Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-25T07:41:07.452Z Has data issue: false hasContentIssue false
  • English
  • Français

The contribution of epidemiology to defining the most appropriate approach to genetic research on schizophrenia

Published online by Cambridge University Press:  11 April 2011

Sarah Tosato  and
Antonio Lasalvia
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Psychosis is thought to have a strong genetic component, but many efforts to discover the underlying putative schizophrenia genes have yielded disappointing results. In fact, no strong associations emerged in the first genome-wide association studies in psychiatry and weakly observed associations were not related to the candidate genes identified in previous studies. These partially successful findings may be explained by the fact that genetic research in psychiatry suffers from confounding issues related to phenotype definition, the considerable degree of phenotypic variability and diagnostic uncertainty, absence of specific neuropathological features and environmental influences. To make progress it is first necessary to deconstruct psychosis based on symptomatology, and then to correlate particular phenotypes with genetic variants. Moreover, it is time to conduct studies that define persistent aspects of the schizophrenic profile that are more likely to represent an underlying biological pathogenesis, as opposed to fluctuating symptoms that are possibly environmentally mediated. In fact, progress in understanding the etiology of schizophrenia will depend upon the availability of good measures of genetic liability as well as relevant environmental exposures during critical periods of an individual's life. If environmental and/or genetic factors are not precisely measured, it is impossible to study their independent effects or interactions.

Type
Editorials
Information
Epidemiology and Psychiatric Sciences , Volume 18 , Issue 2 , June 2009 , pp. 81 - 90
Copyright
Copyright © Cambridge University Press 2009

References

REFERENCES

Alkelai, A., Baum, A., Carless, M., Crowley, J., Dasbanerjee, T., Dempster, E., Docherty, S., Hare, E., Galsworthy, M.J., Grover, D., Glubb, D., Karlsson, R., Mill, J., Sen, S., Quinones, M.P., Vallender, E.J., Verma, R., Vijayan, N.N., Villafuerte, S., Voineskos, A.N., Volk, H., Yu, L., Zimmermann, P. & DeLisi, L.E. (2008). The XVth World Congress of Psychiatric Genetics, October 7–11, 2007: Rapporteur summaries of oral presentations. American Journal of Medical Genetics B Neuropsychiatry and Genetics 147B, 233–277.Google Scholar
Allardyce, J., Gaebel, W., Zielasek, J. & Van Os, J. 2007. Deconstructing Psychosis conference February 2006: the validity of schizophrenia and alternative approaches to the classification of psychosis. Schizophrenia Bulletin 33, 863–867.Google Scholar
Allen, N.C., Bagade, S., McQueen, M.B., Ioannidis, J.P., Kavvoura, F.K., Khoury, M.J., Tanzi, R.E. & Bertram, L. (2008). Systematic metaanalyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature Genetics 40, 827–834.Google Scholar
Andreasen, N.C. & Olsen, S. (1982). Negative v positive schizophrenia. Definition and validation. Archives of General Psychiatry 39, 789–794.CrossRefGoogle ScholarPubMed
Andreasen, N.C., Nopoulos, P., Schultz, S., Miller, D., Gupta, S., Swayze, V. & Flaum, M. (1994). Positive and negative symptoms of schizophrenia: past, present, and future. Acta Psychiatrica Scandinavica, Suppl 384, 51–59.Google Scholar
Baron, M., Gruen, R., Asnis, L. & Kane, J. (1982). Schizoaffective illness, schizophrenia and affective disorders: morbidity risk and genetic transmission. Acta Psychiatrica Scandinavica 65, 253–262.CrossRefGoogle ScholarPubMed
Bleuler, E. (1911). Dementia praecox oder die Gruppe der Schizophrenien. In Handbuch der Psychiatrie (ed. Aschaffenburg, G.). Deuticke: Leipzig.Google Scholar
Bowie, C.R., Reichenberg, A., Patterson, T.L., Heaton, R.K. & Harvey, P.D. (2006). Determinants of real-world functional performance in schizophrenia subjects: correlations with cognition, functional capacity, and symptoms. American Journal of Psychiatry 163, 418–425.CrossRefGoogle ScholarPubMed
Bowie, C.R., Leung, W.W., Reichenberg, A., McClure, M.M., Patterson, T.L., Heaton, R.K. & Harvey, P.D. (2008). Predicting schizophrenia patients' real-world behavior with specific neuropsychological and functional capacity measures. Biological Psychiatry 63, 505–511.Google Scholar
Boydell, J., Van Os, J., McKenzie, K., Allardyce, J., Goel, R., McCreadie, R.G. & Murray, R.M. (2001). Incidence of schizophrenia in ethnic minorities in London: ecological study into interactions with environment. British Medical Journal 323, 1336–1338.CrossRefGoogle ScholarPubMed
Breen, G., Prata, D., Osborne, S., Munro, J., Sinclair, M., Li, T., Staddon, S., Dempster, D., Sainz, R., Arroyo, B., Kerwin, R.W., StCloud, D. & Collier, D. (2006). Association of the dysbindin gene with bipolar affective disorder. American Journal of Psychiatry 163, 1636–1638.Google Scholar
Brown, A.S., Cohen, P., Harkavy-Friedman, J., Babulas, V., Malaspina, D., Gorman, J.M. & Susser, E.S. (2001). A.E. Bennett Research Award. Prenatal rubella, premorbid abnormalities, and adult schizophrenia. Biological Psychiatry 49, 473–486.CrossRefGoogle ScholarPubMed
Brown, A.S., Schaefer, C.A., Quesenberry, C.P. Jr., Liu, L., Babulas, V.P. & Susser, E.S. (2005). Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring. American Journal Psychiatry 162, 767–773.Google Scholar
Cannon, M., Jones, P.B. & Murray, R.M. (2002). Obstetric complications and schizophrenia: historical and meta-analytic review. American Journal of Psychiatry 159, 1080–1092.Google Scholar
Cardno, A.G. & Farmer, A.E. (1995). The case for or against heterogeneity in the etiology of schizophrenia. The genetic evidence. Schizophrenia Research 17, 153–159.Google Scholar
Cardno, A.G. & Gottesman, I.I. (2000). Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics. American Journal of Medical Genetics 97, 12–17.Google Scholar
Cardno, A.G., Marshall, E.J., Coid, B., Macdonald, A.M., Ribchester, T.R., Davies, N.J., Venturi, P., Jones, L.A., Lewis, S.W., Sham, P.C., Gottesman, I.I., Farmer, A.E., McGuffin, P., Reveley, A.M. & Murray, R.M. (1999). Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Archives of General Psychiatry 56, 162–168.Google Scholar
Cardno, A.G., Rijsdijk, F.V., Sham, P.C., Murray, R.M. & McGuffin, P. (2002). A twin study of genetic relationships between psychotic symptoms. American Journal of Psychiatry 159, 539–545.Google Scholar
Carpenter, W.T. Jr, Buchanan, R.W., Kirkpatrick, B., Tamminga, C. & Wood, F. (1993). Strong inference, theory testing, and the neuroanatomy of schizophrenia. Archives of General Psychiatry 50, 825–831.Google Scholar
Caspi, A. & Moffitt, T.E. (2006). Gene-environment interactions in psychiatry: joining forces with neuroscience. Nature Reviews. Neuroscience 7, 583–590.Google Scholar
Caspi, A., Moffitt, T.E., Cannon, M., McClay, J., Murray, R., Harrington, H., Taylor, A., Arseneault, L., Williams, B., Braithwaite, A., Poulton, R. & Craig, I.W. (2005). Moderation of the effect of adolescentonset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biological Psychiatry 57, 1117–1127.Google Scholar
Caspi, A., Sugden, K., Moffitt, T.E., Taylor, A., Craig, I.W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A. & Poulton, R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389.Google Scholar
Cooper, C., Morgan, C., Byrne, M., Dazzan, P., Morgan, K., Hutchinson, G., Doody, G.A., Harrison, G., Leff, J., Jones, P., Ismail, K., Murray, R., Bebbington, P. & Fearon, P. (2008). Perceptions of disadvantage, ethnicity and psychosis. British Journal of Psychiatry 192, 185–190.CrossRefGoogle ScholarPubMed
Craddock, N. & Owen, M.J. (2007). Rethinking psychosis: the disadvantages of a dichotomous classification now outweigh the advantages. World Psychiatry 6, 84–91.Google Scholar
Craddock, N., O'Donovan, M.C. & Owen, M.J. (2006). Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophrenia Bulletin 32, 9–16.Google Scholar
Craddock, N., O'Donovan, M.C. & Owen, M.J. (2008). Genome-wide association studies in psychiatry: lessons from early studies of non-psychiatric and psychiatric phenotypes. Molecular Psychiatry 13, 649–653.Google Scholar
Crow, T.J. (2008). The emperors of the schizophrenia polygene have no clothes. Psychological Medicine 38, 1681–1685.Google Scholar
Davidson, L. & McGlashan, T.H.. (1997). The varied outcomes of schizophrenia. Canadian Journal of Psychiatry 42, 34–43.Google Scholar
DeRosse, P., Funke, B., Burdick, K.E., Lencz, T., Ekholm, J.M., Kane, J M., Kucherlapati, R. & Malhotra, A.K. (2006a). Dysbindin genotype and negative symptoms in schizophrenia. American Journal of Psychiatry 163, 532–534.Google Scholar
Derosse, P., Funke, B., Burdick, K.E., Lencz, T., Goldberg, T.E., Kane, J M., Kucherlapati, R. & Malhotra, A.K. (2006b). COMT genotype and manic symptoms in schizophrenia. Schizophrenia Research 87, 28–31.CrossRefGoogle ScholarPubMed
DeRosse, P., Hodgkinson, C.A., Lencz, T., Burdick, K.E., Kane, J.M., Goldman, D. & Malhotra, A.K. (2007). Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biological Psychiatry 61, 1208–1210.CrossRefGoogle ScholarPubMed
DeRosse, P., Lencz, T., Burdick, K.E., Siris, S.G., Kane, J.M. & Malhotra, A.K. (2008). The genetics of symptom-based phenotypes: toward a molecular classification of schizophrenia. Schizophrenia Bulletin 34, 1047–1053.Google Scholar
Detera-Wadleigh, S.D. & McMahon, F.J. (2006). G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biological Psychiatry 60, 106–114.Google Scholar
Dickinson, D., Bellack, A.S. & Gold, J.M. (2007). Social/communication skills, cognition, and vocational functioning in schizophrenia. Schizophrenia Bulletin 33, 1213–1220.Google Scholar
Dollfus, S. & Everitt, B. (1998). Symptom structure in schizophrenia: two-, three- or four-factor models? Psychopathology 31, 120–130.Google Scholar
Eaton, W.W., Thara, R., Federman, B., Melton, B. & Liang, K.Y. (1995). Structure and course of positive and negative symptoms in schizophrenia. Archives of General Psychiatry 52, 127–134.Google Scholar
Emsley, R., Chiliza, B. & Schoeman, R. (2008). Predictors of longterm outcome in schizophrenia. Current Opinion in Psychiatry 21, 173–177.Google Scholar
Fanous, A.H., Neale, M.C., Straub, R.E., Webb, B.T., O'Neill, A.F., Walsh, D. & Kendler, K.S. (2004). Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 125B, 69–78.Google Scholar
Fanous, A.H., van den Oord, E.J., Riley, B.P., Aggen, S.H., Neale, M.C., O'Neill, F.A., Walsh, D. & Kendler, K.S. (2005). Relationship between a high-risk haplotype in the DTNBP1 (dysbindin) gene and clinical features of schizophrenia. American Journal of Psychiatry 162, 1824–1832.Google Scholar
Funke, B., Finn, C.T., Plocik, A.M., Lake, S., DeRosse, P., Kane, J.M., Kucherlapati, R. & Malhotra, A.K. (2004). Association of the DTNBP1 locus with schizophrenia in a U.S. population. American Journal of Human Genetics 75, 891–898.CrossRefGoogle Scholar
Geddes, J.R., Verdoux, H., Takei, N., Lawrie, S.M., Bovet, P., Eagles, J.M., Heun, R., McCreadie, R.G., McNeil, T.F., O'Callaghan, E., Stober, G., Willinger, U. & Murray, R.M. (1999). Schizophrenia and complications of pregnancy and labor: an individual patient data meta-analysis. Schizophrenia Bulletin 25, 413–423.CrossRefGoogle ScholarPubMed
Gershon, E.S., DeLisi, L.E., Hamovit, J., Nurnberger, J.I. Jr., Maxwell, M.E., Schreiber, J., Dauphinais, D., Dingman, C.W. & Guroff, J.J. (1988). A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder. Archives of General Psychiatry 45, 328–336.Google Scholar
Glatt, S.J., Faraone, S.V. & Tsuang, M.T. (2003). Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. American Journal of Psychiatry 160, 469–476.Google Scholar
Green, E.K., Raybould, R., Macgregor, S., Gordon-Smith, K., Heron, J., Hyde, S., Grozeva, D., Hamshere, M., Williams, N., Owen, M.J., O'Donovan, M.C., Jones, L., Jones, I., Kirov, G. & Craddock, N. (2005). Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Archives of General Psychiatry 62, 642–648.Google Scholar
Harrison, G. (2004). Trajectories of psychosis: towards a new social biology of schizophrenia. Epidemiologia e Psichiatria Sociale 13, 152–157.Google Scholar
Harvey, P D., Koren, D., Reichenberg, A. & Bowie, C.R. (2006). Negative symptoms and cognitive deficits: what is the nature of their relationship? Schizophrenia Bulletin 32, 250–258.Google Scholar
Hegarty, J.D., Baldessarini, R.J., Tohen, M., Waternaux, C. & Oepen, G. (1994). One hundred years of schizophrenia: a meta-analysis of the outcome literature. American Journal of Psychiatry 151, 1409–1416.Google Scholar
Hennah, W., Varilo, T., Kestila, M., Paunio, T., Arajarvi, R., Haukka, J., Parker, A., Martin, R., Levitzky, S., Partonen, T., Meyer, J., Lonnqvist, J., Peltonen, L. & Ekelund, J. (2003). Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Human Molecular Genetics 12, 3151–3159.Google Scholar
Henquet, C., Di, Forti M., Morrison, P., Kuepper, R. & Murray, R.M. (2008). Gene-environment interplay between cannabis and psychosis. Schizophrenia Bulletin 34, 1111–1121.CrossRefGoogle ScholarPubMed
Herken, H. & Erdal, M.E. (2001). Catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. Psychiatric Genetics 11, 105–109.Google Scholar
Hijman, R., Hulshoff, Pol H.E., Sitskoorn, M.M. & Kahn, R.S. (2003). Global intellectual impairment does not accelerate with age in patients with schizophrenia: a cross-sectional analysis. Schizophrenia Bulletin 29, 509–517.Google Scholar
Hyde, T M., Nawroz, S., Goldberg, T.E., Bigelow, L.B., Strong, D., Ostrem, J.L., Weinberger, D.R. & Kleinman, J.E. (1994). Is there cognitive decline in schizophrenia? A cross-sectional study. British Journal of Psychiatry 164, 494–500.Google Scholar
Ivleva, E., Thaker, G, & Tamminga, C.A. (2008). Comparing genes and phenomenology in the major psychoses: schizophrenia and bipolar 1 disorder. Schizophrenia Bulletin 34, 734–742.CrossRefGoogle ScholarPubMed
Jablensky, A. (2006). Subtyping schizophrenia: implications for genetic research. Molecular Psychiatry 11, 815–836.Google Scholar
Jobe, T.H. & Harrow, M. (2005). Long-term outcome of patients with schizophrenia: a review. Canadian Journal of Psychiatry 50, 892–900.CrossRefGoogle ScholarPubMed
Jones, P. & Cannon, M. (1998). The new epidemiology of schizophrenia. Psychiatric Clinics of North America 21, 1–25.Google Scholar
Kay, S.R. & Sevy, S. (1990). Pyramidical model of schizophrenia. Schizophrenia Bulletin 16, 537–545.Google Scholar
Kendler, K S., Karkowski, L.M. & Walsh, D. (1998). The structure of psychosis: latent class analysis of probands from the Roscommon Family Study. Archives of General Psychiatry 55, 492–499.Google Scholar
Kennedy, J.L., Farrer, L.A., Andreasen, N.C., Mayeux, R. & StGeorge-Hyslop, P. (2003). The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science 302, 822–826.Google Scholar
Kirkbride, J.B., Fearon, P., Morgan, C., Dazzan, P., Morgan, K., Tarrant, J., Lloyd, T., Holloway, J., Hutchinson, G., Leff, J.P., Mallett, R.M., Harrison, G.L., Murray, R.M. & Jones, P.B. (2006). Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center AeSOP study. Archives of General Psychiatry 63, 250–258.Google Scholar
Kohn, Y., Danilovich, E., Filon, D., Oppenheim, A., Karni, O., Kanyas, K., Turetsky, N., Korner, M. & Lerer, B. (2004). Linkage disequlibrium in the DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: findings from identity by descent haplotype sharing analysis. American Journal of Medical Genetics, Part B. Neuropsychiatric Genetics 128B, 65–70.Google Scholar
Lasalvia, A., Bonetto, C., Cristofalo, D., Tansella, M. & Ruggeri, M. (2007a). Predicting clinical and social outcome of patients attending ‘real world’ mental health services: a 6-year multi-wave follow-up study. Acta Psychiatrica Scandinavica, Suppl. 437, 16–30.Google Scholar
Lasalvia, A., Bonetto, C., Salvi, G., Bissoli, S., Tansella, M. & Ruggeri, M. (2007b). Predictors of changes in needs for care in patients receiving community psychiatric treatment: a 4-year follow-up study. Acta Psychiatrica Scandinavica, Suppl. 437, 31–41.Google Scholar
Lenzenweger, M.F., Dworkin, R.H. & Wethington, E. (1991). Examining the underlying structure of schizophrenic phenomenology: evidence for a three-process model. Schizophrenia Bulletin 17, 515–524.Google Scholar
Li, T., Zhang, F., Liu, X., Sun, X., Sham, P C., Crombie, C., Ma, X., Wang, Q., Meng, H., Deng, W., Yates, P., Hu, X., Walker, N., Murray, R.M., StCloud, D. & Collier, D.A. (2005). Identifying potential risk haplotypes for schizophrenia at the DTNBP1 locus in Han Chinese and Scottish populations. Molecular Psychiatry 10, 1037–1044.Google Scholar
Liddle, P.F. (1987). The symptoms of chronic schizophrenia. A reexamination of the positive-negative dichotomy. British Journal of Psychiatry 151, 145–151.Google Scholar
Lindenmayer, J.P., Bernstein-Hyman, R. & Grochowski, S. (1994). Five-factor model of schizophrenia. Initial validation. Journal of Nervous and Mental Disease 182, 631–638.Google Scholar
Lysaker, P. & Bell, M. (1995). Negative symptoms and vocational impairment in schizophrenia: repeated measurements of work performance over six months. Acta Psychiatrica Scandinavica 91, 205–208.CrossRefGoogle ScholarPubMed
Maier, W., Lichtermann, D., Minges, J., Hallmayer, J., Heun, R., Benkert, O. & Levinson, D.F. (1993). Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family study. Archives of General Psychiatry 50, 871–883.Google Scholar
Maier, W., Hofgen, B., Zobel, A. & Rietschel, M. (2005). Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? European Archives of Psychiatry and Clinical Neuroscience 255, 159–166.CrossRefGoogle ScholarPubMed
Malaspina, D., Harlap, S., Fennig, S., Heiman, D., Nahon, D., Feldman, D. & Susser, E.S. (2001). Advancing paternal age and the risk of schizophrenia. Archives of General Psychiatry 58, 361–367.Google Scholar
Malla, A K., Norman, R.M., Williamson, P., Cortese, L. & Diaz, F. (1993). Three syndrome concept of schizophrenia. A factor analytic study. Schizophrenia Research 10, 143–150.Google Scholar
McClay, J.L., Fanous, A., van den Oord, E.J., Webb, B.T., Walsh, D., O'Neill, F.A., Kendler, K.S. & Chen, X. (2006). Catechol-Omethyltransferase and the clinical features of psychosis. American Journal of Medical Genetics, Part B. Neuropsychiatric Genetics 141B, 935–938.Google Scholar
McGrath, J. (2008). Hypotheses desert us, while data defend us Schizophrenia Research 102, 27–28.Google Scholar
McGrath, J., Saha, S., Welham, J., El, Saadi O., MacCauley, C. & Chant, D. (2004). A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Medicine 2, 13.CrossRefGoogle ScholarPubMed
Meehl, P.E. (1995). Bootstraps taxometrics. Solving the classification problem in psychopathology. American Psychology 50, 266–275.Google Scholar
