Skip to main content
Log in

The common genetic liability between schizophrenia and bipolar disorder: A review.

  • Published:
Current Psychiatry Reports Aims and scope Submit manuscript

Abstract

Current psychiatric nosology, strongly influenced by Kraepelin’s dichotomy [1,2], classifies schizophrenia and bipolar disorder as separate diagnostic categories. However, growing evidence indicates that the two disorders may be more closely related than was thought in the past. Bipolar disorder and schizophrenia display considerable overlap in epidemiologic features; no risk factor is known to be specific to either. Furthermore, family studies reveal familial co-aggregation of the two disorders, and twin studies suggest a significant overlap in the genes contributing to schizophrenia, schizoaffective disorder, and mania. Finally, despite the difficulties in the identification of convincing genetic loci for psychiatric disorders, there are at least four genomic regions in which linkage has been shown for both schizophrenia and bipolar disorder. Thus, recent evidence increasingly supports a dimensional approach in the understanding of the functional psychoses, and this is expected to have implications for etiologic research and future clinical treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Kraepelin E: Dementia praecox. In Dementia Praecox, Paraphrenia. Edinburgh: Livingstone; 1919:181–184.

    Google Scholar 

  2. Kraepelin E: Manic Depressive Insanity and Paranoia. Edinburgh: Livingstone; 1921.

    Google Scholar 

  3. Brockington IF, Roper A, Copas J, et al.: Schizophrenia, bipolar disorder and depression: a discriminant analysis, using lifetime psychopathology ratings. Br J Psychiatry 1991, 159:485–494.

    PubMed  CAS  Google Scholar 

  4. Taylor D, McConnell H, McConnell D: The Maudsley Prescribing Guidelines, edn 6. London: Martin Dunitz, Ltd.; 2001.

    Google Scholar 

  5. American Psychiatric Association: Diagnostic and Statistical Manual for Mental Disorders, edn 4. Washington, DC: American Psychiatric Association Press; 1994.

    Google Scholar 

  6. World Health Organization: The ICD-10 Classification of Mental and Behavioral Disorders. World Health Organization; 1993.

  7. Wickham H, Walsh C, Asherson P, et al.: Familiality of symptom dimensions in schizophrenia. Schizophr Res 2001, 47:223–232. A factor analysis of symptoms measured by Operational Criteria Checklist for Psychotic Illness (OPCRIT) scores is conducted in a large group of patients with a family history of schizophrenia. The familial relationship of the symptom dimensions obtained, as well as their relationship to clinical characteristics, is investigated.

    Article  PubMed  CAS  Google Scholar 

  8. Jablensky A: The 100-year epidemiology of schizophrenia. Am J Med Genetics 1999, 67:103–105. Review of the epidemiology of schizophrenia with a historical perspective from Kraepelin to the World Health Organization International Survey.

    Google Scholar 

  9. Smith A, Weissman M: Epidemiology. In Handbook of Affective Disorders. Edited by Paykel E. Edinburgh: Churchill-Livingstone; 1992.

    Google Scholar 

  10. Castle D, Wessely S, Murray R: Sex and schizophrenia: effects of diagnostic stringency, and associations with premorbid variables. Br J Psychiatry 1993, 162:658–664.

    PubMed  CAS  Google Scholar 

  11. Guze S, Robins E: Suicide and primary affective disorders. Br J Psychiatry 1970, 117:437–438.

    PubMed  CAS  Google Scholar 

  12. Van Os J, Jones P, Sham P, et al.: Psychosis as a continuum of variation in dimensions of psychopathology. In Search for the Causes of Schizophrenia, vol 4. Edited by Haffner H Gattaz W. Berlin, Heidelberg, and London: Springer; 1999:59–80.

    Google Scholar 

  13. Hultman CM, Sparen P, Takei N, et al.: Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study. Br Med J 1999, 318:421–426.

    CAS  Google Scholar 

  14. McGrath JJ, Van Os J, Hoyos C, et al.: Minor physical anomalies in psychoses: Associations with clinical and putative aetiological variables. Schizophr Res 1995, 18:9–20.

    Article  PubMed  CAS  Google Scholar 

  15. Gutierrez B, Van Os J, Valles V, et al.: Congenital dermatoglyphic malformations in severe bipolar disorder. Psychiatry Res 1998, 78:133–140.

    Article  PubMed  CAS  Google Scholar 

  16. Cannon M, Jones P, Gilvarry C, et al.: Premorbid social functioning in schizophrenia and bipolar disorder: Similarity and differences. Am J Psychiatry 1997, 154:1544–1550.

    PubMed  CAS  Google Scholar 

  17. Elkis H, Friedman L, Wise A, Meltzer HY: Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders: comparisons with controls or patients with schizophrenia. Arch Gen Psychiatry 1995, 52:735–746.

    PubMed  CAS  Google Scholar 

  18. Bradbury T, Miller G: Season of birth in schizophrenia: a review of the evidence, methodology and etiology. Psychol Bull 1985, 98:569–594.

    Article  PubMed  CAS  Google Scholar 

  19. McGrath J, Welham J, Pemberton M: Month of birth, hemisphere of birth and schizophrenia. Br J Psychiatry 1995, 167:783–785.

    PubMed  CAS  Google Scholar 

  20. Davies GJ, Welham J, Torrey EF, McGrath J: Season of birth effect and latitude: a systematic review and meta-analysis of northern hemisphere schizophrenia studies. Schizophr Res 2000, 41:A54.

    Google Scholar 

  21. Sham PC, Maclean CJ, Kendler KS: Risk of Schizophrenia and Age Difference with Older Siblings -Evidence for a Maternal Viral-Infection Hypothesis. Br J Psychiatry 1993, 163:627–633.

    Article  PubMed  CAS  Google Scholar 

  22. Susser E, Hoek HW, Brown A: Neurodevelopmental disorders after prenatal famine: the story of the Dutch Famine Study. Am J Epidemiol 1998, 147:213–216.

    PubMed  CAS  Google Scholar 

  23. Van Os J, Selten JP: Prenatal exposure to maternal stress and later schizophrenia: the May 1940 invasion of the Netherlands. Schizophr Res 1998, 29:17–17.

    Google Scholar 

  24. Torrey EF, Miller J, Rawlings R, Yolken RH: Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res 1997, 28:1–38.

    Article  PubMed  CAS  Google Scholar 

  25. Van Os J, Murray R: Neurodevelopmental and social risk factors across the continuum of psychosis. Br J Psychiatry 2001, in press.

  26. Maier W, Lichtermann D, Minges J, et al.: Continuity and discontinuity of affective-disorders and schizophrenia: results of a controlled family study. Arch Gen Psychiatry 1993, 50:871–883.

    PubMed  CAS  Google Scholar 

  27. Kendler KS, McGuire M, Gruenberg AM, et al.: The Roscommon family study: affective-illness, anxiety disorders, and alcoholism in relatives. Arch Gen Psychiatry 1993, 50:952–960.

    PubMed  CAS  Google Scholar 

  28. Tsuang M, Winokur G, Crowe R: Morbid risks of schizophrenia and affective disorders among first-degree relatives of patients with schizophrenia, mania, depression and surgical conditions. Br J Psychiatry 1980, 137:497–504.

    Article  PubMed  CAS  Google Scholar 

  29. Kendler KS, Gardner CO: The risk for psychiatric disorders in relatives of schizophrenic and control probands: a comparison of three independent studies. Psychol Med 1997, 27:411–419. The results from three independent family studies of schizophrenia including the Danish Adoption Study, the Iowa 500 Family Study, and the Roscommon Family Study are reviewed and re-analyzed using DSM-III-R criteria and meta-analysis techniques.

    Article  PubMed  CAS  Google Scholar 

  30. Kendler KS, Gruenberg AM: An independent analysis of the Copenhagen sample of the Danish Adoption Study of Schizophrenia, VI: the relationship between psychiatric disorders as defied by DSM-III in the relatives and adoptees. Arch Gen Psychiatry 1984, 41:555–564.

    PubMed  CAS  Google Scholar 

  31. Kendler K, Gruenberg AM, Tsuang M: Psychiatric illness in first-degree relatives of schizophrenic and surgical control patients: a family study using DSM-III criteria. Arch Gen Psychiatry 1985, 42:770–779.

    PubMed  CAS  Google Scholar 

  32. Angst J, Frey R, Lohmeyer B, Zerbin-Rudin E: Bipolar manic-depressive psychoses: results of a genetic investigation. Hum Genetics 1980, 55:237–254.

    Article  CAS  Google Scholar 

  33. Baron M, Gruen R, Anis L, Kane J: Schizoaffetive illness, schizophrenia, and affective disorders: morbidity risk and genetic transmission. Acta Psychiatr Scand 1983, 65:253–262.

    Google Scholar 

  34. Scharfetter C, Nusperli M: The group of schizophrenias, schizoaffective disorders and affective disorders. Schizophr Bull 1980, 6:586–591.

    PubMed  CAS  Google Scholar 

  35. Frangos E, Athanassenas G, Tsitourides S, et al.: Prevalence of DSM-III schizophrenia among first-degree relatives of schizophrenic probands. Acta Psychiatr Scand 1985, 72:382–386.

    PubMed  CAS  Google Scholar 

  36. Baron M, Gruen R, Asnis L, Kane L: Schizoaffective illness, schizophrenia and affective disorders: morbid risk and genetic transmission. Acta Psychiatr Scand 1982, 65:253–262.

    PubMed  CAS  Google Scholar 

  37. Slater E, Shields J: Psychotic and Neurotic Illnesses in Twins: Medical Research Counsil Special Report 278. In London: Her Majesty’s Stationery Office; 1953.

    Google Scholar 

  38. Farmer A, McGuffin P, Gottesman I: Twin concordance for DSM-III schizophrenia: scrutinizing the validity of the definition. Arch Gen Psychiatry 1987, 44:634–641.

    PubMed  CAS  Google Scholar 

  39. Cardno AG, Marshall EJ, Coid B, et al.: Heritability estimates for psychotic disorders: the Maudsley Twin psychosis series. Arch Gen Psychiatry 1999, 56:162–168. Recent analysis of the Maudsley twin series (which included the classical Gottesman and Shields samples). Operational diagnostic criteria have been used; heriabilities are estimated for schizophrenia, as well as a range of functional psychotic disorders.

    Article  PubMed  CAS  Google Scholar 

  40. Cardno A, Rijsdijk F, Sham P, et al.: Comorbidity between psychotic disorders in the Maudsley twin psychosis series. Am J Psychiatry 2001, in press.

  41. Field L: Type 1 diabetes. In Analysis of Multifactorial Disease, edn 1. Edited by Bishop T, Sham P. Guilford: BIOS Scientific Publishers Ltd.; 2000:149–177. This is a recent book that reviews the current knowledge on genetic epidemiology and molecular genetic studies for the most common complex diseases (including asthma, diabetes, schizophrenia, and bipolar disorder).

    Google Scholar 

  42. Hanson R, Knowler W: Type 2 diabetes mellitus and maturity-onset diabetes of the young. In Analysis of Multifactorial Disease, edn 1. Edited by Bishop T, Sham P. Guilford: BIOS Scientific Publishers Ltd.; 2000:131–149.

    Google Scholar 

  43. Palmer L, Cookson W: Type 2 diabetes mellitus and maturityonset diabetes of the young. In Analysis of Multifactorial Disease, edn 1. Edited by Bishop T, Sham P. Guilford: BIOS Scientific Publishers Ltd.; 2000:215–239.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Hauser ER, Boehnke M, Guo SW, Risch N: Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations. Genet Epidemiol 1996, 13:117–137.

    Article  PubMed  CAS  Google Scholar 

  46. Lin J, Bale S: Parental transmission and D18S37 allele sharing in bipolar affective disorder. Genet Epidemiol 1997, 14:665–668.

    Article  PubMed  CAS  Google Scholar 

  47. Berrettini WH, Ferraro TN, Goldin LR, et al.: Chromosome-18 DNA markers and manic-depressive illness: evidence for a susceptibility gene. PNAS 1994, 91:5918–5921. This is an excellent review of the common genetic liability between schizophrenia and bipolar disorder, focusing on molecular genetic aspects.

    Article  PubMed  CAS  Google Scholar 

  48. Berrettini WH, Ferraro TN, Goldin LR, et al.: A linkage study of bipolar illness. Arch Gen Psychiatry 1997, 54:27–35.

    PubMed  CAS  Google Scholar 

  49. Stine OC, Xu JF, Koskela R, et al.: Evidence for linkage of bipolar disorder to chromosome-18 with a parent-of-origin effect. Am J Hum Genetics 1995, 57:1384–1394.

    CAS  Google Scholar 

  50. MacKinnon DF, Xu JF, McMahon FJ, et al.: Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry 1998, 155:829–831.

    PubMed  CAS  Google Scholar 

  51. Nothen MM, Cichon S, Rohleder H, 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  PubMed  CAS  Google Scholar 

  52. Turecki G, Grof P, Cavazzoni P, et al.: Lithium responsive bipolar disorder, unilineality, and chromosome 18: a linkage study. Am J Genetics 1999, 88:411–415.

    Article  CAS  Google Scholar 

  53. 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 Genetics 1998, 63:1139–1152.

    Article  CAS  Google Scholar 

  54. Schwab SG, Albus M, Hallmayer J, et al.: Evaluation of a susceptibility gene for schizophrenia on chromosome 6p by multipoint affected sib-pair linkage analysis. Nat Genetics 1995, 11:325–327.

    Article  CAS  Google Scholar 

  55. Schwab SG, Hallmayer J, Albus M, et al.: Further evidence for a susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis. A J Med Genetics 1998, 81:302–307.

    Article  CAS  Google Scholar 

  56. Lin MW, Sham P, Hwu HG, et al.: Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations. Hum Genetics 1997, 99:417–420.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  58. Brzustowicz LM, Honer WG, Chow EWC, et al.: Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genetics 1999, 65:1357.

    Google Scholar 

  59. Kelsoe J, Loetscher E, Spence M, et al.: A susceptibility locus for bipolar disorder on chromosome 22: results of a genome survey. Am J Hum Genetics 1998, 63(suppl):A295.

    Article  Google Scholar 

  60. Detera-Waldeigh S, Badner J, Berrettini W, et al.: Evidence for a bipolar susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. PNAS 1999, 96:5604–5609.

    Article  Google Scholar 

  61. Faraone SV, Matise T, Svrakic D, et al.: Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium. Am J Med Genetics 1998, 81:290–295.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  63. 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 Genetics 1998, 63:1139–1152.

    Article  CAS  Google Scholar 

  64. Foroud T, Castelluccio PF, Koller DL, et al.: Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees. Am J Med Genetics 2000, 96:18–23.

    Article  CAS  Google Scholar 

  65. Gill M, Vallada H, Collier D, et al.: A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Am J Med Genetics 1996, 67:40–45.

    Article  CAS  Google Scholar 

  66. Levinson DF, Wildenauer DB, Schwab SG, et al.: Additional support for schizophrenia linkage on chromosomes 6 and 8: a multicenter study. Am J Med Genetics 1996, 67:580–594.

    Article  Google Scholar 

  67. Moldin SO: The maddening hunt for madness genes. Nat Genetics 1997, 17:127–129.

    Article  CAS  Google Scholar 

  68. Driscoll DA, Spinner NB, Budarf ML, et al.: Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am J Med Genetics 1992, 44:261–268.

    Article  CAS  Google Scholar 

  69. 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 

  70. Murphy KC, Jones LA, Owen MJ: High rates of schizophrenia in adults with velo-cardio-facial syndrome (VCFS). Schizophr Res 2000, 41:29–29.

    Article  Google Scholar 

  71. Lachman HM, Kelsoe JR, Remick RA, et al.: Linkage studies suggest a possible locus for bipolar disorder near the velo-cardio-facial syndrome region on chromosome 22. Am J Med Genetics 1997, 74:121–128.

    Article  CAS  Google Scholar 

  72. Edenberg HJ, Foroud 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 Genetics 1997, 74:238–246.

    Article  CAS  Google Scholar 

  73. 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 

  74. McGuffin P, Owen M: Molecular genetic studies of schizophrenia. Cold Spring Harbor Symp Quant Biol 1996, 61:815–822.

    PubMed  CAS  Google Scholar 

  75. Williams NM, Rees MI, Holmans P, et al.: A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs. Hum Mol Genetics 1999, 8:1729–1739.

    Article  CAS  Google Scholar 

  76. Williams J, Spurlock G, Holmans P, et al.: A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia. Mol Psychiatry 1998, 3:458–458.

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  78. Barden N, Morissette J, Rochette D, et al.: High-density maker MAP supports bipolar affective disorder susceptibility locus on chromosome 12 in a homogeneous population in Quebec. Am J Med Genetics 1997, 74:670–670.

    Google Scholar 

  79. 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 

  80. Kirov G, Murphy KC, Arranz MJ, et al.: Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry 1998, 3:342–345.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bramon, E., Sham, P.C. The common genetic liability between schizophrenia and bipolar disorder: A review.. Curr Psychiatry Rep 3, 332–337 (2001). https://doi.org/10.1007/s11920-001-0030-1

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11920-001-0030-1

Keywords

Navigation