No proof of linkage between schizophrenia-related disorders including schizophrenia and chromosome 2q21 region

  • Harald N. Aschauer
  • Gabriele Fischer
  • Keith E. Isenberg
  • Kurt Meszaros
  • Ulrike Willinger
  • Richard D. Todd
  • Henriette Beran
  • Rainer Strobl
  • Manuela Lang
  • Karoline Fuchs
  • Werner Sieghart
  • Theodore Reich
  • C. Robert Cloninger
Original Articles

Summary

We examined linkage between schizophrenia and schizophrenia-related disorders and five genetic markers on chromosome 2 in fourteen families ascertained through affected probands in St. Louis and Vienna. The chromosomal region 2q21 was considered a candidate locus for schizophrenia because of a report of a balanced translocation 2;18 (q21;q23) in a schizophrenia family. Linkage analyses were conducted for three disease models: a narrow model including schizophrenia only; an intermediate model including a spectrum of schizophrenia-related disorders; and a broad model including major affective disorders. Multipoint linkage analyses excluded linkage across the region (about 50cM) for the intermediate disease model. The same was generally true for the broad affection status model. None of the two-point and multipoint analyses showed definite linkage of schizophrenia to any marker. The most prominent positive association was between D2S44 and a broad affection status model, giving a two-point lod score of 1.71 at 0.20 recombination fraction.

Key words

Schizophrenia Linkage DNA markers Chromosome 2 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. American Psychiatric Association (1987) Diangostic and statistical manual of mental disorders (DSM III-R), revised 3rd edn. American Psychiatric Association, Washington DCGoogle Scholar
  2. Aschauer H, Aschauer-Treiber G, Cloninger CR, Garver DL, Isenberg KE (1989) Heterogeneity of schizophrenia: preliminary evidence for multiple genetic loci. Schizophrenia Res 2: 39Google Scholar
  3. Aschauer HN, Aschauer-Treiber G, Isenberg KE, Todd RD, Knesevich MA, Garver DL, Reich T, Cloninger CR (1990) No evidence for linkage between chromosome 5 markers and schizophrenia. Hum Hered 40: 109–115Google Scholar
  4. Baron M, Gruen RS (1991) Schizophrenia and affective disorder: are they genetically linked. Br J Psychiatry 159: 267–270Google Scholar
  5. Bassett AS (1992) Chromosomal aberrations and schizophrenia. Br J Psychiatry 161: 323–334Google Scholar
  6. Carter CL, Chung CS (1980) Segregation analysis of schizophrenia under a mixed genetic model. Hum Hered 30: 350–356Google Scholar
  7. Clerget-Darpoux F, Babron MC, Bonaiti-Pellie C (1990) Assessing the effect of multiple linkage tests in complex diseases. Genet Epidemiol 7: 245–253Google Scholar
  8. Cloninger CR (1988) Schizophrenic disorders: genetic etiologic factors. In: Kaplan H, Sadock B (eds) Comprehensive Textbook of Psychiatry, volume 5. Williams & Wilkins, Baltimore, pp 732–744Google Scholar
  9. Crowe RR, Black DW, Andreasen NC, Huether M (1990) The Iowa mujltiplex family study of schizophrenia: linkage analyses on chromosome 5. Eur Arch Psychiatr Neurol Sci 239: 290–292Google Scholar
  10. DeLisi LE, Reiss AL, White BJ, Gershon ES (1988) Cytogenetic studies of males with schizophrenia. Schizophrenia Res 1: 277–281Google Scholar
  11. Donis-Keller H, Green P, Helms C, Cartinhour S, Weiffenbach B, Stephens K, Keith TP, Bowden DW, Smith DR, Lander ES, Botstein D, Akots G, Rediker KS, Gravius T, Brown VA, Rising MB, Parker C, Powers JA, Watt DE, Kauffman ER, Bricker A, Phipps P, Muller-Kahle H, Fulton TR, Ng, S, Schumm JW, Braman JC, Knowlton RG, Barker DF, Crooks SM, Lincoln nSE, Daly MJ, Abrahamson J (1987) A genetic linkage map of the human genome. Cell 51: 319–337Google Scholar
  12. Durner M, Greenberg DA, Hodge SE (1992) Inter-and intrafamilial heterogeneity: effective sampling strategies and comparison of analysis methods. Am J Hum Genet 51: 859–870Google Scholar
  13. Elston RC, Namboodiri KK, Spence MA, Rainer JD (1978) A genetic study of schizophrenia pedigrees. Neuropsychobiology 4: 193–206Google Scholar
  14. Feinberg AP, Vogelstein B (1983) A technique for radiolabelling DNA restriction endonuclease fragments to high specific activity. Ann Biochem 132: 6–13Google Scholar
  15. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TP (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643–646Google Scholar
  16. Fyer AJ, Endicott J, Mannuzza S, Klein DF (1985) Schedule for Affective Disorders and Schizophrenia — Lifetime Version, modified for the Study of Anxiety Disorders (SADS-LA). Anxiety Disorders Clinic, New York State Psychiatric Institute, New YorkGoogle Scholar
  17. Genest P, Dumas L, Genest FB (1976) Translocation chromosomique t(2;18) (q21;q23) chez un individu schizophrène et sa fille. Union Med Can 105: 1676–1681Google Scholar
  18. Hallmayer J, Kennedy JL, Wetterberg L, Sjögren B, Kidd KK, Cavalli-Sforza LL (1992a) Exclusion of linkage between the serotonin 2 receptor and schizophrenia in a large swedish kindred. Arch Gen Psychiatry 49: 216–219Google Scholar
  19. Hallmayer J, Maier W, Ackenheil, M, Ertl MA, Schmidt S, Minges J, Lichtermann D, Wildenauer D (1992b) Evidence against linkage of schizophrenia to chromosome 5q11-13 markers in systematically ascertained families. Biol Psychiatry 31: 83–84Google Scholar
  20. Holland T, Gosden C (1990) A balanced chromosomal translocation partially co-segregating with psychotic illness in a family. Psychiatry Res 32: 1–8Google Scholar
  21. Lathrop GM, Laloeul JM (1984) Easy calculations of lod scores and genetic risk on small computers. Am J Hum Gent 36: 460–465Google Scholar
  22. Loranger AW, Susman VL, Oldham JM, Russakoff LM (1987) The personality disorder examination: a preliminary report. J Pers Disord 1: 1–13Google Scholar
  23. Maziade M, DeBraekeleer M, Genest P, Cliche D, Fournier J-P, Garneau Y, Shriqui C, Roy M-A, Nicole L, Raymond V, Vekemans M (1993) A balanced 2∶18 translocation and familial schizophrenia: falling short of an association. Arch Gen Psychiatry 50: 73–75Google Scholar
  24. McGuffin P, Sargant M, Hetti G, Tidmark S, Whatley S, Marchbanks RM (1990) Exclusion of a schizophrenia susceptibility gene from the chromosome 5q11-13 region: new data and a reanalysis of previous reports. Am J Hum Genet 47: 524–535Google Scholar
  25. Moises HW, Gelernter J, Giuffra LA, Zarcone V, Wetterberg L, Civelli O, Kidd KK, Cavalli-Sforza LL, Grandy DK, Kennedy JL, Vinogradov S, Mauer J, Litt M, Sjögren B (1991) No linkage between D2 Dopamine receptor gene region and schizophrenia. Arch Gen Psychiatry 48: 643–647Google Scholar
  26. Neitzel H (1986) A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 73: 320–326Google Scholar
  27. NIH/CEPH Collaborative Mapping Group (1992) A comprehensive genetic linkage map of the human genome. Science 258: 67–86, 148–162.Google Scholar
  28. O'Connell P, Lathrop GM, Nakamura Y, Leppert ML, Lalouel JM, White R (1989) Twenty loci form a continous linkage map of markers for human chromosome 2. Genomics 5: 738–745Google Scholar
  29. O'Rourke DH, Gottesman II, Suarez BK, Rice J, Reich T (1982) Refutation of the general single-locus model for the etiology of schizophrenia. Am J Hum Genet 34: 630–649Google Scholar
  30. Ott J (1991) Analysis of Human Genetic Linkage. Johns Hopkins University Press, BaltimoreGoogle Scholar
  31. Risch N, Baron M (1984) Segregation analysis of schizophrenia and related disorders. Am J Hum Genet 36: 1039–1059Google Scholar
  32. Robins LN, Helzer JE, Croughan JL, Ratcliff KS (1981) National Institute of Mental Health Diagnostic Interview Schedule. Arch Gen Psychiatry 38: 381–389Google Scholar
  33. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular Cloning. A Laboratory Manual, 2nd edn. Laboratory Press, Cold Spring HarbourGoogle Scholar
  34. Sherrington R, Brynjolfsson J, Petursson H, Potter M, Dudleston K, Barraclough B, Wasmuth J, Dobbs M, Gurling H (1988) Localization of a susceptibility locus for schizophrenia on chromosome 5. Nature 336: 164–167Google Scholar
  35. Spurr NK, White R (1991) Report of the committee on the genetic constitution of chromosome 2. Cytogenet Cell Genet 58: 142–169Google Scholar
  36. St. Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ (1990) Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336: 13–16Google Scholar
  37. St. George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D (1987) The genetic defect causing familial Alzheimer's disease maps on chromosome 21. Science 235: 885–890Google Scholar
  38. Taylor MA, Berenbaum SA, Jampala VC, Cloninger CR (1993) Are schizophrenia and affective disorder related? Preliminary data from a family study. Am J Psychiatry 150: 278–285Google Scholar
  39. Tsuang MT, Bucher KD, Fleming JA (1982) Testing the monogenic theory of schizophrenia: an application of segregation analysis to blind family data. Br J Psychiatry 140: 595–599Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Harald N. Aschauer
    • 1
  • Gabriele Fischer
    • 1
  • Keith E. Isenberg
    • 2
  • Kurt Meszaros
    • 1
  • Ulrike Willinger
    • 1
  • Richard D. Todd
    • 2
    • 3
  • Henriette Beran
    • 1
  • Rainer Strobl
    • 1
  • Manuela Lang
    • 1
  • Karoline Fuchs
    • 1
  • Werner Sieghart
    • 1
  • Theodore Reich
    • 2
    • 3
  • C. Robert Cloninger
    • 2
    • 3
  1. 1.Department of PsychiatryUniversity of ViennaWiennaAustria
  2. 2.Department of PsychiatryWashington University Medical SchoolSt. LouisUSA
  3. 3.Department of GeneticsWashington University Medical SchoolSt. LouisUSA

Personalised recommendations