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Recent progress in the search for genes for bipolar disorder

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Abstract

Over many decades, much evidence has been accumulated to demonstrate the strong role of genetic factors in bipolar disorder. Recently, genetic studies of bipolar disorder have turned from proving the role of genetics to identifying the specific genes involved. This has been made possible by the development of powerful methods to identify disease genes by their locations on chromosomes, an approach termed postitional cloning. Currently, about a dozen regions in the genome have been implicated as the location of susceptibility genes for bipolar disorder. Several of these have been replicated and will likely lead to the identification of novel disease mechanisms. An intriguing development is that a few of these are the same locations implicated in studies of schizophrenia, suggesting a greater genetic relationship between these disorders than had been previously thought. It is hoped that the identification of novel disease genes will lead to a better understanding of the pathophysiology of bipolar disorder and to the development of more effective treatments.

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References and Recommended Reading

  1. Nurnberger JI, Gershon ES: Genetics of affective disorders. In Neurobiology of Mood Disorders. Edited by Post RM, Ballanger JC. Baltimore: William and Wilkins; 1984:76–101.

    Google Scholar 

  2. Tsuang MT, Faraone SV: The genetics of mood disorders. Baltimore: Johns Hopkins University Press, 1990.

    Google Scholar 

  3. Rice J, Reich T, Andreasen NC, et al.: The familial transmission of bipolar illness. Arch Gen Psychiatry 1987, 44:441–47.

    PubMed  CAS  Google Scholar 

  4. Spence MA, Flodman PL, Sadovnick AD, et al.: Bipolar disorder: evidence for a major locus. Am J Med Genet 1995, 60:370–376.

    Article  PubMed  CAS  Google Scholar 

  5. Suarez BK, Campe CL, Van Eerdewegh P: Problems of replicating linkage claims in psychiatry In Genetic Approaches to Mental Disorders. Edited by Gershon ES, Cloninger CR. Washington, DC: American Psychiatric Press; 1994:23–46.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Berrettini WH, Ferraro TN, Goldin LR, et al.: Chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. Proc Natl Acad Sci U S A 1994, 91:5918–5921.

    Article  PubMed  CAS  Google Scholar 

  8. Stine OC, Xu J, Koskela R, 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.

    PubMed  CAS  Google Scholar 

  9. Freimer NB, Reus VI, Escamilla MA, 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  PubMed  CAS  Google Scholar 

  10. Straub RE, Lehner T, Luo Y, et al.: A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3. Nat Genet 1994, 8:291–296.

    Article  PubMed  CAS  Google Scholar 

  11. Gurling H, Smyth C, Kalsi G, et al.: Linkage findings in bipolar disorder. Nat Genet 1995, 10:8–9.

    Article  PubMed  CAS  Google Scholar 

  12. Detera-Wadleigh SD, Badner JA, Yoshikawa T, et al.: Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 4, 7, 9, 18, 19, 20, and 21q. Am J Med Genet 1997, 74:254–262.

    Article  PubMed  CAS  Google Scholar 

  13. Detera-Wadleigh SD, Badner JA, Berrettini WH, et al.: A highdensity genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p112. Proc Natl Acad Sci U S A 1999, 96:5604–5609. This is the latest report on the genome scan of the NIMH intramural program family set (different from the Genetics Initiative familiy set). It provides the first report of statistically significant evidence for linkage to chromosome 13.

    Article  PubMed  CAS  Google Scholar 

  14. Baron M, Risch N, Hamburger R, et al.: Genetic linkage between X-chromosome markers and bipolar affective illness. Nature 1987, 326:289–292.

    Article  PubMed  CAS  Google Scholar 

  15. Pekkarinen P, Terwilliger J, Bredbacka PE, et al.: Evidence of a predisposing locus to bipolar disorder on Xq24-q27.1 in an extended finnish pedigree. Genome Res 1995, 5:105–115.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. Ewald H, Degn B, Mors O, et al.: Support for the possiblelocus on chromosome 4p16 for bipolar affective disorder Mol Psychiatry 1998, 3:442–448. This study of Danish families has provided further recent replication for a susceptibility locus for bipolar disorder on 4p16.

    Article  PubMed  CAS  Google Scholar 

  18. Dawson E, Parfitt E, Roberts Q, 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  PubMed  CAS  Google Scholar 

  19. Morissette J, Villeneuve A, Bordeleau L, et al.: Genome-wide search for linkage of bipolar affective disorders in a very large pedigree derived from a homogenous population in Quebec points to alocus of major effect on chromosome 12q23-q24. Am J Med Genet 1999, 88:567–587. The genome scan of an extended family with bipolar disorder from a population isolate in Quebec provides support for the previous report of linkage to 12q.

    Article  PubMed  CAS  Google Scholar 

  20. Pulver AE, Nestadt G, Goldberg R, et al.: Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 1994, 182:476–478.

    Article  PubMed  CAS  Google Scholar 

  21. Papolos DF, Faedda GL, Veit S, et al.: Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 1996, 153:1541–1547.

    PubMed  CAS  Google Scholar 

  22. Pulver AE, Karayiorgou M, Wolyniec PS, et al.: Sequential strategy to identify a susceptibility gene for schizophrenia: report of potential linkage on chromosome 22q12-q13.1: Part 1. Am J Med Genet 1994, 54:36–43.

    Article  PubMed  CAS  Google Scholar 

  23. Lachman HM, Kelsoe JR, Remick RA, et al.: Linkage studies support a possible locus for bipolar disorder in the velocardiofacial syndrome region on chromosome 22. Am J Med Genet 1996, 74:121–128.

    Article  Google Scholar 

  24. Edenberg HJ, Forou T, Conneally PM, et al.: Initial genomic scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 3, 5, 15, 16, 17, and 22. Am J Med Genet 1997, 74:238–246.

    Article  PubMed  CAS  Google Scholar 

  25. Kelsoe JR, Loetscher E, Spence MA, 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 

  26. Lachman HM, Morrow B, Shprintzen R, et al.: Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardiofacial syndrome. Am J Med Genet 1996, 67:468–472.

    Article  PubMed  CAS  Google Scholar 

  27. Stine OC, McMahon FJ, Chen L, et al.: Initial genome scree 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  PubMed  CAS  Google Scholar 

  28. Blouin JL, Dombroski BA, Nath SK, et al.: Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998, 20:70–73.

    Article  PubMed  CAS  Google Scholar 

  29. Ginns EI, St. Jean P, Philibert RA, 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 U S A 1998, 95:15531–15536 In this study, a possible genetic locus which provides protection from bipolar disorder is mapped to chromosome 4 in an extended high-risk family form the Old Order Amish.

    Article  PubMed  CAS  Google Scholar 

  30. Erlenmeyer-Kimling L, Adamo UH, Rock D, et al.: The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up. Arch Gen Psychiatry 1997, 54:1096–1102.

    PubMed  CAS  Google Scholar 

  31. Schwab SG, Hallmayer J, Lerer B, et al.: Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis Am J Hum Genet 1998, 63:1139–1152. This study of schizophrenia is of particular interest because it locates a susceptibility locus to the same region on 18p which has been implicated in bipolar disorder.

    Article  PubMed  CAS  Google Scholar 

  32. Straub RE, MacLean CJ, Martin RB, et al.: A schizophrenia locus may be located in region 10p15-p11. Am J Med Genet 1998, 81:296–301.

    Article  PubMed  CAS  Google Scholar 

  33. Rice JP, Goate A, Williams JT, 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  PubMed  CAS  Google Scholar 

  34. Lesch KP, Bengel D, Heils A, et al.: Association of anxietyrelated traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274:1527–1531.

    Article  PubMed  CAS  Google Scholar 

  35. Furlong RA, Ho L, Walsh C, et al.: Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders. Am J Med Genet 1998, 81:58–63.

    Article  PubMed  CAS  Google Scholar 

  36. Bellivier F, Henry C, Szoke A, et al.: Serotonin transporter gene polymorphisms in patients with unipolar or bipolar depression. Neurosci Lett 1998, 255:143–146.

    Article  PubMed  CAS  Google Scholar 

  37. Collier DA, Stober G, Li T, et al.: A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1996, 1:453–460.

    PubMed  CAS  Google Scholar 

  38. Rees M, Norton N, Jones I, et al.: Association studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Mol Psychiatry 1997, 2:398–402.

    Article  PubMed  CAS  Google Scholar 

  39. Esterling LE, Yoshikawa T, Turner G, et al.: Serotonin transporter (5-HTT) gene and bipolar affective disorder. Am J Med Genet 1998, 81:37–40.

    Article  PubMed  CAS  Google Scholar 

  40. Ewald H, Flint T, Degn B, et al.: A functional variant of the serotonin transporter gene in families with bipolar affective disorder. J Affect Dis 1998, 48:135–144.

    Article  PubMed  CAS  Google Scholar 

  41. Gutierrez B, Arranz MJ, Collier DA, et al.: Serotonin transporter gene and risk for bipolar affective disorder: an association study in Spanish population. Biol Psychiatry 1998, 43:843–847.

    Article  PubMed  CAS  Google Scholar 

  42. Kunugi H, Hattori M, Kato T, et al.: Serotonin transporter gene polymorphisms: ethnic difference and possible association with bipolar affective disorder. Mol Psychiatry 1997, 2:457–462.

    Article  PubMed  CAS  Google Scholar 

  43. Seretti A, Cusin C, Lattuada E, et al.: Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol Psychiatry 1999, 4:280–283.

    Article  PubMed  CAS  Google Scholar 

  44. Chandy KG, Fantino E, Wittekindt O, et al.: Isolation of a novel potassium channel gene hSKCa3 containing a polymorphic CAG repeat: a candidate for schizophrenia and bipolar disorder? Mol Psychiatry 1998, 3:32–37.

    Article  PubMed  CAS  Google Scholar 

  45. Bowen T, Guy CA, Craddock N, et al.: Further support for an association between a polymorphic CAG repeat in the hKCa3 gene and schizophrenia. Mol Psychiatry 1998, 3:266–269.

    Article  PubMed  CAS  Google Scholar 

  46. Stober G, Jatzke S, Meyer J, et al.: Short CAG repeats within the hSKCa3 gene associated with schizophrenia: results of a family-based study. Neuroreport 1998, 9:3595–3599.

    Article  PubMed  CAS  Google Scholar 

  47. Guy CA, Bowen T, Williams N, et al.: No association between a polymorphic CAG repeat in the human potassium channel gene hKCa3 and bipolar disorder. Am J Med Genet 1999, 88:57–60.

    Article  PubMed  CAS  Google Scholar 

  48. McInnis MG, Breschel TS, Margolis RL, et al.: Family-based association analysis of the hSKCa3 potassium channel gene in bipolar disorder. Mol Psychiatry 1999, 4:217–219.

    Article  PubMed  CAS  Google Scholar 

  49. Adams LJ, Mitchell PB, Fielder SL, et al.: A susceptibility locus for bipolar affective disorder on chromosome 4q35. Am J Hum Genet 1998, 62:1084–1091.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Psychiatry, 0603 University of California at San Diego, 92093, La Jolla, CA, USA

    John R. Kelsoe MD

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Kelsoe, J.R. Recent progress in the search for genes for bipolar disorder. Curr Psychiatry Rep 1, 135–140 (1999). https://doi.org/10.1007/s11920-999-0022-0

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