Mockler, D., Riordan, J. & Sharma, T. (1997). Memory and intellectual deficits do not decline with age in schizophrenia. Schizophrenia Research 26, 1–7.CrossRefGoogle Scholar
Mortensen, P B., Pedersen, C.B., Melbye, M., Mors, O. & Ewald, H. (2003). Individual and familial risk factors for bipolar affective disorders in Denmark. Archives of General Psychiatry 60, 1209–1215.Google Scholar
Munafo, M.R., Bowes, L., Clark, T.G. & Flint, J. (2005). Lack of association of the COMT (Va1158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. Molecular Psychiatry 10, 765–770.CrossRefGoogle ScholarPubMed
Munafo, M.R., Thiselton, D.L., Clark, T.G. & Flint, J. (2006). Association of the NRG1 gene and schizophrenia: a meta-analysis. Molecular Psychiatry 11, 539–546.Google Scholar
Murray, R M., Sham, P., Van Os, J., Zanelli, J., Cannon, M. & McDonald, C. (2004). A developmental model for similarities and dissimilarities between schizophrenia and bipolar disorder. Schizophrenia Research 71, 405–416.Google Scholar
Norton, N.Williams, H.J. & Owen, M.J. (2006). An update on the genetics of schizophrenia. Current Opinion in Psychiatry 19, 158–164.Google Scholar
Numakawa, T., Yagasaki, Y., Ishimoto, T., Okada, T., Suzuki, T., Iwata, N., Ozaki, N., Taguchi, T., Tatsumi, M., Kamijima, K., Straub, R.E., Weinberger, D.R., Kunugi, H. & Hashimoto, R. (2004). Evidence of novel neuronal functions of dysbindin. a susceptibility gene for schizophrenia. Human Molecular Genetics 13, 2699–2708.Google Scholar
Owen, M.J., Craddock, N. & Jablensky, A. (2007). The genetic deconstruction of psychosis. Schizophrenia Bulletin 33, 905–911.Google Scholar
Penner, J.D. & Brown, A.S. (2007). Prenatal infectious and nutritional factors and risk of adult schizophrenia. Expert Review on Neurotherapeutics 7, 797–805.Google Scholar
Peralta, V. & Cuesta, M.J. (2000). Clinical models of schizophrenia: a critical approach to competing conceptions. Psychopathology 33, 252–258.Google Scholar
Peralta, V. & Cuesta, M.J. (2003). The diagnosis of schizophrenia: old wine in new bottles. International Journal of Psychology and Psychological Therapy 3, 141–152.Google Scholar
Peralta, V., Cuesta, M.J. & de Leon, J. (1994). An empirical analysis of latent structures underlying schizophrenic symptoms: a four-syndrome model. Biological Psychiatry 36, 726–736.Google Scholar
Raybould, R., Green, E.K., MacGregor, S., Gordon-Smith, K., Heron, J., Hyde, S., Caesar, S., Nikolov, I., Williams, N., Jones, L., O'Donovan, M.C., Owen, M.J., Jones, I., Kirov, G. & Craddock, N. (2005). Bipolar disorder and polymorphisms in the dysbindin gene (DTNBP1). Biological Psychiatry 57, 696–701.Google Scholar
Read, J., Van Os, J., Morrison, A.P. & Ross, C.A. (2005). Childhood trauma, psychosis and schizophrenia: a literature review with theoretical and clinical implications. Acta Psychiatrica Scandinavica 112, 330–350.CrossRefGoogle ScholarPubMed
Rietkerk, T., Boks, M.P., Sommer, I.E., Liddle, P.F., Ophoff, R.A. & Kahn, R.S. (2008). The genetics of symptom dimensions of schizophrenia: review and meta-analysis. Schizophrenia Research 102, 197–205.Google Scholar
Rosenman, S., Korten, A., Medway, J. & Evans, M. (2003). Dimensional vs. categorical diagnosis in psychosis. Acta Psychiatrica Scandinavica 107, 378–384Google Scholar
Ruggeri, M., Lasalvia, A., Tansella, M., Bonetto, C., Abate, M., Thornicroft, G., Allevi, L. & Ognibene, P. (2004). Heterogeneity of outcomes in schizophrenia. 3-year follow-up of treated prevalent cases. British Journal of Psychiatry 184, 48–57.Google Scholar
Ruggeri, M., Nosè, M., Bonetto, C., Cristofalo, D., Lasalvia, A., Salvi, G., Stefani, B., Malchiodi, F. & Tansella, M. (2005). Changes and predictors of change in objective and subjective quality of life: multiwave follow-up study in community psychiatric practice. British Journal of Psychiatry 187, 121–130.Google Scholar
Sanders, A.R., Duan, J., Levinson, D.F., Shi, J., He, D., Hou, C., Burrell, G.J., Rice, J.P., Nertney, D.A., Olincy, A., Rozic, P., Vinogradov, S., Buccola, N.G., Mowry, B.J., Freedman, R., Amin, F., Black, D.W., Silverman, J.M., Byerley, W.F., Crowe, R.R., Cloninger, C.R., Martinez, M. & Gejman, P.V. (2008). No significant association of 14 candidate genes with schizophrenia in a large European ancestry sample: implications for psychiatric genetics. American Journal of Psychiatry 165, 497–506.Google Scholar
Schwab, S.G., Knapp, M., Mondabon, S., Hallmayer, J., Borrmann-Hassenbach, M., Albus, M., Lerer, B., Rietschel, M., Trixler, M., Maier, W. & Wildenauer, D.B. (2003). Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. American Journal of Human Genetics 72, 185–190.Google Scholar
Serretti, A., Lattuada, E., Lorenzi, C., Lilli, R. & Smeraldi, E. (2000).Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses. Molecular Psychiatry 5, 270–274.Google Scholar
Serretti, A., Lilli, R., Lorenzi, C., Lattuada, E. & Smeraldi, E. (2001). DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: a study on 2,011 affected subjects. American Journal of Human Genetics 105, 283–290.Google Scholar
Shenton, M.E., Dickey, C.C., Frumin, M. & McCarley, R.W. (2001). A review of MRI findings in schizophrenia. Schizophrenia Research 49, 1–52.Google Scholar
StClair, D. (2009). Copy number variation and schizophrenia. Schizophrenia Bulletin 35, 9–12.Google Scholar
Stefansson, H., Rujescu, D., Cichon, S., Pietilainen, O.P., Ingason, A., Steinberg, S., Fossdal, R., Sigurdsson, E., Sigmundsson, T., Buizer-Voskamp, J.E., Hansen, T., Jakobsen, K.D., Muglia, P., Francks, C., Matthews, P.M., Gylfason, A., Halldorsson, B.V., Gudbjartsson, D., Thorgeirsson, T.E., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Bjornsson, A., Mattiasdottir, S., Blondal, T., Haraldsson, M., Magnusdottir, B.B., Giegling, I., Moller, H.J., Hartmann, A., Shianna, K.V., Ge, D., Need, A.C., Crombie, C., Fraser, G., Walker, N., Lonnqvist, J., Suvisaari, J., Tuulio-Henriksson, A., Paunio, T., Toulopoulou, T., Bramon, E., Di, Forti M., Murray, R., Ruggeri, M., Vassos, E., Tosato, S., Walshe, M., Li, T., Vasilescu, C., Muhleisen, T.W., Wang, A.G., Ullum, H., Djurovic, S., Melle, I., Olesen, J., Kiemeney, L A., Franke, B., Sabatti, C., Freimer, N.B., Gulcher, J.R., Thorsteinsdottir, U., Kong, A., Andreassen, O.A., Ophoff, R.A., Georgi, A., Rietschel, M., Werge, T., Petursson, H., Goldstein, D.B., Nothen, M.M., Peltonen, L., Collier, D.A., StCloud, D. & Stefansson, K. (2008). Large recurrent microdeletions associated with schizophrenia Nature 455, 232–236.Google Scholar
Straub, R.E., Jiang, Y., MacLean, C.J., Ma, Y., Webb, B.T., Myakishev, M.V., Harris-Kerr, C., Wormley, B., Sadek, H., Kadambi, B., Cesare, A.J., Gibberman, A., Wang, X., O'Neill, F.A., Walsh, D. & Kendler, K.S. (2002). Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. American Journal of Human Genetics 71, 337–348.Google Scholar
Strauss, J.S. & Carpenter, W.T Jr. (1977). Prediction of outcome in schizophrenia. III. Five-year outcome and its predictors. Archives of General Psychiatry 34, 159–163.Google Scholar
Strauss, J.S., Carpenter, W.T. Jr. & Bartko, J.J. (1974). The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophrenia Bulletin 11, 61–69.Google Scholar
Sullivan, P.F. (2008). The dice are rolling for schizophrenia genetics. Psychological Medicine 38, 1693–1696.CrossRefGoogle ScholarPubMed
Sullivan, P.F., Kendler, K.S. & Neale, M.C. (2003). Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry 60, 1187–1192.Google Scholar
Tamminga, C.A. & Holcomb, H.H. (2005). Phenotype of schizophrenia: a review and formulation. Molecular Psychiatry 10, 27–39.Google Scholar
Tang, J.X., Zhou, J., Fan, J.B., Li, X.W., Shi, Y.Y., Gu, N.F., Feng, G.Y., Xing, Y.L., Shi, J.G. & He, L. (2003). Family-based association study of DTNBP1 in 6p22.3 and schizophrenia. Molecular Psychiatry 8, 717–718.Google Scholar
Tosato, S., Dazzan, P. & Collier, D. (2005). Association between the neuregulin 1 gene and schizophrenia: a systematic review. Schizophrenia Bulletin 31, 613–617.Google Scholar
Tosato, S., Ruggeri, M., Bonetto, C., Bertani, M., Marrella, G., Lasalvia, A., Cristofalo, D., Aprili, G., Tansella, M., Dazzan, P., Diforti, M., Murray, R.M. & Collier, D.A. (2007). Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients. American Journal of Medical Genetics, Part B. Neuropsychiatric Genetics 144B, 647–659.Google Scholar
Tsuang, M.T. & Faraone, S.V. (1995). The case for heterogeneity in the etiology of schizophrenia. Schizophrenia Research 17, 161–175.Google Scholar
van den Oord, E.J., Sullivan, P.F., Jiang, Y., Walsh, D., O'Neill, F.A., Kendler, K.S. & Riley, B.P. (2003). Identification of a high-risk haplotype for the dystrobrevin binding protein 1 (DTNBP1) gene in the Irish study of high-density schizophrenia families. Molecular Psychiatry 8, 499–510.Google Scholar
Van Os, J., Hanssen, M., Bak, M., Bijl, R.V. & Vollebergh, W. (2003). Do urbanicity and familial liability coparticipate in causing psychosis? American Journal of Psychiatry 160, 477–482.Google Scholar
Van Os, J., Pedersen, C.B. & Mortensen, P.B. (2004). Confirmation of synergy between urbanicity and familial liability in the causation of psychosis. American Journal of Psychiatry 161, 2312–2314.Google Scholar
Van Os, J., Rutten, B.P. & Poulton, R. (2008). Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophrenia Bulletin 34, 1066–1082.CrossRefGoogle ScholarPubMed
Walsh, T., McClellan, J.M., McCarthy, S.E., Addington, A.M., Pierce, S.B., Cooper, G.M., Nord, A.S., Kusenda, M., Malhotra, D., Bhandari, A., Stray, S.M., Rippey, C.F., Roccanova, P., Makarov, V., Lakshmi, B., Findling, R.L., Sikich, L., Stromberg, T., Merriman, B., Gogtay, N., Butler, P., Eckstrand, K., Noory, L., Gochman, P., Long, R., Chen, Z., Davis, S., Baker, C., Eichler, E.E., Meltzer, P.S., Nelson, S.F., Singleton, A.B., Lee, M.K., Rapoport, J.L., King, M.C. & Sebat, J. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543.Google Scholar
Welcome Trust Case Control Consortium (2007). Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678.Google Scholar
Weiser, M., Van Os, J. & Davidson, M. (2005). Time for a shift in focus in schizophrenia: from narrow phenotypes to broad endophenotypes. British Journal of Psychiatry 187, 203–205.Google Scholar
Weiss, L.A., Shen, Y., Korn, J.M., Arking, D.E., Miller, D.T., Fossdal, R., Saemundsen, E., Stefansson, H., Ferreira, M.A., Green, T., Platt, O.S., Ruderfer, D.M., Walsh, C.A., Altshuler, D., Chakravarti, A., Tanzi, R.E., Stefansson, K., Santangelo, S.L., Gusella, J.F., Sklar, P., Wu, B.L. & Daly, M.J. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine 358, 667–675.Google Scholar
Williams, N.M., O'Donovan, M.C. & Owen, M.J. (2005). Is the dysbindin gene (DTNBP1) a susceptibility gene for schizophrenia? Schizophrenia Bulletin 31, 800–805.Google Scholar
Wong, M.Y., Day, N.E., Luan, J.A., Chan, K.P. & Wareham, N.J. (2003). The detection of gene-environment interaction for continuous traits: should we deal with measurement error by bigger studies or better measurement? International Journal of Epidemiology 32, 51–57.Google Scholar
Zammit, S., Allebeck, P., Dalman, C., Lundberg, I., Hemmingson, T., Owen, M.J. & Lewis, G. (2003). Paternal age and risk for schizophrenia. British Journal of Psychiatry 183, 405–408.CrossRefGoogle ScholarPubMed