Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1993 Feb;52(2):327–334.

Linkage analysis of schizophrenia with five dopamine receptor genes in nine pedigrees

Hilary Coon, William Byerley, John Holik, Mark Hoff, Marina Myles-Worsley, Lars Lannfelt, Pierre Sokoloff, Jean-Charles Schwartz, Merilyne Waldo, Robert Freedman, Rosemarie Plaetke
PMCID: PMC1682188  PMID: 8094267

Abstract

Alterations in dopamine neurotransmission have been strongly implicated in the pathogenesis of schizophrenia for nearly 2 decades. Recently, the genes for five dopamine receptors have been cloned and characterized, and genetic and physical map information has become available. Using these five loci as candidate genes, we have tested for genetic linkage to schizophrenia in nine multigenerational families which include multiple affected individuals. In addition to testing conservative disease models, we have used a neurophysiological indicator variable, the P50 auditory evoked response. Deficits in gating of the P50 response have been shown to segregate with schizophrenia in this sample and may identify carriers of gene(s) predisposing for schizophrenia. Linkage results were consistently negative, indicating that a defect at any of the actual receptor sites is unlikely to be a major contributor to schizophrenia in the nine families studied.

Full text

PDF
331

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler L. E., Gerhardt G. A., Franks R., Baker N., Nagamoto H., Drebing C., Freedman R. Sensory physiology and catecholamines in schizophrenia and mania. Psychiatry Res. 1990 Mar;31(3):297–309. doi: 10.1016/0165-1781(90)90099-q. [DOI] [PubMed] [Google Scholar]
  2. Adler L. E., Pang K., Gerhardt G., Rose G. M. Modulation of the gating of auditory evoked potentials by norepinephrine: pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry. 1988 Jun;24(2):179–190. doi: 10.1016/0006-3223(88)90273-9. [DOI] [PubMed] [Google Scholar]
  3. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buetow K. H., Shiang R., Yang P., Nakamura Y., Lathrop G. M., White R., Wasmuth J. J., Wood S., Berdahl L. D., Leysens N. J. A detailed multipoint map of human chromosome 4 provides evidence for linkage heterogeneity and position-specific recombination rates. Am J Hum Genet. 1991 May;48(5):911–925. [PMC free article] [PubMed] [Google Scholar]
  5. Bunzow J. R., Van Tol H. H., Grandy D. K., Albert P., Salon J., Christie M., Machida C. A., Neve K. A., Civelli O. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature. 1988 Dec 22;336(6201):783–787. doi: 10.1038/336783a0. [DOI] [PubMed] [Google Scholar]
  6. Creese I., Burt D. R., Snyder S. H. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976 Apr 30;192(4238):481–483. doi: 10.1126/science.3854. [DOI] [PubMed] [Google Scholar]
  7. Cross A. J., Crow T. J., Owen F. 3H-Flupenthixol binding in post-mortem brains of schizophrenics: evidence for a selective increase in dopamine D2 receptors. Psychopharmacology (Berl) 1981;74(2):122–124. doi: 10.1007/BF00432676. [DOI] [PubMed] [Google Scholar]
  8. Davidson M., Keefe R. S., Mohs R. C., Siever L. J., Losonczy M. F., Horvath T. B., Davis K. L. L-dopa challenge and relapse in schizophrenia. Am J Psychiatry. 1987 Jul;144(7):934–938. doi: 10.1176/ajp.144.7.934. [DOI] [PubMed] [Google Scholar]
  9. Davis K. L., Kahn R. S., Ko G., Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991 Nov;148(11):1474–1486. doi: 10.1176/ajp.148.11.1474. [DOI] [PubMed] [Google Scholar]
  10. Dearry A., Gingrich J. A., Falardeau P., Fremeau R. T., Jr, Bates M. D., Caron M. G. Molecular cloning and expression of the gene for a human D1 dopamine receptor. Nature. 1990 Sep 6;347(6288):72–76. doi: 10.1038/347072a0. [DOI] [PubMed] [Google Scholar]
  11. Endicott J., Spitzer R. L. A diagnostic interview: the schedule for affective disorders and schizophrenia. Arch Gen Psychiatry. 1978 Jul;35(7):837–844. doi: 10.1001/archpsyc.1978.01770310043002. [DOI] [PubMed] [Google Scholar]
  12. Eubanks J. H., Altherr M., Wagner-McPherson C., McPherson J. D., Wasmuth J. J., Evans G. A. Localization of the D5 dopamine receptor gene to human chromosome 4p15.1-p15.3, centromeric to the Huntington's disease locus. Genomics. 1992 Mar;12(3):510–516. doi: 10.1016/0888-7543(92)90442-u. [DOI] [PubMed] [Google Scholar]
  13. Freedman R., Adler L. E., Gerhardt G. A., Waldo M., Baker N., Rose G. M., Drebing C., Nagamoto H., Bickford-Wimer P., Franks R. Neurobiological studies of sensory gating in schizophrenia. Schizophr Bull. 1987;13(4):669–678. doi: 10.1093/schbul/13.4.669. [DOI] [PubMed] [Google Scholar]
  14. Freedman R., Adler L. E., Waldo M. C., Pachtman E., Franks R. D. Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients. Biol Psychiatry. 1983 May;18(5):537–551. [PubMed] [Google Scholar]
  15. Giros B., Martres M. P., Sokoloff P., Schwartz J. C. Clonage du gène du récepteur dopaminergique D3 humain et identification de son chromosome. C R Acad Sci III. 1990;311(13):501–508. [PubMed] [Google Scholar]
  16. Grandy D. K., Marchionni M. A., Makam H., Stofko R. E., Alfano M., Frothingham L., Fischer J. B., Burke-Howie K. J., Bunzow J. R., Server A. C. Cloning of the cDNA and gene for a human D2 dopamine receptor. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9762–9766. doi: 10.1073/pnas.86.24.9762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grandy D. K., Zhou Q. Y., Allen L., Litt R., Magenis R. E., Civelli O., Litt M. A human D1 dopamine receptor gene is located on chromosome 5 at q35.1 and identifies an EcoRI RFLP. Am J Hum Genet. 1990 Nov;47(5):828–834. [PMC free article] [PubMed] [Google Scholar]
  18. Hauge X. Y., Grandy D. K., Eubanks J. H., Evans G. A., Civelli O., Litt M. Detection and characterization of additional DNA polymorphisms in the dopamine D2 receptor gene. Genomics. 1991 Jul;10(3):527–530. doi: 10.1016/0888-7543(91)90431-d. [DOI] [PubMed] [Google Scholar]
  19. Judd L. L., McAdams L., Budnick B., Braff D. L. Sensory gating deficits in schizophrenia: new results. Am J Psychiatry. 1992 Apr;149(4):488–493. doi: 10.1176/ajp.149.4.488. [DOI] [PubMed] [Google Scholar]
  20. Junien C., van Heyningen V., Evans G., Little P., Mannens M. Report of the second chromosome 11 workshop. Genomics. 1992 Mar;12(3):620–625. doi: 10.1016/0888-7543(92)90461-z. [DOI] [PubMed] [Google Scholar]
  21. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Litt M., al-Dhalimy M., Zhou Q., Grandy D., Civelli O. A TaqI RFLP at the DRD1 locus. Nucleic Acids Res. 1991 Jun 11;19(11):3161–3161. doi: 10.1093/nar/19.11.3161-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Moises H. W., Gelernter J., Giuffra L. A., Zarcone V., Wetterberg L., Civelli O., Kidd K. K., Cavalli-Sforza L. L., Grandy D. K., Kennedy J. L. No linkage between D2 dopamine receptor gene region and schizophrenia. Arch Gen Psychiatry. 1991 Jul;48(7):643–647. doi: 10.1001/archpsyc.1991.01810310061011. [DOI] [PubMed] [Google Scholar]
  24. Nagamoto H. T., Adler L. E., Waldo M. C., Freedman R. Sensory gating in schizophrenics and normal controls: effects of changing stimulation interval. Biol Psychiatry. 1989 Mar 1;25(5):549–561. doi: 10.1016/0006-3223(89)90215-1. [DOI] [PubMed] [Google Scholar]
