Intellectual Functioning as an Endophenotype for Schizophrenia

  • Odette de Wilde


Different studies have shown that abnormal cognitive functioning is present in patients with schizophrenia even in the early phase of the disease. Cognitive deficits in patients with schizophrenia are characterised by a generalised intellectual deficit, coupled with abnormalities in specific neuropsychological domains such as working memory, attention and executive functioning.

Intellectual deficits have been suggested to precede psychosis in patients with schizophrenia and also to be a risk factor for developing schizophrenia. If the presence of intellectual deficits would coincide with increased risk to develop schizophrenia they should be present in excess of general population levels in the biological relatives of individuals with schizophrenia.

Studies investigating intellectual functioning in first-degree relatives of patients with schizophrenia indeed have shown deficits in intellectual functioning paralleling the degree of genetic liability in that performance of the relatives fell between the performance of the patients and the controls.

In this chapter recent results in literature investigating the evidence, that a generalized intellectual deficit coupled with deficits in specific domains is also present in first-degree relatives of patients with schizophrenia, is reviewed and discussed in the light of its usefulness in identifying schizophrenia susceptibility genes.


Schizophrenia endophenotype intelligence 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gray JR, Thompson PM. Neurobiology of intelligence: science and ethics. Nat Rev Neurosci 2004; 5: 471–482.PubMedCrossRefGoogle Scholar
  2. 2.
    Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.PubMedCrossRefGoogle Scholar
  3. 3.
    Cannon TD, Keller MC. Endophenotypes in the genetic analyses of mental disorders. Ann Rev Clin Psychology 2006; 2: 267–290.CrossRefGoogle Scholar
  4. 4.
    Bilder RM, Goldman RS, Robinson D, et al. Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. Am J Psychiatry 2000; 157: 549–559.PubMedCrossRefGoogle Scholar
  5. 5.
    de Wilde OM, Dingemans PM, Bour LJ, et al. Generalized intellectual deficit as an endophenotype in young patients with recent onset schizophrenia and unaffected young siblings 2008 (in press).Google Scholar
  6. 6.
    Weickert TW, Goldberg TE. The course of cognitive deficits in schizophrenia. In: Sharma T, Harvey P, eds. Cognition in Schizophrenia; Impairments, Importance and Treatment Strategies. New York: Oxford University Press, 2000, pp. 3–15.Google Scholar
  7. 7.
    Reichenberg A, Weiser M, Rapp MA, et al. Elaboration on premorbid intellectual performance in schizophrenia; pre-morbid intellectual decline and risk for schizophrenia. Arch Gen Psychiatry 2005; 62: 1297–1304.PubMedCrossRefGoogle Scholar
  8. 8.
    Woodberry KA, Giuliano AJ, Seidman LJ. Premorbid IQ in schizophrenia: a meta-analytic review. Am J Psychiatry 2008; doi: 10.1176/appi.ajp.2008.07081242.Google Scholar
  9. 9.
    Neisser U, Boodoo G, Bouchard TJ Jr, et al. Ingelligence: knows and unknowns. Am Psychol 1996; 51: 77–101.CrossRefGoogle Scholar
  10. 10.
    Caroll, J. Human Cognitive Abilities: A Survey of Factor Analytic Studies. Cambridge: Cambridge University Press, 1993.Google Scholar
  11. 11.
    Kaufman AS, Kaufman NL. Manual for the Kaufman Adolescent and Adult Intelligence Test (KAIT). Circle Pines, MN: American Guidance Service, 1993.Google Scholar
  12. 12.
    Wechsler D. Manual for the Wechsler Adult Intelligence Scale (WAIS). New York: The Psychological Corporation, 1955.Google Scholar
  13. 13.
    Tulsky DS, Chelune GJ, Ivnik RJ, et al. Clinical interpretation of the WAIS-III and WMS-III. Academic Press, New York, 2003.Google Scholar
  14. 14.
    Raven J, Raven JC, Court JH. Manual for Raven's Progressive Matrices and Vocabulary Scales. Section 4: The Advanced Progressive Matrices. San Antonio, TX: Harcourt Assessment, 1998.Google Scholar
  15. 15.
    Nelson HE. The National Adult Reading Test (NART): Test Manual. Windsor, Canada: NFER-Nelson, 1982.Google Scholar
  16. 16.
    De Geus EJC, Boomsma DI. A genetic neuroscience approach to human cognition. Eur Psychol 2001; 6 (4): 241–253.CrossRefGoogle Scholar
  17. 17.
    Posthuma D, Mulder EJCM, Boomsma DI, et al. Genetic analysis of IQ, processing speed and stimulus response incongruency effects. Biol Psychology 2002; 61: 157–182.CrossRefGoogle Scholar
  18. 18.
    Kravariti E, Toulopoulou T, Mapua-Filbey F, et al. Intellectual asymmetry and genetic liability in first-degree relatives of probands with schizophrenia. Brit J Psychiatry 2006; 188: 186–187.CrossRefGoogle Scholar
  19. 19.
    McIntosh AM, Harrison LK, Forrester K, et al. Neuropsychological impairments in people with schizophrenia or bipolar disorder and their unaffected relatives. Brit J Psychiatry 2005; 186: 378–385.CrossRefGoogle Scholar
  20. 20.
    Toulopoulou T, Picchioni M, Rijsdijk F, et al. Substantial genetic overlap between neurocognition and schizophrenia; genetic modeling in twin samples. Arch Gen Psychiatry 2007; 64 (12): 1348–1355.PubMedCrossRefGoogle Scholar
  21. 21.
    Kremen WS, Lyons MJ, Boake C, et al. A discordant twin study of premorbid cognitive ability in schizophrenia. J Clin Exp Neuropsychol 2006; 28: 208–224.PubMedCrossRefGoogle Scholar
  22. 22.
    Cannon TD, Huttunen MO, Lonnqvist J, et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Gen 2000; 67(2): 369–382.CrossRefGoogle Scholar
  23. 23.
    Barrantes-Vidal N, Aguilera M, Campanera S, et al. Working memory in siblings of schizophrenia patients. Schizophr Res 2007; 95: 70–75.PubMedCrossRefGoogle Scholar
  24. 24.
    Kremen WS, Faraone SV, Seidman LJ, et al. Neuropsychological risk indicators for schizophrenia: a preliminary study of female relatives of schizophrenic and bipolar probands. Psychiatry Res 1998; 79: 227–240.PubMedCrossRefGoogle Scholar
  25. 25.
    Birkett P, Sigmundsson T, Sharma T, et al. Executive function and genetic predisposition to schizophrenia—the Maudsley family study. Am J Med Genet B Neuropsychiatr Genet 2008; 147(3):285–293.PubMedGoogle Scholar
  26. 26.
    Egan MF, Goldberg TE, Gscheidle T, et al. Relative risk for cognitive impairments in siblings of patients with schizophrenia. Biol Psychiatry 2000; 50(2): 98–107.CrossRefGoogle Scholar
  27. 27.
    Burdick KE, Goldberg JF, Harrow M, et al. Neurocognition as a stable endophenotype in bipolar disorder and schizophrenia. J Nerv Ment Dis 2006; 194: 255–260.PubMedCrossRefGoogle Scholar
  28. 28.
    Krabbendam L, Marcelis M, Delespaul P, et al. Single or multiple familial cognitive risk factors in schizophrenia? Am J Med Gen 2001; 105: 183–188.CrossRefGoogle Scholar
  29. 29.
    Nuechterlein KH, Green MF, Kern RS, et al. The MATRICS consensus battery, part 1: test selection, reliability and validity. Am J Psychiatry 2008; 165(2): 203–213.PubMedCrossRefGoogle Scholar
  30. 30.
    Kern RS, Nuechterlein KH, Green MF, et al. The MATRICS consensus cognitive battery, part 2: co-norming and standardization. Am J Psychiatry 2008; 165(2): 214–220.PubMedCrossRefGoogle Scholar
  31. 31.
    Green MF. Cognitive impairment and functional outcome in schizophrenia and bipolar disorder. J Clin Psychiatry 2006; 67(10); e12.PubMedCrossRefGoogle Scholar
  32. 32.
    Cannon TD, Kaprio J, Lönnqvist J, et al. The genetic epidemiology of schizophreniain a Finnish Twin cohort: a population-based modelling study. Arch Gen Psychiatry 1998; 55: 67–74.PubMedCrossRefGoogle Scholar
  33. 33.
    Tunbridge EM, Harrison PJ, Weinberger DR. Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006; 60: 141–151.PubMedCrossRefGoogle Scholar
  34. 34.
    Burdick KE, Lencz T, Funke B, et al. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet 2006; 15: 1563–1568.PubMedCrossRefGoogle Scholar
  35. 35.
    Donohoe G, Morris DW, Clarke S, et al. Variance in neu-rocognitive performance is associated with dysbindin-1 in schizophrenia: a preliminary study. Neuropsychologia 2007; 45: 454–458.PubMedCrossRefGoogle Scholar
  36. 36.
    Callicott JH, Straub RE, Pezawas L, et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102: 8627–8632.PubMedCrossRefGoogle Scholar
  37. 37.
    Hall J, Whalley HC, Job DE, et al. A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms. Nat Neurosc 2006; 9: 1477–1478.CrossRefGoogle Scholar
  38. 38.
    Zinkstok J, de Wilde O, van Amelsfoort T, et al. Association between the DTNBP1 gene and intelligence: a case-control study in young patients with schizophrenia and related disorders and unaffected siblings. Behav Brain funct 2007; 3: 19.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Odette de Wilde
    • 1
  1. 1.Department of PsychiatryAcademic Medical Center, University of AmsterdamThe Netherlands

Personalised recommendations