The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia

David L Braff, Gregory A Light, David L Braff, Gregory A Light

Abstract

Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.

Figures

Figure 1.. Genetic architecture of complex disorders.…
Figure 1.. Genetic architecture of complex disorders. This illustrates a major conundrum of research into complex human disorders. The Huntington's gene was identified 20 years ago, but has not yet led to a genetic “cure.” The profoundly important potential of genetic treatments for even more “complex genetic disorders” (eg, schizophrenia, hypertension, and diabetes) will depend on related scientific advances.
Figure 2.. The vulnerability-stress 2-hit model of…
Figure 2.. The vulnerability-stress 2-hit model of schizophrenia. “High” levels of vulnerability interacting with high levels of stressors (eg, neonatal hypoxema or adolescent stimulant abuse) may “evoke” the emergence of schizophrenia. Despite the view of schizophrenia as a “genetic disorder,” 50% of causation is genetic and 50% or so of the disorder is caused by “nongenetic” second hits.
Figure 3.. The effects of a loss…
Figure 3.. The effects of a loss of normal gating. In the left panel, an individual with intact filtering and inhibition filters out irrelevant sensory stimuli. In the right panel, impaired gating leads to a sequence of sensory inundation, cognitive fragmentation, and disorganized thinking.
Figure 4.. Prepulse inhibition (PPI) is a…
Figure 4.. Prepulse inhibition (PPI) is a profound decrease in startle response magnitude when the startling pulse is preceded by a weak prepulse. PPI is an operational measure of sensorimotor gating.
Figure 5.. Zuditory click pairs are presented…
Figure 5.. Zuditory click pairs are presented to subjects; the electroencephalogram (EEG) is averaged across trials. The P50 component of the averaged event-related potential (ERP) is measured in response to the first and second clicks. The percentage of P50 amplitude reduction from the first to the second click is referred to as P50 suppression or P50 gating, and is considered an operational measure of sensory gating. Deficient P50 suppression is often seen in patients with schizophrenia, their clinically unaffected family members, and individuals with schizotypal personality disorder.

References

    1. Bleuler E. Dementia Praecox. New York: International Universities Press; 1911/1950
    1. Singer MT. The consensus Rorschach and family transaction. J Proj Tech Pers Assess. 1968;32:348–351.
    1. Singer MT., Wynne LC. Differentiating characteristics of parents of childhood schizophrenics, childhood neurotics, and young adult schizophrenics. Am J Psychiatry. 1963;120:234–243.
    1. Kety SS., Rosenthal D., Wender PH., Schulsinger F. The types and prevalence of mental illness in the biological and adoptive families of adopted schizophrenics. In: Rosenthal D, Kety S, eds. The Transmission of Schizophrenia. New York, NY: Pergamon Press; 1968:345–362.
    1. Meehl PE. Schizotaxia revisited. Arch Gen Psychiatry. 1989;46:935–944.
    1. Faraone SV., Tsuang D., Tsuang MT. Genetics of Mental Disorders: A Guide for Students, Clinicians, and Researchers. New York, NY: Guilford; 1999
    1. Braff DL., Freedman R. Endophenotypes in studies of the genetics of schizophrenia. In: Davis KL, Charney DS, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, PA: Lippincott, Williams & Wilkins; 2002:703–716.
    1. McDonald C., Murray RM. Early and late environmental risk factors for schizophrenia. Brain Res Brain Res Rev. 2000;31:130–137.
    1. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44:660–669.
    1. Lipska BK., Swerdlow NR., Geyer MA., Jaskiw GE., Braff DL., Weinberger DR. Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology (Berl). 1995;122:35–43.
    1. Schork NJ. Extended multipoint identity-by-descent analysis of human quantitative traits: efficiency, power, and modeling considerations. Am J Hum Genet. 1993;53:1306–1319.
    1. Schork NJ. Genome partitioning and whole-genome analysis. Adv Genet. 2001;42:299–322.
    1. Schork NJ., Nath SK., Fallin D., Chakravarti A. Linkage disequilibrium analysis of biallelic DNA markers, human quantitative trait loci, and threshold-defined case and control subjects. Am J Hum Genet. 2000;67:1208–1218.
    1. Fallin D., Schork NJ. Accuracy of haplotype frequency estimation for biallelic loci, via the expectation-maximization algorithm for unphased diploid genotype data. Am J Hum Genet. 2000;67:947–959.
    1. McDowell JE., Myles-Worsley M., Coon H., et al. Measuring liability for schizophrenia using optimized antisaccade stimulus parameters. Psychophysiology. 1999;36:138–141.
    1. Holzman PS., Coleman M., Lenzenweger MF., et al. Working memory deficits, antisaccades, and thought disorder in relation to perceptual aberration. In: Raine A, Lencz T, et al, eds. Schizotypal Personality. New York, NY: Cambridge University Press; 1995:353–381.
    1. Clementz BA., Grove WM., lacono WG., et al. Smooth-pursuit eye movement dysfunction and liability for schizophrenia: implications for genetic modeling. J Abnorm Psychol. 1992;101:117–129.
    1. Thaker GK., Cassady S., Adami H., et al. Eye movements in spectrum personality disorders: Comparison of community subjects and relatives of schizophrenic patients. Am J Psychiatry. 1996;153:362–368.
    1. Kinney DK., Holzman PS., Jacobson B., et al. Thought disorder in schizophrenic and control adoptees and their relatives. Arch Gen Psychiatry. 1997;54:475–479.
    1. Perry W., Braff DL. Thought disorder and the group of schizophrenia. Schizophr Res. 1993;9:107.
    1. Perry W., Cadenhead KS., Braff DL. Thought disorder in the group of schizophrenias. Biol Psychiatry. 1992;31:117–118A.
    1. Cadenhead KS., Perry W., Shafer K., et al. Cognitive functions in schizotypal personality disorder. Schizophr Res. 1999;37:123–132.
    1. Perry W., Heaton RK., Potterat E., et al. Working memory in schizophrenia: transient “on line” storage versus executive functioning. Schizophr Bull. 2005. In press.
    1. Cadenhead KS., Shafer K., Perry W., et al. Working memory in the schizophrenia spectrum. Biol Psychiatry. 1998;43:127S.
    1. Clementz BA., Geyer MA., Braff DL. P50 suppression among schizophrenia and normal comparison subjects: a methodological analysis. Biol Psychiatry. 1997;41:1035–1044.
    1. Clementz BA., Geyer MA., Braff DL. Poor P50 suppression among schizophrenia patients and their first-degree biological relatives. Am J Psychiatry. 1998;155:1691–1694.
    1. Cadenhead KS., Light GA., Geyer MA., Braff DL. Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder. Am J Psychiatry. 2000;157:55–59.
    1. Cadenhead KS., Geyer MA., Butler RW., et al. Information processing deficits of schizophrenia patients: Relationship to clinical ratings, gender and medication status. Schizophr Res. 1997;28:51–62.
    1. Maier W., Franke P., Kopp B., et al. Reaction time paradigms in subjects at risk for schizophrenia. Schizophr Res. 1994;13:35–43.
    1. Sarkin AJ., Dionisio DP., Hillix WA., et al. Positive and negative schizotypal symptoms relate to different aspects of crossover reaction time task performance. Psychiatry Res. 1998;81:241–249.
    1. Braff DL., Grillon C., Geyer MA. Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry. 1992;49:206–215.
    1. Braff DL., Swerdlow NR., Geyer MA. Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am J Psychiatry. 1999;156:596–602.
    1. Cadenhead KS., Swerdlow NR., Shafer KM., et al. Modulation of the startle response and startle laterality in relatives of schizophrenic patients and schizotypal personality disordered subjects: evidence of inhibitory deficits. Am J Psychiatry. 2000;157:1660–1668.
    1. Nuechterlein KH., Asarnow RF., Subotnik KL., et al. Neurocognitive vulnerability factors for schizophrenia: Convergence across genetic risk studies and longitudinal trait/state studies. In: Lenzenweger MF, Dworkin RH, eds. Origins and Development of Schizophrenia: Advances in Experimental Psychopathology. Washington, DC: American Psychological Association; 1998:299–327.
    1. D’Amato T., Saoud M., Triboulet P., et al. Vulnerability to schizophrenia. I: Familial nature of neuropsychologic indicators. Encephale. 1998;24:442–448.
    1. Ito M., Kanno M., Mori Y., et al. Attention deficits assessed by Continuous Performance Test and Span of Apprehension Test in Japanese schizophrenic patients. Schizophr Res. 1997;23:205–211.
    1. Buchanan RW., Strauss ME., Breier A., et al. Attentional impairments in deficit and nondeficit forms of schizophrenia. Am J Psychiatry. 1997;154:363–370.
    1. Miller MB., Chapman LJ., Chapman JP., et al. Schizophrenic deficit in span of apprehension. J Abnorm Psychol. 1990;99:313–316.
    1. Elkins IJ., Cromwell RL., Asarnow RF. Span of apprehension in schizophrenic patients as a function of distractor masking and laterality. J Abnorm Psychol. 1992;101:53–60.
    1. Toomey R., Faraone SV., Seidman LJ., et al. Association of neuropsychological vulnerability markers in relatives of schizophrenic patients. Schizophr Res. 1998;31:89–98.
    1. Franke P., Maier W., Hardt J., et al. Attentional abilities and measures of schizotypy: their variation and covariation in schizophrenic patients, their siblings, and normal control subjects. Psychiatry Res. 1994;54:259–272.
    1. Roitman SE., Cornblatt BA., Bergman A., et al. Attentional functioning in schizotypal personality disorder. Am J Psychia try. 1997;154:655–660.
    1. Goldberg TE., Torrey EF., Gold JM., et al. Genetic risk of neuropsychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder. Schizophr Res. 1995;17:77–84.
    1. Trestman RL., Horvath T., Kalus O., et al. Event-related potentials in schizotypal personality disorder. J Neuropsychiatry Clin Neurosci. 1996;8:33–40.
    1. Frangou S., Sharma T., Alarcon G., et al. The Maudsley Family Study, II: Endogenous event-related potentials in familial schizophrenia. Schizophr Res. 1997;23:45–53.
    1. Cadenhead KS., Perry W., Braff DL. The relationship of information-processing deficits and clinical symptoms in schizotypal personality disorder. Biol Psychiatry. 1996;40:853–858.
    1. Saccuzzo DS., Cadenhead KS., Braff DL. Backward versus forward visual masking deficits in schizophrenic patients: centrally, not peripherally, mediated. Am J Psychiatry. 1996;153:1564–1570.
    1. Gottesman II., Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636–645.
    1. Piatt JR. Stong inference: certain systematic methods of scientific thinking may produce much more rapid progress than others. Science. 1964;146:347–352.
    1. Buervenich S., Carmine A., Arvidsson M., et al. NURR1 mutations in cases of schizophrenia and manic-depressive disorder. Am J Med Genet. 2000;96:808–813.
    1. Harrison PJ., Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40–68.
    1. Lalouel JM., Le Mignon L., Simon M., et al. Genetic analysis of idiopathic hemochromatosis using both qualitative (disease status) and quantitative (serum iron) information. Am J Hum Genet. 1985;37:700–718.
    1. Leppert M., Burt R., Hughes JP., et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med. 1990;322:904–908.
    1. Insel TR., Collins FS. Psychiatry in the genomics era. Am J Psychiatry. 2003;160:616–620.
    1. Watson JD., Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171:737–738.
    1. Penney JB., Jr., Young AB. Speculations on the functional anatomy of basal ganglia disorders. Annu Rev Neurosci. 1983;6:73–94.
    1. Swerdlow NR., Koob GF. Dopamine, schizophrenia, mania, and depression: Toward a unified hypothesis of cortico-stratio-pallido-thalamic function. Behav Brain Sci. 1987;10:197–245.
    1. Andreasen NC. A unitary model of schizophrenia: Bleuler's “fragmented phrene” as schizencephaly. Arch Gen Psychiatry. 1999;56:781–787.
    1. Braff DL. Connecting the “dots” of brain dysfunction in schizophrenia: what does the picture look like? Arch Gen Psychiatry. 1999;56:791–793.
    1. Light GA. Probing cortico-cortical interactions that underlie the multiple sensory, cognitive, and “real-world” functional deficits in schizophrenia patients. Behav Brain Sci. 2005. In press.
    1. Braff DL., Geyer MA. Sensorimotor gating and schizophrenia. Human and animal model studies. Arch Gen Psychiatry. 1990;47:181–188.
    1. Light GA., Braff DL. Human and animal studies of schizophrenia-related gating deficits. Curr Psychiatry Rep. 1999;1:31–40.
    1. Light GA., Braff DL. Do self-reports of perceptual anomalies reflect gating deficits in schizophrenia patients? Biol Psychiatry. 2000;47:463–467.
    1. Light GA., Braff DL. Sensory gating deficits in schizophrenia: can we parse the effects of medication, nicotine use, and changes in clinical status? Clin Neurosci Res. 2003:47–54.
    1. Schwarzkopf SB., Lamberti JS., Smith DA. Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition. Biol Psychiatry. 1993;33:815–828.
    1. Cadenhead KS., Light GA., Geyer MA., McDowell JE., Braff DL. Neurobiological measures of schizotypal personality disorder: defining an inhibitory endophenotype? Am J Psychiatry. 2002;159:869–871.
    1. Light GA., Braff DL. Measuring P50 suppression and prepulse inhibition in a single recording session. Am J Psychiatry. 2001;158:2066–2068.
    1. Brenner CA., Edwards CR., Carroll CA., Kieffaber PD., Hetrick WP. P50 and acoustic startle gating are not related in healthy participants. Psychophysiology. 2004;41:702–78.
    1. Braff D., Stone C., Callaway E., Geyer M., Glick I., Bali L. Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology. 1978;15:339–343.
    1. Cadenhead KS., Geyer MA., Braff DL. Impaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder. Am J Psychiatry. 1993;150:1862–1867.
    1. Swerdlow NR., Martinez ZA., Hanlon FM., et al. Toward understanding the biology of a complex phenotype: rat strain and substrain differences in the sensorimotor gating-disruptive effects of dopamine agonists. J Neurosci. 2000;20:4325–4336.
    1. Swerdlow NR., Platten A., Kim YK., et al. Sensitivity to the dopaminergic regulation of prepulse inhibition in rats: evidence for genetic, but not environmental determinants. Pharmacol Biochem Behav. 2001;70:219–226.
    1. Swerdlow NR., Shoemaker JM., Pitcher L., et al. Genetic differences in startle gating-disruptive effects of apomorphine: evidence for central mediation. Behav Neurosci. 2002;116:682–690.
    1. Swerdlow NR., Shoemaker JM., Platten A., Pitcher L., Goins J., Auerbach PP. Heritable differences in the dopaminergic regulation of sensorimotor gating. I. Apomorphine effects on startle gating in albino and hooded outbred rat strains and their F1 and N2 progeny. Psychopharmacology (Berl). 2004;174:441–451.
    1. Swerdlow NR., Shoemaker JM., Auerbach PP., Pitcher L., Goins J., Platten A. Heritable differences in the dopaminergic regulation of sensorimotor gating. II. Temporal, pharmacologic and generational analyses of apomorphine effects on prepulse inhibition. Psychopharmacology (Berl). 2004;174:452–462.
    1. Swerdlow NR., Kuczenski R., Goins JC., et al. Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists. Pharmacol Biochem Behav. 2005;80:203–211.
    1. Ellenbroek BA., van Luijtelaar G., Frenken M., Cools AR. Sensory gating in rats: lack of correlation between auditory evoked potential gating and prepulse inhibition. Schizophr Bull. 1999;25:777–788.
    1. Swerdlow NR., Braff DL., Taaid N., Geyer MA. Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry. 1994;51:139–154.
    1. Geyer MA., Krebs-Thomson K., Braff DL., Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001;156:117–154.
    1. Swerdlow NR., Geyer MA., Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001;156:194–215.
    1. National Institute of Mental Health Consortium of Genetics of Schizophrenia. The genetics of endophenotypes and schizophrenia. Available at: . 2005 Mar Accessed 22;
    1. Adler LE., Pachtman E., Franks RD., Pecevich M., Waldo MC., Freedman R. Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry. 1982;17:639–654.
    1. Freedman R., Coon H., Myles-Worsley M., et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A. 1997;94:587–592.
    1. Judd LL., McAdams L., Budnick B., Braff DL. Sensory gating deficits in schizophrenia: new results. Am J Psychiatry. 1992;149:488–493.
    1. Waldo M., Myles-Worsley M., Madison A., Byerley W., Freedman R. Sensory gating deficits in parents of schizophrenics. Am J Med Genet. 1995;60:506–511.
    1. Siegel C., Waldo M., Mizner G., Adler LE., Freedman R. Deficits in sensory gating in schizophrenic patients and their relatives. Evidence obtained with auditory evoked responses. Arch Gen Psychiatry. 1984;41:607–612.
    1. Waldo MC., Adler LE., Freedman R. Defects in auditory sensory gating and their apparent compensation in relatives of schizophrenics. Schizophr Res. 1988;1:19–24.
    1. Cadenhead KS., Shafer K., Light GA., et al. Vulnerability markers in schizotypal personality disorder: defining a phenotype. Biol Psychiatry. 2000;47:37S.
    1. Adler LE., Hoffer LD., Wiser A., Freedman R. Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry. 1993;150:1856–1861.
    1. Adler LE., Hoffer LJ., Griffith J., Waldo MC., Freedman R. Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol Psychiatry. 1992;32:607–616.
    1. Stevens KE., Kern WR., Mahnir VM., Freedman Selective α7-nicotinic agonists normalize inhibition of auditory response in DBA mice. Psychopharmacology. 1998;136:320–327.
    1. Leonard S., Gault J., Hopkins J., et al. Association of promoter variants in the aynicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch Gen Psychiatry. 2002;59:1085–1096.
    1. Nagamoto HT., Adler LE., Hea RA., Griffith JM., McRae KA., Freedman R. Gating of auditory P50 in schizophrenics: unique effects of clozapine. Biol Psychiatry. 1996;40:181–188.
    1. Nagamoto HT., Adler LE., McRae KA., et al. Auditory P50 in schizophrenics on clozapine: improved gating parallels clinical improvement and changes in plasma 3-methoxy-4-hydroxyphenylglycol. Neuropsychobiology. 1999;39:10–17.
    1. Light GA., Geyer MA., Clementz BA., Cadenhead KS., Braff DL. Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry. 2000;157:767–771.
    1. Lohr JB., Braff DL. The value of referring to recently introduced antipsychotics as “second generation.”. Am J Psychiatry. 2003;160:1371–1372.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren