Executive subprocesses in working memory: Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia Goldberg T.E., Egan M.F., Gscheidle T., Coppola R., Weickert T., Kolachana B.S., Goldman D., Weinberger D.R. Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States; Laboratory of Neurogenetics, Intramural Research Program, Natl. Inst. Alcohol Abuse/Alcoholism, Bethesda, MD, United States; Clinical Brain Disorders Branch, National Institute of Mental Health, Mail Stop Code 1379, 10 Center Dr., Bethesda, MD 20892, United States Abstract: Background: Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. Methods: Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls (N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol-O-methyltransferase (COMT) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. Results: A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. Conclusions: A prefrontal cognitive mechanism common to the 1and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition. Year: 2003 Source title: Archives of General Psychiatry Volume: 60 Issue: 9 Page : 889-896 Cited by: 314 Link: Scorpus Link
Correspondence Address: Goldberg, T.E.; Clinical Brain Disorders Branch, National Institute of Mental Health, Mail Stop Code 1379, 10 Center Dr., Bethesda, MD 20892, United States; email:
[email protected] Document Type: Article Source: Scopus Authors with affiliations: 1. Goldberg, T.E., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States, Clinical Brain Disorders Branch, National Institute of Mental Health, Mail Stop Code 1379, 10 Center Dr., Bethesda, MD 20892, United States 2. Egan, M.F., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States 3. Gscheidle, T., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States 4. Coppola, R., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States 5. Weickert, T., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States 6. Kolachana, B.S., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States 7. Goldman, D., Laboratory of Neurogenetics, Intramural Research Program, Natl. Inst. Alcohol Abuse/Alcoholism, Bethesda, MD, United States 8. Weinberger, D.R., Clinical Brain Disorders Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, United States
References: 1.
Park, S., Holzman, P.S., Schizophrenics show spatial working memory deficits (1992) Arch Gen Psychiatry, 49, pp. 975-982
2.
Elliott, R., McKenna, P.J., Robbins, T.W., Sahakian, B.J., Neuropsychological evidence for frontostriatal dysfunction in schizophrenia (1995) Psychol Med, 25, pp. 619-630
3.
Condray, R., Steinhauer, S.R., Van Kammen, D.P., Kasparek, A., Working memory capacity predicts language comprehension in schizophrenic patients (1996) Schizophr Res, 20, pp. 1-13
4.
Gold, J.M., Carpenter, C., Randolph, C., Goldberg, T.E., Weinberger, D.R., Auditory working memory and Wisconsin Card Sorting Test performance in schizophrenia (1997) Arch Gen Psychiatry, 54, pp. 159-165
5.
Pantelis, C., Barnes, T.R., Nelson, H.E., Tanner, S., Weatherley, L., Owen, A.M., Robbins, T.W., Frontal-striatal cognitive deficits in patients with chronic schizophrenia (1997) Brain, 120, pp. 1823-1843
6.
Goldberg, T.E., Patterson, K., Taqqu, Y., Wilder, K., Capacity limitations in short term memory in schizophrenia (1998) Psychol Med, 28, pp. 665-673
7.
Weickert, T.W., Goldberg, T.E., Gold, J.M., Bigelow, L.B., Egan, M.F., Weinberger, D.R., Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect (2000) Arch Gen Psychiatry, 57, pp. 907-913
8.
Heaton, R.K., Gladsjo, J.A., Palmer, D.W., Kuck, J., Marcotte, T.D., Jeste, D.V., Stability and course of neuropsychological deficits in schizophrenia (2001) Arch Gen Psychiatry, 58, pp. 24-32
9.
Franke, P., Maier, W., Hain, C., Klingler, T., Wisconsin Card Sorting Test: An indicator of vulnerability to schizophrenia? (1992) Schizophr Res, 6, pp. 243-249
10. Yurgelun-Todd, D., Kinney, D.K., Patterns of neuropsychological deficits that discriminate schizophrenic individuals from siblings and control subjects (1993) J Neuropsychiatry Clin Neurosci, 5, pp. 294-300 11. Faraone, S., Seidman, L.J., Kremen, W.S., Pepple, J.R., Lyons, M.J., Tsuang, M.T., Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: A diagnostic efficiency analysis (1995) J Abnorm Psychol, 104, pp. 286-304 12. Goldberg, T.E., Ragland, J.D., Torrey, E.F., Weinberger, D.R., Genetic risk of neuropsychological impairment in schizophrenia: A study of monozygotic twins discordant and concordant for the disorder (1995) Schizophr Res, 17, pp. 77-84 13. Park, S., Holzman, P.S., Goldman-Rakic, P.S., Spatial working memory deficits in the relatives of schizophrenic patients (1995) Arch Gen Psychiatry, 52, pp. 821-828 14. Keefe, R.S.E., Silverman, J.M., Mohs, R.C., Siever, L.J., Harvey, P.D., Friedman, L., Roitman, S.E., Davis, K.L., Eye tracking, attention, and schizoptypal symptoms in nonpsychotic relatives of patients with schizophrenia (1997) Arch Gen Psychiatry, 54, pp. 169-176 15. Stratta, P., Daneluzzo, E., Mattei, P., Bustini, M., Casacchia, M., Rossi, A., No deficit in Wisconsin Card Sorting Test performance of schizophrenic patients' first-degree relatives (1997) Schizophr Res, 26, pp. 147-151 16. Cannon, T.D., Huttunen, M.O., Lonnqvist, J., Tuulio-Henriksson, A., Pirkola, T., Glahn, D., Finkelstein, J., Koshenvuo, M., The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia (2000) Am J Hum Genet, 67, pp. 369-382 17. Conklin, H.M., Curtis, C.E., Katsanis, J., Iacono, W.G., Verbal working memory impairment in schizophrenia patients and their first degree relatives (2000) Am J Psychiatry, 157, pp. 275-277 18. Egan, M.F., Goldberg, T.E., Gscheidle, T., Weirich, M., Rawlings, R., Hyde, T.M., Bigelow, L., Weinberger, D.R., Relative risk for cognitive impairments in siblings of patients with schizophrenia (2001) Biol Psychiatry, 50, pp. 98-107 19. Egan, M.F., Goldberg, T.E., Kolachana, B.S., Callicott, J.H., Mazzanti, C.M., Straub, R.E., Goldman, D., Weinberger, D.R., Effect of COMT Val108/158 Met genotype on frontal lobe function and risk of schizophrenia (2001) Proc Natl Acad Sci U S A, 98, pp. 6917-6922 20. Weinshilboum, R.M., Otterness, D.M., Szulmanski, C.L., Methylation pharmacogenetics: Catechol-O-methyl-transferase, thiopurine transferase, and histamine N-methyltransferase (1999) Annu Rev Pharmacol Toxicol, 39, pp. 19-52 21. Weinberger, D.R., Berman, K.F., Prefrontal function in schizophrenia: Confounds and controversies (1996) Philos Trans R Soc Lond B Biol Sci, 351, pp. 1495-1503 22. Malhotra, A.K., Mazzanti, C., Goldman, D., Goldberg, T.E., A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition (2002) Am J Psychiatry, 159, pp. 652-654 23. Joober, R., Gauthier, J., Lal, S., Bloom, D., Lalonde, P., Rouleau, G., Benkelfat, L., Labelle, A., Catechol-Omethyltransferase val-108/158-met gene variants associated with performance on the Wisconsin Card Sorting Test (2002) Arch Gen Psychiatry, 59, pp. 662-663 24. Li, T., Ball, D., Zhao, J., Murray, R.M., Liu, X., Sham, P.C., Collier, D.A., Family based linkage disequilibrium mapping using SNP marker haplotypes: Applications to a potential locus for schizophrenia at chromosome 22Q11 (2000) Mol Psychiatry, 5, pp. 77-84 25. Gevins, A.S., Morgan, N.H., Bressler, S.L., Cutillo, B.A., White, R.M., Illes, J., Greer, D.S., Zeitlin, G.M., Human neuroelectric patterns predict performance accuracy (1987) Science, 235, pp. 580-585 26. Cohen, J.D., Peristein, W.M., Braver, T.S., Nystrom, L.E., Noll, D.C., Jonides, J., Smith, E.E., Temporal dynamics of brain activity during a working memory task (1997) Nature, 386, pp. 604-608 27. Callicott, J.H., Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited (2000) Cereb Cortex,
10, pp. 1078-1092 28. Salthouse, T.A., The processing-speed theory of adult age differences in cognition (1996) Psychol Rev, 103, pp. 403-428 29. Egan, M.F., Goldberg, T.E., Gscheidle, T., Weirich, M., Bigelow, L.B., Weinberger, D.R., Relative risk of attention deficits in siblings of patients with schizophrenia (2000) Am J Psychiatry, 157, pp. 1309-1316 30. (1994) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, , Washington, DC: American Psychiatric Association 31. Gordon, M., (1988) CPT, , Syracuse, NY: Gordon Diagnostic Systems 32. Wechsler, D., (1981) WAIS-R Manual, , New York, NY: Psychological Corp 33. Jastak, S., Wilkinson, G.S., (1984) Wide Range Achievement Test-Revised (WRAT-R), , Wilmington, Del: Jastak Assessment Systems 34. Littell, R.C., Milliken, G.A., Stroup, W.W., Wolfingwer, R.D., (1996) SAS System for Mixed Models (Version 6.12), , Cary, NC: SAS Institute Inc 35. Risch, N., Merikangas, K., The future of genetic studies of complex human diseases (1996) Science, 273, pp. 1516-1517 36. Goldman-Rakic, P.S., Muly E.C. III, Williams, G.V., D(1) receptors in prefrontal cells and circuits (2000) Brain Res Rev, 31, pp. 295-301 37. Miller, E.K., The prefrontal cortex and cognitive control (2000) Nat Rev Neurosci, 1, pp. 59-65 38. Gogos, J.A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., Karayiorgou, M., Catechol-O-methyltransferasedeficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior (1998) Proc Natl Acad Sci U S A, 95, pp. 9991-9996 39. Lewis, D.A., Sesack, S.R., Levey, A.I., Rosenberg, D.R., Dopamine axons in primate prefrontal cortex (1998) Adv Pharmacol, 42, pp. 703-706 40. Riley, B.P., McGuffin, P., Linkage and associated studies of schizophrenia (2000) Am J Med Genet, 97, pp. 23-44 41. Weinberger, D.R., Egan, M.F., Bertolino, A., Callicott, J., Mattay, V.S., Lipska, B.K., Berman, K.F., Goldberg, T.E., Prefrontal neurons and the genetics of schizophrenia (2001) Biol Psychiatry, 50, pp. 825-844 42. Freedman, R., Adler, L.E., Leonard, S., Alternative phenotypes for the complex genetics of schizophrenia (1999) Biol Psychiatry, 45, pp. 551-558 43. Cornblatt, B.A., Malhotra, A.K., Impaired attention as an endophenotype for molecular genetic studies of schizophrenia (2001) Am J Med Genet, 105, pp. 11-15 44. Bray, N.J., Owen, M.J., Searching for schizophrenia genes (2001) Trends Mol Med, 7, pp. 169-174 45. Crofts, H., Dalley, J.W., Collins, P., Van Denderen, J.C., Everitt, B.J., Robbins, T.W., Roberts, A.C., Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set (2001) Cereb Cortex, 11, pp. 1015-1026 46. Gao, W.-J., Krimer, L.S., Goldman-Rakic, P.S., Presynaptic dopamine regulation of recurrent excitation by D1 receptors in prefrontal circuits (2001) Proc Natl Acad Sci U S A, 98, pp. 295-300 47. Seamans, J.K., Gorelova, N., Durstewitz, D., Yang, C.R., Bidirectional modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons (2001) J Neurosci, 21, pp. 3628-3638 48. Nystrom, L.E., Braver, T.S., Sabb, F.W., Delgado, M.R., Noll, D.C., Cohen, J.D., Working memory for letters, shapes, and locations (2000) Neuroimage, 11, pp. 424-446 49. Robbins, T.W., Chemical neuromodulation of frontal-executive functions in humans and other animals (2000) Exp Brain Res, 133, pp. 130-138 50. Goldman-Rakic, P.S., The physiological approach: Functional architecture of working memory and disordered cognition in
schizophrenia (1999) Biol Psychiatry, 46, pp. 650-651 51. Smith, E.E., Jonides, J., Storage and executive processes in the frontal lobes (1999) Science, 283, pp. 1657-1661 52. Owen, A.M., Herrod, N.J., Menon, D.K., Clark, J.C., Downey, S.P., Carpenter, T.A., Minhas, P.S., Pickard, J.D., Redefining the functional organization of working memory processes within human lateral prefrontal cortex (1999) Eur J Neurosci, 11, pp. 567-574 53. D'Esposito, M., Postle, B.R., Rypma, B., Prefrontal cortical contributions to working memory: Evidence from event-related fMRI studies (2000) Exp Brain Res, 133, pp. 3-11