  25. Ott J. Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4175–4178. doi: 10.1073/pnas.86.11.4175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Patterson T., Spohn H. E., Bogia D. P., Hayes K. Thought disorder in schizophrenia: cognitive and neuroscience approaches. Schizophr Bull. 1986;12(3):460–472. doi: 10.1093/schbul/12.3.460. [DOI] [PubMed] [Google Scholar]
  27. Plaetke R., Byerley W. F., Koehler W. Programs for determining parameters in complex genetic models for linkage analysis: GEN-PAR and EPI-PAR. Genet Epidemiol. 1991;8(6):425–427. doi: 10.1002/gepi.1370080609. [DOI] [PubMed] [Google Scholar]
  28. Seeman P., Ulpian C., Bergeron C., Riederer P., Jellinger K., Gabriel E., Reynolds G. P., Tourtellotte W. W. Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science. 1984 Aug 17;225(4663):728–731. doi: 10.1126/science.6147018. [DOI] [PubMed] [Google Scholar]
  29. Siegel C., Waldo M., Mizner G., Adler L. E., Freedman R. Deficits in sensory gating in schizophrenic patients and their relatives. Evidence obtained with auditory evoked responses. Arch Gen Psychiatry. 1984 Jun;41(6):607–612. doi: 10.1001/archpsyc.1984.01790170081009. [DOI] [PubMed] [Google Scholar]
  30. Sokoloff P., Giros B., Martres M. P., Bouthenet M. L., Schwartz J. C. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990 Sep 13;347(6289):146–151. doi: 10.1038/347146a0. [DOI] [PubMed] [Google Scholar]
  31. Sunahara R. K., Guan H. C., O'Dowd B. F., Seeman P., Laurier L. G., Ng G., George S. R., Torchia J., Van Tol H. H., Niznik H. B. Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature. 1991 Apr 18;350(6319):614–619. doi: 10.1038/350614a0. [DOI] [PubMed] [Google Scholar]
  32. Sunahara R. K., Niznik H. B., Weiner D. M., Stormann T. M., Brann M. R., Kennedy J. L., Gelernter J. E., Rozmahel R., Yang Y. L., Israel Y. Human dopamine D1 receptor encoded by an intronless gene on chromosome 5. Nature. 1990 Sep 6;347(6288):80–83. doi: 10.1038/347080a0. [DOI] [PubMed] [Google Scholar]
  33. Van Tol H. H., Bunzow J. R., Guan H. C., Sunahara R. K., Seeman P., Niznik H. B., Civelli O. Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature. 1991 Apr 18;350(6319):610–614. doi: 10.1038/350610a0. [DOI] [PubMed] [Google Scholar]
  34. Waldo M. C., Carey G., Myles-Worsley M., Cawthra E., Adler L. E., Nagamoto H. T., Wender P., Byerley W., Plaetke R., Freedman R. Codistribution of a sensory gating deficit and schizophrenia in multi-affected families. Psychiatry Res. 1991 Dec;39(3):257–268. doi: 10.1016/0165-1781(91)90092-4. [DOI] [PubMed] [Google Scholar]
  35. Waldo M. C., Freedman R. Gating of auditory evoked responses in normal college students. Psychiatry Res. 1986 Nov;19(3):233–239. doi: 10.1016/0165-1781(86)90102-2. [DOI] [PubMed] [Google Scholar]
  36. Weiffenbach B., Falls K., Bricker A., Hall L., McMahon J., Wasmuth J., Funanage V., Donis-Keller H. A genetic linkage map of human chromosome 5 with 60 RFLP loci. Genomics. 1991 May;10(1):173–185. doi: 10.1016/0888-7543(91)90498-4. [DOI] [PubMed] [Google Scholar]
  37. Wyatt R. J., Alexander R. C., Egan M. F., Kirch D. G. Schizophrenia, just the facts. What do we know, how well do we know it? Schizophr Res. 1988 Jan-Feb;1(1):3–18. doi: 10.1016/0920-9964(88)90034-5. [DOI] [PubMed] [Google Scholar]
  38. Zhou Q. Y., Grandy D. K., Thambi L., Kushner J. A., Van Tol H. H., Cone R., Pribnow D., Salon J., Bunzow J. R., Civelli O. Cloning and expression of human and rat D1 dopamine receptors. Nature. 1990 Sep 6;347(6288):76–80. doi: 10.1038/347076a0. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES