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Review of bipolar molecular linkage and association studies

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Abstract

This paper reviews the history of molecular genetic linkage and linkage disequilibrium (LD) or association studies of bipolar disorder (BPD). The topic is introduced with a brief discussion of various genetic concepts, including linkage and linkage disequilibrium. It is emphasized that criteria for declaring linkage must include independent confirmation by multiple groups of investigators. Given that the inherited susceptibility for BPD is most likely explained by multiple genes of small effect, simulations indicate that universal confirmation of valid linkages cannot be expected due to sampling variation and genetic heterogeneity. With this background, several valid linkages of BPD to genomic regions are reviewed, including some which may be shared with schizophrenia. These results suggest that nosology must be changed to reflect the genetic origins of the multiple disorders which are collectively described by the term, BPD. The history of BPD LD studies is reviewed, using monoamine oxidase as as an example. Some suggestions of improving these BPD LD are offered.

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References and Recommended Reading

  1. Berrettini WH: Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia. Biol Psychiatry 2000, 47:245–251. This paper is a good summary of epidemiologic and molecular evidence for shared susceptibility between bipolar disorders and schizophrenia.

    Article  PubMed  CAS  Google Scholar 

  2. Gershon ES, Hamovit J, Guroff JJ, et al.: A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry 1982, 39:1157–1167.

    PubMed  CAS  Google Scholar 

  3. Weissman MM, Gershon ES, Kidd KK, et al.: Psychiatric disorders in the relatives of probands with affective disorder. Arch Gen Psychiatry 1984, 41:13–21.

    PubMed  CAS  Google Scholar 

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

    Google Scholar 

  5. Winokur G, Tsuang MT, Crowe RR: The Iowa 500: affective disorder in relatives of manic and depressed patients. Am J Psychiatry 1982, 139:209–212.

    PubMed  CAS  Google Scholar 

  6. Winokur G, Coryell W, Keller M, et al.: A family study of manic-depressive (bipolar I) disease: is it a distinct illness separable from primary unipolar depression? Arch Gen Psychiatry 1995, 52:367–373.

    PubMed  CAS  Google Scholar 

  7. Helzer JE, Winokur G: A family interview study of male manic-depressives. Arch Gen Psychiatry 1974, 31:73–77.

    PubMed  CAS  Google Scholar 

  8. James NM, Chapman CJ: A genetic study of bipolar affective disorder. Br J Psychiatry 1975, 126:449–456.

    Article  PubMed  CAS  Google Scholar 

  9. Johnson GFS, Leeman MM: Analysis of familial factors in bipolar affective illness. Arch Gen Psychiatry 1977, 34:1074–1083.

    PubMed  CAS  Google Scholar 

  10. 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, 50:871–83.

    PubMed  CAS  Google Scholar 

  11. 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 

  12. Suarez B, Harpe 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 Association Press; 1994:23–46.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. McInnes LA, Escamilla MA, Service SK, et al.: A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci U S A 1996, 93:13060–13065.

    Article  PubMed  CAS  Google Scholar 

  15. Ginns EI, St Jean P, Philibert RA, et al.: A genome 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.

    Article  PubMed  CAS  Google Scholar 

  16. Goldin LR, Gershon ES, Berrettini WH, et al.: Description of the Genetic Analysis Workshop 10 bipolar disorder linkage data sets. Genet Epidemiol 1997, 14:563–568.

    Article  PubMed  CAS  Google Scholar 

  17. Harada S, Agarwal DP, Goedde HW: Aldehyde dehydrogenase deficiency as cause of the flushing reaction to alcohol in Japanese. Lancet 1982, 8253:982.

    Google Scholar 

  18. Berrettini W, Ferraro T, Choi H, et al.: Linkage studies of bipolar illness. Arch Gen Psychiatry 1997, 54:32–39.

    Google Scholar 

  19. Falk CT, Rubenstein P: Haplotype relative risks: an easy reliable way to construct proper control samples for risk calculations. Ann Hum Genet 1987, 51:227–233.

    PubMed  CAS  Google Scholar 

  20. Ott J: Statistical properties of the haplotype relative risk. Genet Epidemiol 1989, 6:127–130.

    Article  PubMed  CAS  Google Scholar 

  21. Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993, 52:506–516.

    PubMed  CAS  Google Scholar 

  22. Spielman RS, Ewens WJ: A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet 1998, 62:450–458.

    Article  PubMed  CAS  Google Scholar 

  23. Lazzeroni LC, Lange K: A conditional inference framework for extending the transmission/disequilibrium test. Hum Hered 1998, 48:67–81.

    Article  PubMed  CAS  Google Scholar 

  24. Monks SA, Kaplan NL, Weir BS: A comparative study of sibship tests of linkage and/or association. Am J Hum Genet 1998, 63:1507–1516.

    Article  PubMed  CAS  Google Scholar 

  25. Reich DE, Goldstein DB: Detecting association in a case-control study while correcting for population stratification. Genet Epidemiol 2001, 20:4–16.

    Article  PubMed  CAS  Google Scholar 

  26. Craddock N, Daniels J, Roberts E, et al.: No evidence for allelic association between bipolar disorder and MAOA gene polymorphisms. Am J Med Genet 1995, 60:322–324.

    Article  PubMed  CAS  Google Scholar 

  27. Lim LC, Powell J, Sham P, et al.: Evdience for a genetic association between alleles of MAOA gene and bipolar affective disorder. Am J Med Genet 1995, 60:325–331.

    Article  PubMed  CAS  Google Scholar 

  28. Nothen MM, Eggermann K, Albus M, et al.: Association analyses of the MAOA gene in bipolar affective disorder by using family based controls. Am J Hum Genet 1995, 57:975–977.

    PubMed  CAS  Google Scholar 

  29. Parsian A, Todd RD: Genetic association between monoamine oxidase and manic-depressive illness: comparison of relative risk and haplotype relative risk data. Am J Med Genet 1997, 74:475–479.

    Article  PubMed  CAS  Google Scholar 

  30. Furlong RA, Ho L, Rubinszstein JS, et al.: Analysis of the MAOA gene in bipolar affective disorder by association studies, meta-analyses and sequencing of the promoter. Am J Med Genet 1999, 88:398–406.

    Article  PubMed  CAS  Google Scholar 

  31. Turecki G, Grof P, Cavazzoni P, et al.: MAOA: association and linkage studies with lithium responsive bipolar disorder. Psychiatr Genet 1999, 9:13–16.

    Article  PubMed  CAS  Google Scholar 

  32. Preisig M, Bellivier F, Fenton BT, et al.: Association between bipolar disorder and MAOA gene polymorphisms: results of a multicetner study. Am J Psychiatry 2000, 157:948–959.

    Article  PubMed  CAS  Google Scholar 

  33. Kawada Y, Hattori M, Dai XY: Possible association between MAOA gene and bipolar affective disorder. Am J Hum Genet 1995, 56:335–336.

    PubMed  CAS  Google Scholar 

  34. Muramatsu T, Matsushita S, Kanba S, et al.: MAO genes polymorphisms and mood disorder. Am J Med Genet 1997, 19:494–496.

    Article  Google Scholar 

  35. Kunugi H, Ishida S, Kato T, et al.: A functional polymorphism in the promoter region of MAOA gene and mood disorders. Mol Psychiatry 1999, 4:393–395.

    Article  PubMed  CAS  Google Scholar 

  36. Berrettini WH: On the interpretation of association studies in behavioral disorders. Mol Psychiatry 1997, 2:274–275.

    Article  PubMed  CAS  Google Scholar 

  37. Berrettini W, Ferraro T, Goldin L, 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 

  38. 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 

  39. Kelsoe JR, Spence MA, Loetscher E, et al.: A genome survey indicates a susceptibility locus for bipolar disorder on chromosome 22. Proc Natl Acad Sci U S A 2001, 98:585–590.

    Article  PubMed  CAS  Google Scholar 

  40. 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 

  41. 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 homogeneous population in Quebec points to a locus of major effect on chromosome 12q23-q24. Am J Med Genet 1999, 88:567–587.

    Article  PubMed  CAS  Google Scholar 

  42. Blackwood DHR, 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 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  45. Detera-Wadleigh SD, Badner JA, Goldin LR, 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.

    PubMed  CAS  Google Scholar 

  46. Smyth C, Kalsi G, Brynjolfsson J, et al.: Further tests for linkage of bipolar affective disorder to the tyrosine hydroxylase gene locus on chromosome 11p15 in a new series of multiplex British affective disorder pedigrees. Am J Psychiatry 1996, 153:271–274.

    PubMed  CAS  Google Scholar 

  47. Kwok JB, Adams LJ, Salmon JA, et al.: Non-parametric simulation-based statistical analyses for bipolar affective disorder locus on chromosome 21q22.3. Am J Med Genet 1999, 88:99–102.

    Article  PubMed  CAS  Google Scholar 

  48. Aita VM, Liu J, Knowles JA, 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  PubMed  CAS  Google Scholar 

  49. Detera-Wadleigh SD, Hsieh WT, Berrettini WH, et al.: Genetic linkage mapping for a susceptibility locus to bipolar illness: Chromosomes 2, 3, 4, 7, 9, 10p, 11p, 22, and Xpter. Neuropsychiatr Genet 1997, 74:206–218.

    Google Scholar 

  50. Detera-Wadleigh SD, Badner JA, Berrettini WH, et al.: Evidence for a bipolar susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci U S A 1999, 96:5604–5609.

    Article  PubMed  CAS  Google Scholar 

  51. McMahon FJ, Hopkins PJ, Xu J, 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  PubMed  CAS  Google Scholar 

  52. De Bruyn A, Souery D, Mendelbaum K, et al.: Linkage analysis of families with bipolar illness and chromosome 18 markers. Biol Psychiat 1996, 39:679–88.

    Article  Google Scholar 

  53. Ewald H, Degn B, Mors B, Kruse TA: Significant linkage between bipolar affective disorder and chromosome 12q24. Psychiatr Genet 1998, 8:131–140.

    Article  PubMed  CAS  Google Scholar 

  54. Ewald H, Degn B, Mors B, Kruse TA: Support for the possible locus on chromosome 4p15 for bipolar affective disorder. Mol Psychiatry 1998, 3:442–448.

    Article  PubMed  CAS  Google Scholar 

  55. Nothen MM, Cichon S, Franzek E, et al.: Systematic search for susceptibility genes in bipolar affective disorder: evidence for disease loci at 18p and 4 p. Am J Hum Genet 1997, 61:A288.

    Google Scholar 

  56. 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.

    Article  PubMed  CAS  Google Scholar 

  57. Freimer NB, Reus VI, Escamilla MA, et al.: Genetic maping 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 

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  1. Departments of Psychiatry and Genetics, and Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, 415 Curie Blvd, Room 111, 19104, Philadelphia, PA, USA

    Wade Berrettini MD, PhD

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  1. Wade Berrettini MD, PhD
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Berrettini, W. Review of bipolar molecular linkage and association studies. Curr Psychiatry Rep 4, 124–129 (2002). https://doi.org/10.1007/s11920-002-0045-2

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