: 23–34

    Article  CAS  PubMed  Google Scholar 

  22. Freimer NB, Reus VI, Escamilla MA, McInnes LA, Spesny M, Leon P et al. Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22–q23 Nat Genet 1996; 12: 436–441

    Article  CAS  PubMed  Google Scholar 

  23. McMahon FJ, Hopkins PJ, Xu J, McInnis MG, Shaw S, Cardon L et al. Linkage of bipolar affective disorder to chromosome 18 markers in a new pedigree series Am J Hum Genet 1997; 61: 1397–1404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Detera-Wadleigh SD, Badner JA, Goldin LR, Berrettini WH, Sanders AR, Rollins DY et al. Affected-sib-pair analyses reveal support of prior evidence for a susceptibility locus for bipolar disorder, on 21q Am J Hum Genet 1996; 58: 1279–1285

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 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 

  26. Byerley W, Holik J, Hoff M, Coon H . Search for a gene predisposing to manic-depression on chromosome 21 Am J Med Genet 1995; 60: 231–233

    Article  CAS  PubMed  Google Scholar 

  27. Gurling H, Smyth C, Kalsi G, Moloney E, Rifkin L, O'Neill J et al. Linkage findings in bipolar disorder Nat Genet 1995; 10: 8–9

    Article  CAS  PubMed  Google Scholar 

  28. Aita VM, Liu J, Knowles JA, Terwilliger JD, Baltazar R, Grunn A et al. A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus Am J Hum Genet 1999; 64: 210–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mendlewicz J, Fleiss JL . Linkage studies with X-chromosome markers in bipolar (manic-depressive) and unipolar (depressive) illnesses Biol Psychiatry 1974; 9: 261–294

    CAS  PubMed  Google Scholar 

  30. 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 

  31. Baron M, Freimer NF, Risch N, Lerer B, Alexander JR, Straub RE et al. Diminished support for linkage between manic depressive illness and X-chromosome markers in three Israeli pedigrees Nat Genet 1993; 3: 49–55

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Adams LJ, Mitchell PB, Fielder SL, Rosso A, Donald JA, Schofield PR . A susceptibility locus for bipolar affective disorder on chromosome 4q35 Am J Hum Genet 1998; 62: 1084–1091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Friddle C, Koskela R, Ranade K, Hebert J, Cargill M, Clark CD et al. Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype Am J Hum Genet 2000; 66: 205–215

    Article  CAS  PubMed  Google Scholar 

  35. Foroud T, Castelluccio PF, Koller DL, Edenberg HJ, Miller M, Bowman E et al. Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees Am J Med Genet 2000; 96: 18–23

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Ewald H . Genetics of bipolar affective disorders In: Marneros AAJ (ed) Bipolar Disorders—100 Years After Manic-Depressive Insanity Kluwer Academic Publishers: Dordrecht 2000; pp 243–280

    Google Scholar 

  38. Baron M . Genetics of schizophrenia and the new millennium: progress and pitfalls Am J Hum Genet 2001; 68: 299–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Berrettini WH . Are schizophrenic and bipolar disorders related? A review of family and molecular studies Biol Psychiatry 2000; 48: 531–538

    Article  CAS  PubMed  Google Scholar 

  40. Ewald H, Mors O, Flint T, Koed K, Eiberg H, Kruse TA . A possible locus for manic depressive illness on chromosome 16p13 Psychiatr Genet 1995; 5: 71–81

    Article  CAS  PubMed  Google Scholar 

  41. Ewald H, Mors O, Koed K, Eiberg H, Kruse TA . Susceptibility loci for bipolar affective disorder on chromosome 18? A review and a study of Danish families Psychiatr Genet 1997; 7: 1–12

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Diagnostic criteria for research World Health Organization: Geneva 1993

  44. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edn American Psychiatric Association: Washington 1994

  45. Ewald H, Mors O, Friedrich U, Flint T, Kruse T . Exclusion of linkage between manic depressive illness and tyrosine hydroxylase and dopamine D2 receptor genes Psychiatr Genet 1994; 4: 13–22

    Article  CAS  PubMed  Google Scholar 

  46. Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P et al. The 1993–94 Genethon human genetic linkage map Nat Genet 1994; 7: 246–339

    Article  CAS  PubMed  Google Scholar 

  47. Lathrop GM, Lalouel JM, Julier C, Ott J . Strategies for multilocus linkage analysis in humans Proc Natl Acad Sci USA 1984; 81: 3443–3446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Markianos K, Daly MJ, Kruglyak L . Efficient multipoint linkage analysis through reduction of inheritance space Am J Hum Genet 2001; 68: 963–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ott J, Terwilliger JD . Assessing the evidence for linkage in psychiatric genetics In: Mendlewicz J, Hippius H (eds) Genetic Research in Psychiatry Springer-Verlag: Berlin 1992; pp 245–249

    Chapter  Google Scholar 

  50. Sham PC . Statistics in Human Genetics John Wiley & Sons: New York 1998

    Google Scholar 

  51. Terwilliger JD, Ott J . Handbook of Human Genetic Linkage The Johns Hopkins University Press: Bathmore, London 1994

    Google Scholar 

  52. Freimer NB, Sandkuijl LA, Blower SM . Incorrect specification of marker allele frequencies: effects on linkage analysis Am J Hum Genet 1993; 52: 1102–1110

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hodge SE . Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simultation results for single-gene diseases with no heterogeneity Genet Epidemiol 1992; 9: 191–206

    Article  CAS  PubMed  Google Scholar 

  54. Hodge SE, Greenberg DA . Sensitivity of lod scores to changes in diagnostic status Am J Hum Genet 1992; 50: 1053–1066

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Weeks DE, Ott J, Lathrop GM . SLINK: a general simulation program for linkage analysis Am J Hum Genet 1990; 47 Suppl: A204

    Google Scholar 

  57. Lander ES, 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 

  58. Nyholt DR . All LODs are not created equal Am J Hum Genet 2000; 67: 282–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rao DC, Gu C . False positives and false negatives in genome scans Adv Genet 2001; 42: 487–498

    Article  CAS  PubMed  Google Scholar 

  60. Terwilliger JD, Shannon WD, Lathrop GM, Nolan JP, Goldin LR, Chase GA et al. True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage mapping Am J Hum Genet 1997; 61: 430–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Detera-Wadleigh SD . Chromosomes 12 and 16 workshop Am J Med Genet 1999; 88: 255–259

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, VanEerdewegh P et al. Genome-wide search for genes affecting the risk for alcohol dependence Am J Med Genet 1998; 81: 207–215

    Article  CAS  PubMed  Google Scholar 

  65. Cao Q, Martinez M, Zhang J, Sanders AR, Badner JA, Cravchik A et al. Suggestive evidence for a schizophrenia susceptibility locus on chromosome 6q and a confirmation in an independent series of pedigrees Genomics 1997; 43: 1–8

    Article  CAS  PubMed  Google Scholar 

  66. Martinez M, Goldin LR, Cao Q, Zhang J, Sanders AR, Nancarrow DJ et al. Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q Am J Med Genet 1999; 88: 337–343

    Article  CAS  PubMed  Google Scholar 

  67. Levinson DF, Holmans P, Straub RE, Owen MJ, Wildenauer DB, Gejman PV et al. Multicenter linkage study of schizophrenia candidate regions on chromosomes 5q, 6q, 10p, and 13q: schizophrenia linkage collaborative group III Am J Hum Genet 2000; 67: 652–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Haines JL . Affected relative pair analysis In: Haines JL, Pericak-Vance MA (eds) Approaches to Gene Mapping in Complex Human Diseases Wiley-Liss: New York 1998; pp 305–321

    Google Scholar 

  69. Cichon S, Schmidt-Wolf G, Schumacher J, Muller DJ, Hurter M, Schulze TG et al. A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25–q26 Mol Psychiatry 2001; 6: 342–349

    Article  CAS  PubMed  Google Scholar 

  70. Kelsoe JR, Loetscher E, Spence MA, Fouget M, Sadovnick AD, Remick RA et al. A genome survey of bipolar disorder indicates a susceptibility locus on chromosome 22 Am J Med Genet 1998; 81: 461–462

    Google Scholar 

  71. Ewald H, Flint T, Wang AG, Mors O, Vang M, Jensen P, Kruse TA . Evidence for a shared segment on chromosome 10q26 in patients with bipolar affective disorder from the Faroe Islands Am J Med Genet (Neuropsychiatr Genet) 2002; 114: 196–204

    Article  Google Scholar 

  72. Levinson DF, Mahtani MM, Nancarrow DJ, Brown DM, Kruglyak L, Kirby A et al. Genome scan of schizophrenia Am J Psychiatry 1998; 155: 741–750

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank director and senior psychiatrist Aksel Bertelsen, WHO Reference and Training Centre for ICD-10 Classification of Mental and Behavioural Disorders, WHO Reference and Training Centre for Schedules for Clinical Assessment in Neuropsychiatry (SCAN), Department of Psychiatric Demography, Psychiatric Hospital in Aarhus, for thorough reading of all reports and medical records, as well as performing the diagnostic evaluations; and Agata El Daoud, Department of Biological Psychiatry, Psychiatric Hospital in Aarhus, for assisting with the genotypings.

This work has been supported by the Danish Medical Council grant No. 9303757 and grant No. 9902769, the Lundbeck Foundation, grant No. 21/91, grants from Psykiatrisk Forskningsfond, Ejner Geert-Jørgensens foundation, a grant from NovoCare (Novo Nordisk Farmaka Denmark) and Ingeborg and Leo Dannins foundation.

We thank the organising committees of the European Science Foundation concerted action, ‘The Molecular Neurobiology of Mental Illness’ and the scientific and technical staff of Généthon, Paris, France.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H Ewald.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ewald, H., Flint, T., Kruse, T. et al. 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 7, 734–744 (2002). https://doi.org/10.1038/sj.mp.4001074

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001074

Keywords

This article is cited by

Search

Quick links