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:

Do susceptibility loci contribute to the expression of more than one mental disorder? A view from the genetics of Alzheimer's disease

Molecular Psychiatry volume 5, pages 131–136 (2000)Cite this article

Abstract

The susceptibility of developing most major psychiatric disorders is determined in part by contributions from risk alleles at multiple genetic loci. The central aim of this article is to highlight evidence from studies of neurodegenerative disorders suggesting that some of these alleles are shared by more than one psychiatric disorder, and to explore mechanisms that may underly these pleiotropic effects. The identification of constellations of susceptibility alleles associated with particular mental disorders will provide opportunities for new insights into the molecular and cellular pathophysiology of these disorders, and will have a major impact on psychiatric research and clinical care. This approach to reducing the variance in etiopathogenesis is also likely to be important for achieving the optimal use of available treatments (maximizing effectiveness and minimizing side effects), and for the discovery of novel medications or other interventions.

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

Similar content being viewed by others

References

  1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders, 4th edition American Psychiatric Press: Washington, DC 1994

    Google Scholar 

  2. Jorm AF, Korten AE, Henderson AS . The prevalence of dementia: a quantitative integration of the literature Acta Psychiatr Scand 1987; 76: 465–479

    Article  CAS  PubMed  Google Scholar 

  3. Evans DA, Funkenstein HH, Albert MS, Scherr PA, Cook NR, Chown MJ et al. Prevalence of Alzheimer's disease in a community population of older persons: higher than previously reported JAMA 1989; 262: 2551–2556

    Article  CAS  PubMed  Google Scholar 

  4. Bachman DL, Wolf PA, Linn R, Konefel JE, Cobb J, Belanger A et al. Prevalence of dementia and probable senile dementia of the Alzheimer type in the Framingham Study Neurology 1992; 42: 115–119

    Article  CAS  PubMed  Google Scholar 

  5. Khachaturian ZS . Diagnosis of Alzheimer's disease Arch Neurol 1985; 42: 1097–1105

    Article  CAS  PubMed  Google Scholar 

  6. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain CJ, Brownlee LM et al. The consortium to establish a registry for Alzheimer's disease (CERAD) Neurology 1991; 41: 479–486

    Article  CAS  PubMed  Google Scholar 

  7. Zubenko GS . Molecular neurobiology of Alzheimer's disease (syndrome?) Harvard Rev Psychiatry 1997; 5: 177–213

    Article  CAS  Google Scholar 

  8. Goate AM, Chartier-Harlin M-C, Mullan M, Brown J, Crawford F, Fidani L et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease Nature 1991; 349: 704–706

    Article  CAS  PubMed  Google Scholar 

  9. Murrell J, Farlow M, Ghetti B, Benson MD . A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease Science 1991; 254: 97–99

    Article  CAS  PubMed  Google Scholar 

  10. Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14 Science 1992; 258: 668–671

    Article  CAS  PubMed  Google Scholar 

  11. St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14 Nature Genet 1992; 2: 330–334

    Article  CAS  PubMed  Google Scholar 

  12. Alzheimer's Disease Collaborative Group . The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families Nature Genet 1995; 11: 219–222

    Article  Google Scholar 

  13. Sherrington R, Govaev EI, Liang Y, Rogaeva EA, Levesque G, Ikdea M et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease Nature 1995; 375: 754–760

    Article  CAS  PubMed  Google Scholar 

  14. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH et al. Candidate gene for the chromosome 1 familial Alzheimer's disease locus Science 1995; 269: 973–977

    Article  CAS  PubMed  Google Scholar 

  15. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene Nature 1995; 376: 775–778

    Article  CAS  PubMed  Google Scholar 

  16. Holland AJ . Down's syndrome and dementia of the Alzheimer type. In: Burns A and Levy R (eds) Dementia Chapman and Hall: London 1994; pp695–708

    Chapter  Google Scholar 

  17. Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop PH, Pericak-Vance MA, Joo SH et al. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease Neurology 1993; 43: 1467–1472

    Article  CAS  PubMed  Google Scholar 

  18. APOE and Alzheimer Disease Meta Analysis Consortium . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease JAMA 1997; 278: 1349–1356

    Article  Google Scholar 

  19. 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 

  20. Rebeck GW, Reiter JS, Strickland DK, Hyman BT . Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions Neuron 1993; 11: 575–580

    Article  CAS  PubMed  Google Scholar 

  21. Schmechel D, Saunders A, Strittmatter W, Crain BJ, Hulette CM, Joo SH et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease Proc Natl Acad Sci USA 1993; 90: 9649–9653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zubenko GS, Stiffler S, Stabler S, Kopp U, Hughes HB, Cohen BM et al. Association of the apolipoprotein E ε4 allele with clinical subtypes of autopsy-confirmed Alzheimer's disease Am J Med Genet (Neuropsychiatr Genet) 1994; 54: 199–205

    Article  CAS  Google Scholar 

  23. Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer's disease Nature Genet 1994; 7: 180–184

    Article  CAS  PubMed  Google Scholar 

  24. Post F . The significance of affective symptoms in old age. Maudsley Monographs 10 Oxford University Press: Oxford, UK 1962

    Google Scholar 

  25. Post F . The management and nature of depressive illnesses in late life: a follow-through study Br J Psychiatry 1972; 121: 393–404

    Article  CAS  PubMed  Google Scholar 

  26. Murphy E . The prognosis of depression in old age Br J Psychiatry 1983; 142: 111–119

    Article  CAS  PubMed  Google Scholar 

  27. Baldwin RC, Jolley DJ . The prognosis of depression in old age Br J Psychiatry 1986; 149: 574–583

    Article  CAS  PubMed  Google Scholar 

  28. Reding M, Haycox J, Blass J . Depression in patients referred to a dementia clinic: a three-year prospective study Arch Neurol 1985; 42: 894–896

    Article  CAS  PubMed  Google Scholar 

  29. Reynolds CF III, Kupfer DJ, Hoch CC, Stack JA, Houck PR, Sewitch DE . Two-year follow-up of elderly patients with mixed depression and dementia: clinical and electroencephalographic sleep findings J Am Geriatr Soc 1986; 34: 793–799

    Article  PubMed  Google Scholar 

  30. Kral VA, Emery OB . Long-term follow-up of depressive pseudodementia of the aged Can J Psychiatry 1989; 34: 445–446

    Article  CAS  PubMed  Google Scholar 

  31. Alexopoulos GS, Young RC, Abrams RC, Meyers B, Shamoian CA . Chronicity and relapse in geriatric depression Biol Psychiatry 1989; 26: 551–564

    Article  CAS  PubMed  Google Scholar 

  32. Alexopoulos GS, Meyers BS, Young RC, Mattis S, Kakuma T . The course of geriatric depression with ‘reversible dementia’: a controlled study Am J Psychiatry 1993; 150: 1693–1698

    Article  CAS  PubMed  Google Scholar 

  33. Zubenko GS, Henderson R, Stiffler JS, Stabler S, Rosen J, Kaplan BB . Association of the APOE ε4 allele with clinical subtypes of late life depression Biol Psychiatry 1996; 40: 1008–1016

    Article  CAS  PubMed  Google Scholar 

  34. Cantillon M, Harwood D, Barker W, St George-Hyslop P, Tsuda T, Ekatarina R et al. No association between apolipoprotein E genotype and late-onset depression in Alzheimer's disease Biol Psychiatry 1997; 41: 246–248

    Article  CAS  PubMed  Google Scholar 

  35. Heidrich A, Thome J, Rösler M . Apolipoprotein E-ε4 allele frequency in late-onset depression Biol Psychiatry 1997; 41: 912–914

    Article  CAS  PubMed  Google Scholar 

  36. Holmes C, Russ C, Kirov G, Aitchison KJ, Powell JF, Collier DA et al. Apolipoprotein E: depressive illness, depressive symptoms, and Alzheimer's disease Biol Psychiatry 1998; 43: 159–164

    Article  CAS  PubMed  Google Scholar 

  37. Zubenko GS . University of Pittsburgh School of Medicine, unpublished results

  38. French LR, Schuman LM, Mortimer JA, Hutton JT, Boatman RA, Christians B . A case-control study of dementia of the Alzheimer type Am J Epidemiol 1985; 121: 414–421

    Article  CAS  PubMed  Google Scholar 

  39. Shalat SL, Seltzer B, Pidcock C, Baker EL . Risk factors for Alzheimer's disease: a case-control study Neurology 1987; 37: 1630–1633

    Article  CAS  PubMed  Google Scholar 

  40. Broe GA, Henderson AS, Creasey H, McCusker E, Korten AE, Jorm AF et al. A case-control study of Alzheimer's disease in Australia Neurology 1990; 40: 1698–1707

    Article  CAS  PubMed  Google Scholar 

  41. Jorm AF, Van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A et al. Psychiatric history and related exposures as risk factors for Alzheimer's disease: a collaborative re-analysis of case-control studies Int J Epidemiol 1991; 20: S43–S47

    Article  PubMed  Google Scholar 

  42. Kokmen E, Beard CM, Chandra V, Offord KP, Schoenberg BS, Ballard DJ . Clinical risk factors for Alzheimer's disease: a population-based case-control study Neurology 1991; 41: 1393–1397

    Article  CAS  PubMed  Google Scholar 

  43. Van Duijn CM, Clayton DG, Chandra V, Fratiglioni L, Graves AB, Heyman A et al. Interaction between genetic and environmental risk factors for Alzheimer's disease: a reanalysis of case-control studies Genet Epidemiol 1994; 11: 539–551

    Article  CAS  PubMed  Google Scholar 

  44. Speck CE, Kukull WA, Brenner DE, Bowen JD, McCormick WC, Teri L et al. History of depression as a risk factor for Alzheimer's disease Epidemiology 1995; 6: 366–369

    Article  CAS  PubMed  Google Scholar 

  45. Zubenko GS, Rifai AH, Mulsant BH, Sweet RA, Pasternak RE . Premorbid history of major depression and the depressive syndrome of Alzheimer's disease Am J Geriatr Psychiatry 1996; 4: 85–90

    PubMed  Google Scholar 

  46. Pearlson GD, Ross CA, Lohr WD, Rovner BW, Chase GA, Folstein MF et al. Association between family history of affective disorder and the depressive syndrome of Alzheimer's disease Am J Psychiatry 1990; 147: 452–456

    Article  CAS  PubMed  Google Scholar 

  47. Zubenko GS . Neurobiology of major depression in Alzheimer's disease Int Psychogeriatrics (in press)

  48. Pericak-Vance MA, Haines JL . Genetic susceptibility to Alzheimer's disease Trends Genet 1995; 11: 504–508

    Article  CAS  PubMed  Google Scholar 

  49. Zubenko GS, Stiffler JS, Hughes, Hurtt M, Kaplan BB . Initial results of a genome survey for novel Alzheimer's disease risk genes: association with a locus on the X-chromosome Am J Med Genet (Neuropsychiatr Genet) 1998; 81: 196–205

    Article  CAS  Google Scholar 

  50. Zubenko GS, Hughes HB, Stiffler JS, Hurtt MR, Kaplan BB . A genome survey for novel Alzheimer's disease risk loci: results at 10cM resolution Genomics 1998; 50: 121–128

    Article  CAS  PubMed  Google Scholar 

  51. Zubenko GS, Hughes HB, Stiffler JS . Clinical and neurobiological correlates of D10S1423 genotype in Alzheimer's disease Biol Psychiatry 1999; 46: 740–749

    Article  CAS  PubMed  Google Scholar 

  52. Zubenko GS, Hughes HB, Stiffler JS . Clinical and neurobiological correlates of DXS1047 genotype in Alzheimer's disease Biol Psychiatry 1999; 46: 173–181

    Article  CAS  PubMed  Google Scholar 

  53. Zubenko GS, Hughes HB, Stiffler JS . Neurobiological correlates of a putative risk allele for Alzheimer's disease on chromosome 12q Neurology 1999; 52: 725–732

    Article  CAS  PubMed  Google Scholar 

  54. Zubenko GS, Moossy J . Major depression in primary dementia: clinical and neuropathologic correlates Arch Neurol 1988; 45: 1182–1186

    Article  CAS  PubMed  Google Scholar 

  55. Zubenko GS, Moossy J, Kopp U . Neurochemical correlates of major depression in primary dementia Arch Neurol 1990; 47: 1107–1111

    Article  CAS  PubMed  Google Scholar 

  56. Faraone SV, Matise T, Svrakic D, Pepple J, Malaspina D, Suarez B et al. Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium Am J Med Genet (Neuropsychiatric Genetics) 1998; 81: 290–295

    Article  CAS  Google Scholar 

  57. Schwab S, Hallmayer J, Albus M, Lerer B, Hanses C, Kanyas K et al. Further evidence for susceptibility locus on chromosome 10p14-p11 in 72 families with schizophrenia by nonparametric linkage analysis Am J Med Genet (Neuropsychiatric Genetics) 1998; 81: 302–307

    Article  CAS  Google Scholar 

  58. Straub RE, MacLean C, Martin RB, Ma Y, Myakishev MV, Harris-Kerr C et al. A schizophrenia locus may be located in region 10p15–p11 Am J Med Genet (Neuropsychiatric Genetics) 1998; 81: 296–301

    Article  CAS  Google Scholar 

  59. Rice JP, Goate A, Williams JT, Bierut L, Dorr D, Wu W et al. Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12 Am J Med Genet (Neuropsychiatric Genetics) 1997; 74: 247–253

    Article  CAS  Google Scholar 

  60. Paterson AD, Petronis A . Sex-based linkage analysis of alcoholism Genet Epi (in press)

  61. Paterson AD, Petronis A . Transmission ratio distortion in females on chromosome 10p11–p15 Am J Med Genet (Neuropsychiatric Genetics) 1999; 88: 657–661

    Article  CAS  Google Scholar 

  62. Zubenko GS, Sunderland T . Geriatric psychopharmacology: why does age matter? Harvard Rev Psychiatry (in press)

  63. Trottier Y, Devys D, Imbert G, Saudon F, An I, Lutz Y et al. Cellular localisation of the Huntington's disease protein and discrimination of the normal and mutated form Nature Genet 1995; 10: 104–110

    Article  CAS  PubMed  Google Scholar 

  64. Landwehrmeyer GB, McNeil SM, Dure LS, Ge P, Alzawa H, Huang Q et al. Huntington's disease gene: regional and cellular expression in brain of normal and affected individuals Ann Neurol 1995; 37: 218–230

    Article  CAS  PubMed  Google Scholar 

  65. Wurtman RJ . Choline metabolism as a basis for the selective vulnerability of cholinergic neurons Trends Neurosci 1992; 15: 117–122

    Article  CAS  PubMed  Google Scholar 

  66. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM . Decreased brain choline uptake in older adults JAMA 1995; 274: 902–907

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Supported by research grants MH43261, MH45968, MH/AG47346, and MH60866. Dr Zubenko is the recipient of Independent Scientist Award MH00540 from the National Institutes for Mental Health.

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, 15213, PA, USA

    G S Zubenko

  2. Department of Biological Sciences, Mellon College of Science, Carnegie-Mellon University, Pittsburgh, 15213, PA, USA

    G S Zubenko

Authors
  1. G S Zubenko
    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

Zubenko, G. Do susceptibility loci contribute to the expression of more than one mental disorder? A view from the genetics of Alzheimer's disease. Mol Psychiatry 5, 131–136 (2000). https://doi.org/10.1038/sj.mp.4000713

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000713

Keywords

This article is cited by

Search

Advanced search

Quick links