Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Millennium Article
  • Published:

Psychiatric genetics: back to the future

Molecular Psychiatry volume 5, pages 22–31 (2000)Cite this article

Abstract

For the last decade or more geneticists have been predicting that advances in molecular genetics are going to revolutionise our understanding of psychiatric disorders and human behavior. However, with a few exceptions, these expectations have yet to be fulfilled. As the century draws to a close and we contemplate the prospect of the complete sequence of the human genome it seems timely to consider the state of the field and to consider carefully how it might advance, the problems to be faced and the resources required.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Neale MC, Cardon LR . Methodology for Genetic Studies of Twins and Families NATO ASI Series: Kluwer Academic Publishers: Dordrecht 1992

    Book  Google Scholar 

  2. McGuffin P, Owen MJ, O'Donovan MC, Thapar A, Gottesman I . Seminars in Psychiatric Genetics Gaskell: London 1994

    Google Scholar 

  3. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ . Major depression and generalized anxiety disorder: same genes, (partly) different environments? Arch Gen Psychiatry 1992; 49: 716–722

    Article  CAS  PubMed  Google Scholar 

  4. Kendler KS, Tsuang MT, Hays P . Age at onset in schizophrenia: a familial perspective Arch Gen Psychiatry 1987; 44: 881–890

    Article  CAS  PubMed  Google Scholar 

  5. Neale MC, Eaves LJ, Hewitt JK, MacLean CJ, Meyer JM, Kendler KS . Analysing the relationship between age at onset and risk to relatives Am J Hum Genet 1989; 45: 226–239

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kendler KS, Karkowski-Shuman L, O'Neill FA, Straub RE, MacLean CJ, Walsh D . Resemblance of psychotic symptoms and syndromes in affected sibling pairs from the Irish study of high-density schizophrenia families: evidence for possible etiologic heterogeneity Am J Psychiatry 1997; 154: 191–198

    Article  CAS  PubMed  Google Scholar 

  7. Kendler KS, Neale M, Kessler R et al. A twin study of recent life events and difficulties Arch Gen Psychiatry 1993; 50: 789–796

    Article  CAS  PubMed  Google Scholar 

  8. Thapar A, McGuffin P . Genetic influences on life events in childhood Psychol Med 1996; 26: 813–820

    Article  CAS  PubMed  Google Scholar 

  9. McGuffin P, Katz R, Bebbington P . The Camberwell Collaborative Depression Study III. Depression and adversity in the relatives of depressed probands Br J Psychiatry 1988; 152: 775–782

    Article  CAS  PubMed  Google Scholar 

  10. Owen MJ, McGuffin P . Genetics and psychiatry Br J Psychiatry 1997; 171: 201–202

    Article  CAS  PubMed  Google Scholar 

  11. Precott CA, Kendler KS . Age at first drink and risk for alcoholism: a noncausal association Alc Clin Exp Res 1999; 23: 101–107

    Google Scholar 

  12. Tienari P, Lyman CW, Moring J, Lahti I, Naarala M, Sorri A et al. The Finnish adoptive family study of schizophrenia: implications for family research Br J Psychiatry 1994; 164: (suppl 23) 20–26

    Article  Google Scholar 

  13. Cadoret RJ, Yates WR, Troughton E, Woodworth G, Stewart E . Gene-environment interaction in the genesis of aggressivity and conduct disorder Arch Gen Psychiatry 1995; 52: 916–924

    Article  CAS  PubMed  Google Scholar 

  14. Lendon C, Ashall F, Goate AM . Exploring the etiology of Alzheimer disease using molecular genetics JAMA 1997; 277: 825–831

    Article  CAS  PubMed  Google Scholar 

  15. Hardy J, Gwinn-Hardy K . Genetic classification of primary neurodegenerative disease Science 1998; 282: 1075–1079

    Article  CAS  PubMed  Google Scholar 

  16. Hardy J, Israël A . Alzheimer's disease: in search of γ-secretase Nature 1999; 398: 466–467

    Article  CAS  PubMed  Google Scholar 

  17. McGuffin P, Owen MJ . Molecular genetic studies of schizophrenia Cold Spring Harb Symp Quant Biol 1996; 61: 815–822

    Article  CAS  PubMed  Google Scholar 

  18. Suarez BK, Hampe CL, Van Eerdewegh P . Problems of replicating linkage claims in psychiatry. In: Gershon ES, Cloninger CR (eds) . Genetic Approaches to Mental Disorders American Psychiatric Press: Washington, DC 1994; 23–46

    Google Scholar 

  19. Risch N, Merikangas K . The future of genetic studies of complex human diseases Science 1996; 273: 1516–1517

    Article  CAS  PubMed  Google Scholar 

  20. Owen MJ, Holmans P, McGuffin P . Association studies in psychiatric genetics Mol Psychiatry 1997; 2: 270–273

    Article  CAS  PubMed  Google Scholar 

  21. Risch N, Teng J . The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases: I. DNA pooling Genome Res 1998; 8: 1273–1288

    Article  CAS  PubMed  Google Scholar 

  22. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type-4 allele and the risk of Alzheimer's disease in late-onset families Science 1993; 261: 921–923

    Article  CAS  PubMed  Google Scholar 

  23. National Institute on Aging/Alzheimer's Association Working Group . Apolipoprotein E genotyping in Alzheimer's disease Lancet 1996; 347: 1091–1095

    Article  Google Scholar 

  24. Williams J, Spurlock G, McGuffin P et al. Association between schizophrenia and the T102C polymorphism of 5-hydroxytryptamine type 2a receptor gene Lancet 1996; 347: 1294–1296

    Article  CAS  PubMed  Google Scholar 

  25. Williams J, McGuffin P, Nothen M, Owen MJ and the EMASS Collaborative Group . Meta-analysis of association between the 5HT2a receptor T102C polymorphism and schizophrenia Lancet 1997; 349: 1221

    Article  CAS  PubMed  Google Scholar 

  26. Houwen RHJ, Baharloo S, Blankenship K et al. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis Nature Genet 1994; 8: 380–386

    Article  CAS  PubMed  Google Scholar 

  27. Kruglyak L . Prospects for whole-genome linkage disequilibrium mapping of common disease genes Nature Genet 1999; 22: 139–144

    Article  CAS  PubMed  Google Scholar 

  28. Owen MJ . Will schizophrenia become a graveyard for molecular geneticists? Psychol Med 1992; 22: 289–293

    Article  CAS  PubMed  Google Scholar 

  29. Collins FS, Guyer MS, Chakravarti A . Variation on a theme: cataloging human DNA sequence variation Science 1997; 278: 1580–1581

    Article  CAS  PubMed  Google Scholar 

  30. Wang DG, Fan JB, Siao CJ et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome Science 1998; 280: 1077–1082

    Article  CAS  PubMed  Google Scholar 

  31. Jorde LB, Watkins WS, Carlson M, Groden J, Albertson H, Thliveris A et al. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region Am J Hum Genet 1994; 54: 884–898

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes Nature Genet 1999; 22: 231–238

    Article  CAS  PubMed  Google Scholar 

  33. Kendler KS, MacLean CJ, Ma YL, O'Neill FA, Walsh D, Straub RE . Market-to-marker linkage disequilibrium on chromosomes 5q, 6p and 8p in the Irish high-density schizophrenia pedigrees Am J Med Genet 1999; 88: 29–33

    Article  CAS  PubMed  Google Scholar 

  34. Petruhkin K, Fischer SG, Pirastu M, Tanzi RF, Chrnov I, Devoto M et al. Mapping cloning and genetic characterization of the region containing in Wilson disease gene Nature Genet 1993; 5: 338

    Article  Google Scholar 

  35. Peterson AC, Di Rienzo A, Lehesjoki A-E, de la Chapelle A, Slatkin M, Freimer NB . The distribution of linkage disequilibrium over anonymous genome regions Hum Mol Genet 1995; 4: 887–894

    Article  CAS  PubMed  Google Scholar 

  36. Lander ES . Array of hope Nature Genet 1999; 21: (suppl) 3–4

    Article  CAS  PubMed  Google Scholar 

  37. Barcellos LF, Klitz W, Field L, Tobias R, Bowcock AM, Wilson R et al. Association of mapping of disease loci by use of a pooled DNA genomic screen Am J Hum Genet 1997; 61: 734–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Biomed European Bipolar Collaborative Group . No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene Br J Psychiatry 1997; 170: 526–528

    Article  Google Scholar 

  39. Barden N, Morissette J, Shink E, Rochette D, Gagne B, Bordeleau L et al. Confirmation of bipolar affective disorder susceptibility locus on chromosome 12 in the region of the Darier disease gene Am J Med Genet 1998; 81: 475

    Google Scholar 

  40. Kirov G, Murphy KC, Arranz MJ, Jones I, McCandless F, Kunugi H et al. Low activity allele of catecho-o-methyl transferase gene associated with rapid cycling bipolar affective disorder Mol Psychiatry 1998; 3: 342–345

    Article  CAS  PubMed  Google Scholar 

  41. Fisher PJ, Turic D, Williams NM, McGuffin P, Asherson P, Ball D et al. DNA pooling identifies QTLs for general cognitive ability in children on chromosome 4 Hum Mol Genet 1999; 8: 915–922

    Article  CAS  PubMed  Google Scholar 

  42. Hoogendoorn B, Owen MJ, Oefner PJ, Williams N, Austin J, O'Donovan MC . Genotyping single nucleotide polymorphisms by primer extension and high performance liquid chromatography Hum Genet 1999; 104: 89–93

    Article  CAS  PubMed  Google Scholar 

  43. DeLisi LE . A critical overview of recent investigations into the genetics of schizophrenia Curr Opin Psychiatry 1999; 12: 29–39

    Article  Google Scholar 

  44. Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits Am J Hum Genet 1995; 57: 439–454

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, DeFries JC . Quantitative trait locus for reading disability on chromosome 6 Science 1994; 266: 276–279

    Article  CAS  PubMed  Google Scholar 

  46. Page GP, Amos CI . Comparison of linkage-disequilibrium methods for localization of genes influencing quantitative traits in humans Am J Hum Genet 1999; 64: 1194–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Waldman ID, Rowe DC, Abramowitz A et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity Am J Hum Genet 1998; 63: 1767–1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Flint J . Freeze! Nat Genet 1997; 17: 250–251

    Article  CAS  PubMed  Google Scholar 

  49. Flint J, Corley R, DeFries JC et al. A simple genetic-basis for a complex psychological trait in laboratory mice Science 1995; 269: 1432–1435

    Article  CAS  PubMed  Google Scholar 

  50. Murphy KC, Jones LA, Owen MJ . Elevated rates of schizophrenia in adults with velo-cardio-facial syndrome Arch Gen Psychiatry 1999; 56: 940–945

    Article  CAS  PubMed  Google Scholar 

  51. Lindsay EA, Botta A, Jureuc V et al. Congenital heart disease in mice deficient for the DiGeorge Syndrome region Nature 1999; 40: 379–383

    Google Scholar 

  52. Sham PC . Statistical methods in psychiatric genetics Stat Meth Med Res 1998; 7: 279–300

    Article  CAS  Google Scholar 

  53. Nuffield Council on Bioethics . Mental Disorders and Genetics: the Ethical Context Nuffield Council on Bioethics: London 1998

    Google Scholar 

  54. Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ et al. Heritability estimates for psychotic disorders Arch Gen Psychiatry 1999; 56: 162–168

    Article  CAS  PubMed  Google Scholar 

  55. Kendler KS, Pedersen NL, Neale MC, Mathé AA . A pilot Swedish twin study of affective illness including hospital- and population-ascertained subsamples: results of model fitting Behav Genet 1995; 3: 217–232

    Article  Google Scholar 

  56. Kendler KS, Walters EE, Neale MC, Kessler RC, Heath AC, Eaves LJ . The structure of the genetic and environmental risk factors for six major psychiatric disorders in women: phobia, generalized anziety disorder, panic disorder, bulimia, major depression and alcoholism Arch Gen Psychiatry 1995; 52: 374–383

    Article  CAS  PubMed  Google Scholar 

  57. Straub RE, MacLean CJ, O'Neill FA, Walsh D, Kendler KS . Support for a possible schizophrenia vulnerability locus in a region of 5q22–31 in Irish families Mol Psychiatry 1997; 2: 148–155

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6, and 8 . Additional support for schizophrenia linkage on chromosomes 6 and 8: a multicentre study Am J Med Genet 1996; 67: 580–594

  60. Wildenauer DB, Schwab SG, Hallmayer J, Lerer B, Albus M, Borrman M et al. Genome scan for autosomal genes conferring risk to schizophrenia in a German/Israeli sample Am J Med Genet 1998; 81: 454

    Google Scholar 

  61. Schizophrenia Collaborative Linkage Group . A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12 Am J Med Genet 1996; 67: 40–45

    Article  Google Scholar 

  62. Ginns EI, Ott J, Egeland JA, Allen CR, Fann CSJ, Pauls DL et al. A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish Nature Genet 1996; 12: 431–435

    Article  CAS  PubMed  Google Scholar 

  63. Blackwood DHR, He L, Morris SW, McLean A, Whitton C, Thomson M et al. A locus for bipolar affective disorder on chromosome 4p Nature Genet 1996; 12: 427–430

    Article  CAS  PubMed  Google Scholar 

  64. Ewald H, Mors O, Flint T, Koed K, Eiberg H, Kruse TA . A possible locus for manic depressive illness on chromosome 16p13 Psychiatr Genet 1995; 5: 71–81

    Article  CAS  PubMed  Google Scholar 

  65. Stine OC, Xu J, Koskela R, McMahon FJ, Gschwend M, Friddle C et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect Am J Hum Genet 1995; 57: 1384

