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  • Original Research Article
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Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series

Abstract

Bipolar (BP) disorder or manic depressive illness is a major psychiatric disorder for which numerous family, twin and adoption studies support a substantial genetic contribution. Recently, we reported the results of a genome-wide search for BP disorder susceptibility loci in 20 pedigrees. Suggestive evidence for linkage was found in this study at three markers on 13q, representing possibly two peaks separated by 18 cM. We have now collected a second set of 32 pedigrees segregating BP disorder and have tested for evidence of linkage to markers on human chromosome 13q. In this sample, we have replicated the linkage result in 13q32 at D13S154 (lod=2.29), the more proximal of the two original peaks. When all 52 pedigrees were combined, the multipoint maximum lod score peaked approximately 7 cM proximal to D13S154 (lod=3.40), with a second peak occurring between D13S225 and D13S796 (lod=2.58). There have been several other reports of significant linkage to both BP disorder and schizophrenia in this region of chromosome 13. These pedigrees provide additional evidence for at least one locus for BP disorder in 13q32, and are consistent with other reports of a possible genetic overlap between these disorders.

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References

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

    Google Scholar 

  2. Tsuang MT, Faraone SV . The Genetics of Mood Disorders. Johns Hopkins University Press: Baltimore, MD, 1990.

    Google Scholar 

  3. 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. Proc Natl Acad Sci USA 2001; 98: 585–590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G et al. Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 1998; 20: 70–73.

    Article  CAS  PubMed  Google Scholar 

  6. Brzustowicz LM, Honer WG, Chow EW, Little D, Hogan J, Hodgkinson K, et al. Linkage of familial schizophrenia to chromosome 13q32. Am J Hum Genet 1999; 65: 1096–1103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

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

    Google Scholar 

  9. Lathrop GM, Lalouel JM . Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet 1984; 36: 460–465.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cottingham Jr RW, Idury RM, Schaffer AA . Faster sequential genetic linkage computations. Am J Hum Genet 1993; 53: 252–263.

    PubMed  PubMed Central  Google Scholar 

  11. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . MERLIN—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  PubMed  Google Scholar 

  12. Ott J . Analysis of Human Genetic Linkage. 3rd edn. Johns Hopkins University Press: Baltimore, (1999).

    Google Scholar 

  13. 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 

  14. Stine OC, McMahon FJ, Chen L, Xu J, Meyers DA, MacKinnon DF, et al. Initial genome screen 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  CAS  PubMed  Google Scholar 

  15. 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 

  16. Cichon S, Schumacher J, Muller DJ, Hurter M, Windemuth C, Strauch K et al. A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q. Hum Mol Genet 2001; 10: 2933–2944.

    Article  CAS  PubMed  Google Scholar 

  17. Coon H, Jensen S, Hoff M, Holik J, Plaetke R, Reimherr F, et al. A genome-wide search for genes predisposing to manic-depression, assuming autosomal dominant inheritance. Am J Hum Genet 1993; 52: 1234–1249.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 

  19. 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 

  20. Kelsoe JR . Recent progress in the search for genes for bipolar disorder. Curr Psychiatry Rep 1999; 1: 135–140.

    Article  CAS  PubMed  Google Scholar 

  21. Berrettini WH . Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia. Biol Psychiatry 2000; 47: 245–251.

    Article  CAS  PubMed  Google Scholar 

  22. Wildenauer DB, Schwab SG, Maier W, Detera-Wadleigh SD . Do schizophrenia and affective disorder share susceptibility genes? Schizophr Res 1999; 39: 107–111.

    Article  CAS  PubMed  Google Scholar 

  23. Lin MW, Sham P, Hwu HG, Collier D, Murray R, Powell JF . Suggestive evidence for linkage of schizophrenia to markers on chromosome 13 in Caucasian but not Oriental populations. Hum Genet 1997; 99: 417–420.

    Article  CAS  PubMed  Google Scholar 

  24. Shaw SH, Kelly M, Smith AB, Shields G, Hopkins PJ, Loftus J et al. A genome-wide search for schizophrenia susceptibility genes. Am J Med Genet 1998; 81: 364–376.

    Article  CAS  PubMed  Google Scholar 

  25. Spitzer RL, Williams JBW, Gibbon M . Structured Clinical Interview for DSM-3-R (SCID). New York State Psychiatric Institute Biometrics Research: New York, 1987.

    Google Scholar 

  26. Don RH, Cox PT, Wainwright BJ, Baker K, Mattick JS . ‘Touchdown’ PCR to circumvent spurious priming during gene amplification. Nucleic Acids Res 1991; 19: 4008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Matise TC, Perlin M, Chakravarti A . Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map. Nat Genet 1994; 6: 384–390.

    Article  CAS  PubMed  Google Scholar 

  29. 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 

  30. Broman KW, Murray JC, Sheffield VC, White RL, Weber JL . Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 1998; 63: 861–869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Terwilliger JD, Speer M, Ott J . Chromosome-based method for rapid computer simulation in human genetic linkage analysis. Genet Epidemiol 1993; 10: 217–224.

    Article  CAS  PubMed  Google Scholar 

  32. Ott J . Linkage probability and its approximate confidence interval under possible heterogeneity. Genet Epidemiol Suppl 1986; 1: 251–257.

    Article  CAS  PubMed  Google Scholar 

  33. Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 

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Acknowledgements

We thank the family members who participated in this study, without whom it would not have been possible. This work was supported by Novartis Pharma AG, and by grants to JRK from the Department of Veterans Affairs and the National Institute of Mental Health (NIMH) (MH47612, MH59567), the UCSD Mental Health Clinical Research Center (MH30914), and the UCSD General Clinical Research Center (M01 RR00827). We also acknowledge the statistical assistance of John Brown.

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Correspondence to J R Kelsoe.

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Shaw, S., Mroczkowski-Parker, Z., Shekhtman, T. et al. Linkage of a bipolar disorder susceptibility locus to human chromosome 13q32 in a new pedigree series. Mol Psychiatry 8, 558–564 (2003). https://doi.org/10.1038/sj.mp.4001267

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