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Berrettini WH, Ferraro TN, Goldin LR et al. Pericentromeric chromosome 18 DNA markers and manic-depressive illness: evidence for a susceptibility gene Proc Natl Acad Sci 1994; 91: 5918–5921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe I et al. A possible vulnerability locus for bipolar affective disorder on chromosome 21q22.3 Nature Genet 1994; 8: 291–296

    Article  CAS  PubMed  Google Scholar 

  68. Kelsoe JR, Loetscher E, Spence MA, Foguet M, Sadovnick AD, Remick RA et al. A genome survey of bipolar disorder indicates a susceptibility locus on chromosome 22 Am J Med Genet 1998; 81: 461–462

    Google Scholar 

  69. Pekkarinen P, Bredbacka PE, Terwilliger J et al. Evidence for a susceptibility locus for manic depressive disorder in Xq26 Am J Hum Genet 1994; 55: 133

    Google Scholar 

  70. Philippe A, Martinez M, GuilloudBataille M, Gillberg C, Rastam M, Sponheim E et al. Genome-wide scan for autism susceptibility genes Hum Mol Genet 1999; 8: 805–812

    Article  CAS  PubMed  Google Scholar 

  71. International Molecular Genetic Study of Autism Consortium . A full genome screen for autism with evidence for linkage to a region on chromosome 7q Hum Mol Genet 1998; 7: 571–578

    Article  Google Scholar 

  72. Reich T, Edenberg HJ, Goate A, Williams JT, Rice JP, VanEerdewegh P et al. Genome-wide search for genes affecting the risk for alcohol dependence Am J Med Genet 1998; 81: 207–215

    Article  CAS  PubMed  Google Scholar 

  73. Kehoe PG, Wavrant De Vrieze F, Crook R, Wu WS, Holman P, Fenton I et al. A full genome scan for late onset Alzheimer's disease Hum Mol Genet 1999; 8: 237–245

    Article  CAS  PubMed  Google Scholar 

  74. Pericak-Vance MA, Bass ML, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA et al. Complete genomic screen in late-onset familial Alzheimer's disease Neurobiol Aging 1998; 19: S39–S42

    Article  CAS  PubMed  Google Scholar 

  75. Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nature Genet 1995; 11: 241–247

    Article  CAS  PubMed  Google Scholar 

  76. Blacker D, Wilcox MA, Laird NM, Rodes L, Horvath SM, Go RCP et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease Nature Genet 1998; 19: 357–360

    Article  CAS  PubMed  Google Scholar 

  77. Kehoe PG, Carsten R, Mcllroy S, Williams H, Holmans P, Holmes C et al. Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer's disease Nature Genet 1999; 21: 71–72

    Article  CAS  PubMed  Google Scholar 

  78. Williams J, Spurlock G, Holmans P, Mant R, Murphy K, Jones L et al. A meta-analysis and transmission disequilibrium study of association between the dopamine D3 receptor gene and schizophrenia Mol Psychiatry 1998; 3: 141–149

    Article  CAS  PubMed  Google Scholar 

  79. Collier DA, Arranz MJ, Sham P, Battersby S, Vallada H, Gill P et al. The serotonin transporter is a potential susceptibility factor for bipolar affective disorder Neuroreport 1996; 7: 1675–1679

    Article  CAS  PubMed  Google Scholar 

  80. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwin GM et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression Lancet 1996; 347: 731–733

    Article  CAS  PubMed  Google Scholar 

  81. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region Science 1996; 274: 1527–1531

    Article  CAS  PubMed  Google Scholar 

  82. Cook EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE et al. Association of attention-deficit disorder and the dopamine transporter gene Am J Hum Genet 1995; 56: 993–998

    CAS  PubMed  PubMed Central  Google Scholar 

  83. LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N et al. Dopamine D4 receptor gene polymorphism is associated with attention-deficit hyperactivity disorder Mol Psychiatry 1996; 1: 121–124

    CAS  PubMed  Google Scholar 

  84. Rieder MJ, Taylor SL, Clark AG, Nickerson DA . Sequence variation in human Angiotensin Converting Enzyme Nature Genet 1999; 22: 59–62

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are supported by a Cooperative Group Grant from the Medical Research Council.

Author information

Authors and Affiliations

  1. Division of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK

    M J Owen, A G Cardno & M C O'Donovan

  2. Division of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK

    M J Owen & A G Cardno

Authors
  1. M J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A G Cardno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M C O'Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Owen, M., Cardno, A. & O'Donovan, M. Psychiatric genetics: back to the future. Mol Psychiatry 5, 22–31 (2000). https://doi.org/10.1038/sj.mp.4000702

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000702

Keywords

This article is cited by

Search

Advanced search

Quick links