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Deconstructing a complex disease?

The overview of the evidence suggests that phenotypic variability has been confounding the search for the causes of schizophrenia since the inception of the diagnostic category. Attempts at redefining its boundaries by either 'lumping' or 'splitting' strategies²⁴ have been undertaken over decades, with limited success. Most such attempts, based on various rearrangements of clinical symptoms and syndromes have ended in a failure to find natural boundaries between proposed clinical subtypes, either by locating a 'zone of rarity' between them, or by demonstrating a nonlinear relationship between the symptom profiles and a validating variable, such as outcome or heritability.⁵¹ The inconsistent and poorly replicated results of genetic linkage and association studies using the diagnostic category as the sole schizophrenia phenotype are kindling discontent with the current nosology of schizophrenia, based on the recognition that 'current nosology, now embedded in DSM-IV, although useful for other purposes, does not define phenotypes for genetic study'.¹⁹⁴ It is now almost certain that the current broad diagnostic concept of schizophrenia does not demarcate a specific genetic entity.

Schizophrenia geneticists are facing a particularly difficult situation, seeking to discover specific genes contributing to an overinclusive diagnostic category for which no specific biological substrate has yet been identified – most likely due to extensive genetic heterogeneity and an admixture of different underlying disease subtypes. Many 'top-down' attempts have been made to define an overarching disturbance in schizophrenia, sought in 'a weakening of the mainsprings of volition' and 'loss of inner unity of mental activities';¹ 'structural loosening of associations';⁴⁵^,³⁰⁵ 'intrapsychic ataxia';³⁰⁶ 'neurointegrative defect';³⁰⁷ 'cognitive dysmetria';³⁰⁸ and 'dysconnection disorder'.³⁰⁹^,³¹⁰ Although intuitively appealing, such formulations achieve little more than highlighting one or another of the many facets of a complex syndrome. It is doubtful that a specific genetic basis for a causa prima explaining the phenomenology of schizophrenia will ever be found. In contrast, it appears almost certain that the genetic polymorphisms and neurobiological deficits underlying schizophrenia are multiple, varied, and partly shared with predisposition to other disorders, although they primarily express a 'common final pathway' within the schizophrenia spectrum. Such polymorphisms and deficits need not be intrinsically pathological and may represent extreme variants of normal structure and function. Above a certain density threshold, their additive or nonlinear interaction could give rise to the diagnostic symptoms in probands, but subclinical manifestations as endophenotype traits will be detectable in otherwise healthy people, with a higher relative risk in biological relatives of probands.

While reasoning along such lines is increasingly common among researchers, the approaches proposed to deal with the phenotype bottleneck in schizophrenia research differ substantially. On one hand, there are proposals to abandon the 'Kraepelinian dichotomy' of schizophrenic and affective disorders in favour of a 'psychosis-spectrum illness'⁹^,³¹¹ or a 'shift from narrow phenotypes to broad endophenotypes', associated with an even broader spectrum of abnormal behaviours and emotions.³¹² On the other hand, there is an emerging 'splitting' agenda seeking and testing narrowly constrained phenotypes that may tag distinct variants or subtypes of schizophrenia,³¹³ resolving at least part of its aetiological heterogeneity. 'Candidate' endophenotypes or markers of pathogenetic processes affecting cognition, brain morphology and neurophysiology constitute the mainstay of this approach. Several genetic linkage and association studies employing such endophenotypes have produced promising results¹⁷⁵^,¹⁷⁶^,¹⁷⁹^,¹⁸⁰^,¹⁹¹^,¹⁹²^,²⁴³^,³⁰²^,³¹⁴ that set a high priority for replication.

In the absence of direct evidence that schizophrenia is either a homogeneous multifactorial disease or an amalgamation of aetiologically distinct component disorders, both 'lumping' and 'splitting' strategies are legitimate and should be put to the test. The question is, which approach holds at present greater promise for advancing schizophrenia genetics? Two arguments reinforce doubts that greater power for genetic studies would be achieved by redefining the clinical boundaries of the phenotype. First, lumping different disorders into an expanding phenotype of 'psychosis' runs against the grain of a large body of clinical research indicating that psychotic symptoms in the context of schizophrenia, other nonaffective psychotic illnesses, and affective disorders are phenomenologically different³¹⁵ and may be influenced by different genetic mechanisms, notwithstanding partial overlap in their effects. This would increase, rather than decrease, heterogeneity. Secondly, despite the availability of diagnostic criteria for research and structured diagnostic instruments, misclassification error in the fine-grain assessment of symptoms is likely to remain a factor compounding further the heterogeneity of family or case–control samples collected at different sites and at different times. Such heterogeneity is likely to be a serious problem in whole-genome association studies, which require very large case-control samples, feasible only by pooling data collections from multiple sites. In contrast, subtyping strategies are supported by mounting evidence that sample stratification, particularly using quantitative traits as covariates, can reduce heterogeneity and substantially increase power.³¹⁶^,³¹⁷^,³¹⁸^,³¹⁹^,³²⁰^,³²¹ This approach has scored successes in the genetics of other complex diseases and its application to schizophrenia genetics will bring the disorder into the mainstream of current research into the common genetic diseases.

What kind of data would constitute supportive evidence for distinct component disorders or subtypes within schizophrenia? Converging evidence from endophenotype-based studies suggests that measures of neurocognitive dysfunction arguably provide the largest effect sizes and increases in relative risk to relatives among a host of 'candidate' endophenotypes,²³⁶^,²³⁷^,²⁴¹^,²⁸¹^,²⁹⁴^,²⁹⁵ being also cost efficient for phenotyping large samples. In particular, several characteristic patterns of short-term and working memory impairment against a background of generalized cognitive deficit have been replicated across studies and are present in a substantial proportion ( 50%) of schizophrenia patients. As many of neurocognitive tests tap into several component processes, composite endophenotypes, integrating multiple neurocognitive measures, are more likely to capture variation that is genetically influenced than single-feature endophenotypes. The subtypes generated by such approaches should be capable of classifying individuals, rather than variables, and the resulting classification is likely to be polythetic (based on subsets of correlated features, rather than on the presence of all defining attributes). Whether subtypes are discrete taxa, that is, identifiable by marked areas of discontinuity with other subtypes; dimensional, representing continua with fuzzy boundaries; or hybrid (class-quantitative, with dimensions superimposed on discrete categories), is testable with taxometric methods common in biological classifications.³²³^,³²⁴ In the context of genetic research, the most significant criterion of their validity will be the gain in predictive power and 'process understanding'³²⁵ in the sense of mechanistic explanation of disease phenomena.

To sum up, we do not know whether schizophrenia is a single process with pleiotropic manifestations at the level of cerebral organization, or a collection of aetiologically unrelated but dynamically interacting processes. Although there are good grounds for the suspicion that schizophrenia is not a homogeneous entity, this has never been directly demonstrated, mainly because few studies of the appropriate kind have ever been undertaken. Its manifestations in toto do not fit neatly into the proposed disease models, although reasoning by analogy suggests an affinity to other complex multifactorial diseases, such as cancer, ischemic heart disease, or diabetes. For the time being, the clinical concept of schizophrenia is supported by empirical evidence that its multiple facets form a broad syndrome with some internal cohesion and a characteristic evolution over time. The dissection of the syndrome into modular endophenotypes with specific neurocognitive or neurophysiological underpinnings is beginning to be perceived as a promising approach in schizophrenia genetics. The current evidence is neither final nor static, and needs to be re-examined as new concepts and technologies coming from molecular genetics, cognitive science, or brain imaging bring forth new perspectives on disease causation and brain function. This must be complemented by a refined, reliable, and valid phenotyping not only at the level of symptoms, but involving correlated neurobiological features. The study of endophenotypes cutting across the conventional diagnostic boundaries may reveal unexpected patterns of associations with symptoms, personality traits, or behaviour. The mapping of clinical phenomenology on specific brain dysfunction (and vice versa) is becoming feasible and the resulting functional psychopathology³²²^,³²⁶ may in the future substantially recast the present nosology.

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References

Kraepelin E. Psychiatrie. 8 Auflage. Barth: Leipzig, 1909. [Reprinted English translation: Dementia Praecox and Paraphrenia. Krieger Publishing: Huntington, New York, 1971].

World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research. WHO: Geneva, 1993.

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

Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 2004; 10: 40–68. | Article | ChemPort |

Norton N, Williams HJ, Owen MJ. An update on the genetics of schizophrenia. Curr Opin Psychiatry 2006; 19: 158–164. | Article |

Bentall RP, Jackson HF, Pilgrim D. Abandoning the concept of 'schizophrenia': some implications of validity arguments for psychological research into psychotic phenomena. Br J Clin Psychol 1988; 27: 303–324.

Boyle M. Schizophrenia. A Scientific Delusion?. Routledge: London and New York, 1990.

Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–366. | Article | PubMed | ISI |

Jablensky A. Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci 2000; 250: 274–285. | Article | PubMed | ChemPort |

Jablensky A. The epidemiological horizon. In: Hirsch SR, Weinberger DR (eds). Schizophrenia, 2nd edn. Blackwell Publishing: Massachusetts, USA, 2003, pp. 203–231.

Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE et al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Nonogr Suppl 1992; 20: 1–97. | ChemPort |

DeLisi LE, Nasrallah HA. Current controversies in schizophrenia research. I. Is schizophrenia a heterogeneous disorder? Schizophr Res 1995; 17: 133. | Article |

Goldberg TE, Weinberger DR. A case against subtyping in schizophrenia. Schizophr Res 1995; 17: 147–152. | Article | ChemPort |

Cardno AG, Farmer AE. The case for or against heterogeneity in the etiology of schizophrenia. The genetic evidence. Schizophr Res 1995; 17: 153–159. | Article | ChemPort |

Heinrichs RW. Meta-analysis and the science of schizophrenia: variant evidence or evidence of variants? Neurosci Biobehav Rev 2004; 28: 379–394. | Article |

Ghosh S, Watanabe RM, Valle TT, Hauser ER, Magnuson VL, Langefeld CD et al. The Finland-United States Investigation of Non-Insulin-Dependent Diabetes Mellitus Genetics (FUSION) Study. I. An autosomal genome scan for genes that predispose to Type 2 diabetes. Am J Hum Genet 2000; 67: 1174–1185. | PubMed | ISI | ChemPort |

Laitinen T, Daly MJ, Rioux JD, Kauppi P, Laprise C, Petäys T et al. A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat Genet 2001; 28: 87–91 (letter). | Article | PubMed | ISI | ChemPort |

Shao Y, Cuccaro ML, Hauser ER, Raiford KL, Menold MM, Wolpert CM et al. Fine mapping of autistic disorder to chromosome 15q11–q13 by use of phenotypic subtypes. Am J Hum Genet 2003; 72: 539–548. | Article | PubMed | ISI | ChemPort |

Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small GW, Roses AD et al. Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. Am J Hum Genet 2003; 73: 1041–1051. | Article | PubMed | ISI | ChemPort |

McKusick VA. On lumpers and splitters, or the nosology of genetic disease. Perspect Biol Med 1969; Winter: 298–312.

Smith CAB. Testing for heterogeneity of recombinant values in human genetics. Ann Hum Genet 1963; 27: 175–182. | PubMed | ISI | ChemPort |

Risch N. A new statistical test for linkage heterogeneity. Am J Hum Genet 1988; 42: 353–364. | PubMed | ChemPort |

Duerr RH. The genetics of inflammatory bowel disease. Gastroenterol Clin North Am 2002; 31: 63–76. | Article |

Miterski B, Drynda S, Boschow G, Klein W, Oppermann J, Kekow J et al. Complex genetic predisposition in adult and juvenile rheumatoid arthritis. BMC Genet 2004; 5: 2. | Article | PubMed |

Shen H, Liu Y, Liu P, Recker RR, Deng HW. Nonreplication in genetic studies of complex diseases – lessons learned from studies of osteoporosis and tentative remedies. J Bone Miner Res 2005; 20: 365–376. | Article | ChemPort |

Ammar N, Nelis E, Merlini L, Barisic N, Amouri R, Ceuterick C et al. Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease. Neuromuscul Disord 2003; 13: 720–728. | Article |

Stojkovic T, Latour P, Viet G, de Seze J, Hurtevent JF, Vandenberghe A et al. Vocal cord and diaphragm paralysis, as clinical features of a French family with autosomal recessive Charcot-Marie-Tooth disease, associated with a new mutation in the GDAP1 gene. Neuromuscul Disord 2004; 14: 261–264. | Article |

Cohn JA, Neoptolemos JP, Feng J, Yan J, Jiang Z, Greenhalf W et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat 2005; 26: 303–307. | Article | ChemPort |

Larriba S, Bonache S, Sarquella J, Ramos MD, Gimenez J, Bassas L et al. Molecular evaluation of CFTR sequence variants in male infertility of testicular origin. Int J Androl 2005; 28: 284–290. | Article | ChemPort |

Chesler EJ, Lu L, Shou S, Qu Y, Gu J, Wang J et al. Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 2005; 37: 233–242. | Article | PubMed | ISI | ChemPort |

Zubenko GS. Do susceptibility loci contribute to the expression of more than one mental disorder? A view from the genetics of Alzheimer's disease. Mol Psychiatry 2000; 5: 131–136. | Article | PubMed | ChemPort |

Holliday E, Mowry B, Chant D, Nyholt D. The importance of modelling heterogeneity in complex disease: application to NIMH schizophrenia genetics initiative data. Hum Genet 2005; 117: 160–167. | Article | PubMed |

Gottesman II, Bertelsen A. Confirming unexpressed genotypes for schizophrenia. Risks in the offspring of Fischer's Danish identical and fraternal discordant twins. Arch Gen Psychiatry 1989; 46: 867–872. | PubMed | ISI | ChemPort |

Bearden CE, Reus VI, Freimer NB. Why genetic investigation of psychiatric disorders is so difficult. Curr Opin Genet Dev 2004; 14: 280–286. | Article | ChemPort |

Tsuang MT, Lyons MJ, Faraone SV. Heterogeneity of schizophrenia. Conceptual models and analytic strategies. Br J Psychiatry 1990; 156: 17–26. | PubMed | ChemPort |

Gibbons RD, Dorus E, Ostrow DG, Pandey GN, Davis JM, Levy DL. Mixture distributions in psychiatric research. Biol Psychiatry 1984; 19: 935–961. | ChemPort |

Moldin SO, Rice JP, Gottesman II, Erlenmeyer-Kimling L. Psychometric deviance in offspring at risk for schizophrenia: II. Resolving heterogeneity through admixture analysis. Psychiatry Res 1990; 32: 311–322. | Article | ChemPort |

Bleuler E. Lehrbuch der Psychiatrie. Springer Verlag: Berlin, 1920 [Reprinted English translation: Textbook of Psychiatry. Arno Press: New York, 1976.].

Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R. Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 1972; 26: 57–63. | PubMed | ChemPort |

Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait. Evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60: 1187–1192. | Article | PubMed | ISI |

Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48. | Article | PubMed | ISI | ChemPort |

Wittgenstein L. Philosophische Bemerkunen II Band. Springer Verlag: Vienna, 1964.

Kendell R, Jablensky A. Distinguishing between the validity and utility of psychiatric diagnoses. Am J Psychiatry 2003; 160: 4–12. | Article | PubMed | ISI |

Stassen HH, Scharfetter C, Winokur G, Angst J. Familial syndrome patterns in schizophrenia, schizoaffective disorder, mania, and depression. Eur Arch Psychiatry Clin Neurosci 1988; 237: 115–123. | ChemPort |

Bebbington P. Recent findings in bipolar affective disorder. Psychol Med 2004; 34: 767–776. | Article |

Keefe RSE, Frescka E, Apter SH, Davidson M, Macaluso JM, Hirschowitz J et al. Clinical characteristics of Kraepelinian schizophrenia: replication and extension of previous findings. Am J Psychiatry 1996; 153: 806–811. | ChemPort |

Bralet M-C, Loas G, Yon V, Maréchal V. Clinical characteristics and risk factors for Kraepelinian subtype of schizophrenia: replication of previous findings and relation to summer birth. Psychiatry Res 2002; 111: 147–154. | Article |

Roy M-A, Lehoux C, Émond C, Laplante L, Bouchard R-H, Everett J et al. A pilot neuropsychological study of Kraepelinian and non-Kraepelinian schizophrenia. Schizophr Res 2003; 62: 155–163. | Article |

Kasanin J. The acute schizoaffective psychosis. Am J Psychiatry 1933; 90: 97–126.

Langfeld G. The prognosis of schizophrenia. Acta Psychiatria Neurologica Scandinavica (Suppl 110). Munksgaard: Copenhagen, 1956.

Stephens JH, Astrup C. Prognosis in 'process' and 'non-process' schizophrenia. Am J Psychiatry 1963; 119: 945–953.

Tsuang MT, Winokur G. Criteria for subtyping schizophrenia. Arch Gen Psychiatry 1974; 31: 43–47. | PubMed | ChemPort |

Schneider K. Klinische Psychopathologie, 8th edn. Thieme: Stuttgart, 1950 [English translation Hamilton MW, Anderson EW: Clinical Psychopathology. Grune and Stratton: New York, 1959.].

Spitzer RL, Endicott J, Robins E. Research diagnostic criteria. Rationale and reliability. Arch Gen Psychiatry 1978; 35: 773–782. | PubMed | ISI | ChemPort |

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. American Psychiatric Association: Washington, DC, 1980.

Wing JK, Cooper JE, Sartorius N. Measurement and Classification of Psychiatric Symptoms. An Instruction Manual for the PSE and CATEGO Program. Cambridge University Press: London, England, 1974.

Loftus J, DeLisi LE, Crow TJ. Factor structure and familiality of first-rank symptoms in sibling pairs with schizophrenia and schizoaffective disorder. Br J Psychiatry 2000; 177: 15–19. | Article | PubMed | ChemPort |

Cardno AG, Sham PC, Farmer AE, Murray RM, McGuffin P. Heritability of Schneider's first-rank symptoms. Br J Psychiatry 2002; 180: 35–38. | Article | PubMed |

Kendler KS, Myers JM, O'Neill FA, Martin R, Murphy B, MacLean CJ, et al. Clinical features of schizophrenia and linkage to chromosomes 5q, 6p, 8p, and 10p in the Irish Study of High-Density Schizophrenia Families. Am J Psychiatry 2000; 157: 402–408. | Article | PubMed | ChemPort |

Leonhard K. Classification of Endogenous Psychoses and their Differentiated Etiology, 2nd edn. Springer Verlag: Vienna, New York, 1999.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rd edn, Revised. American Psychiatric Association: Washington, DC, 1987.

Franzek E, Beckmann H. Different genetic background of schizophrenia spectrum psychoses: a twin study. Am J Psychiatry 1998; 155: 76–83. | ChemPort |

Beckmann H, Franzek E, Stöber G. Genetic heterogeneity in catatonic schizophrenia: a family study. Am J Med Genet Neuropsychiatry Genet 1996; 67: 289–300. | Article | ChemPort |

Stöber G, Saar K, Rüschendorf F, Meyer J, Nürnberg G, Jatzke S et al. Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15. Am J Hum Genet 2000; 67: 1201–1207. | PubMed | ChemPort |

Stöber G, Seelow D, Rüschendorf F, Ekici A, Beckmann H, Reis A. Periodic catatonia: confirmation of linkage to chromosome 15 and further evidence for genetic heterogeneity. Hum Genet 2002; 111: 323–330. | Article | PubMed |

Meyer J, Ortega G, Schraut K, Nürnberg G, Rüschendorf F, Saar K et al. Exclusion of the neuronal nicotinic acetylcholine receptor alpha7 subunit gene as a candidate for catatonic schizophrenia in a large family supporting the chromosome 15q13–22 locus. Mol Psychiatry 2002; 7: 220–223. | Article | ChemPort |

Kury S, Rubie C, Moisan JP, Stöber G. Mutation analysis of the zinc transporter gene SLC30A4 reveals no association with periodic catatonia on chromosome 15q15. J Neural Transm 2003; 110: 1329–1332. | Article | ChemPort |

McKeane DP, Meyer J, Dobrin SE, Melmed KM, Ekawardhani S, Tracy NA et al. No causative DLL4 mutations in periodic catatonia patients from 15q15 linked families. Schizophr Res 2005; 75: 1–3. | Article | ChemPort |

Meyer J, Huberth A, Ortega G, Syagailo YV, Jatzke S, Mössner R et al. A missense mutation in a novel gene encoding a putative cation channel is associated with catatonic schizophrenia in a large pedigree. Mol Psychiatry 2001; 6: 302–306. | Article | PubMed | ChemPort |

Devaney JM, Donarum EA, Brown KM, Meyer J, Stöber G, Lesch KP et al. No missense mutation of WKL1 in a subgroup of probands with schizophrenia. Mol Psychiatry 2002; 7: 419–423. | Article | ChemPort |

Rüdin E. Studien über Vererbung und Enstehung geistiger Störungen, I: Zur Vererbung und Neuenstehung der Dementia praecox (Studies on the inheritance and origin of mental Illness, I: The problem of the inheritance and primary origin of Dementia praecox). Monographien aus dem Gesamtgebeit der Neurologie und Psychiatrie, No. 12. Springer Verlag: Berlin, 1916.

Kallman FJ. The Genetics of Schizophrenia. Augustin: New York, 1938.

Kendler KS, Gruenberg AM. An independent analysis of the Danish Adoption Study of Schizophrenia. VI. The relationship between psychiatric disorders as defined by DSM-III in the relatives and adoptees. Arch Gen Psychiatry 1984; 41: 555–564. | ChemPort |

Baron M, Risch N. The spectrum concept of schizophrenia: evidence for a genetic-environmental continuum. J Psychiatry Res 1987; 21: 257–267. | Article | ChemPort |

Rado S. Theory and therapy: the theory of schizotypal organization and its application to the treatment of decompensated schizotypal behaviour. In: Scher SC, Davis HR (eds) The Outpatient Treatment of Schizophrenia. Grune and Stratton: New York, 1960.

Meehl PE. Schizotaxia, schizotypy, schizophrenia. American Psychologist 1962; 17: 827–838 [Reprinted in Meehl PE. Psychodiagnosis: selected papers. University of Minnesota Press: Minneapolis, 1973, pp 135–155.]. | Article |

Chapman LJ, Chapman JP. Scales for rating psychotic and psychotic-like experiences as continua. Schizophr Bull 1980; 6: 476–489.

Kety SS, Wender PH, Jacobsen B, Ingraham LJ, Jansson L, Faber B. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Arch Gen Psychiatry 1994; 51: 442–455. | PubMed | ISI | ChemPort |

Kendler KS, Neale MC, Walsh D. Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study. Am J Psychiatry 1995; 152: 749–754. | PubMed | ChemPort |

Tienari P, Wynne LC, Läksy K, Moring J, Nieminen P, Sorri A et al. Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish Adoptive Family Study of Schizophrenia. Am J Psychiatry 2003; 160: 1587–1594. | Article |

Fogelson DL, Nuechterlein KH, Asarnow RF, Payne DL, Subotnik KL, Giannini CA. The factor structure of schizophrenia spectrum personality disorders: signs and symptoms in relatives of psychotic patients from the UCLA family members study. Psychiatry Res 1999; 87: 137–146. | Article |

Fosatti A, Maffei C, Battaglia M, Bagnato M, Donati D, Donini M et al. Latent class analysis of DSM-IV schizotypal personality disorder criteria in psychiatric patients. Schizophr Bull 2001; 27: 59–71.

Suhr JA, Spitznagel MB. Factor versus cluster models of schizotypal traits. I. A comparison of unselected and highly schizotypal samples. Schizophr Res 2001; 52: 231–239. | Article | ChemPort |

Kendler KS, McGuire M, Gruenberg AM, Walsh D. Schizotypal symptoms and signs in the Roscommon Family Study. Arch Gen Psychiatry 1995; 52: 296–303. | ChemPort |

Torgersen S, Onstad S, Skre I, Edvardsen J, Kringlen E. 'True' schizotypal personality disorder: a study of co-twins and relatives of schizophrenic probands. Am J Psychiatry 1993; 150: 1661–1667. | ChemPort |

Fanous A, Gardner C, Walsh D, Kendler KS. Relationship between positive and negative symptoms of schizophrenia and schizotypal symptoms in nonpsychotic relatives. Arch Gen Psychiatry 2001; 58: 669–673. | Article | PubMed | ChemPort |

Cadenhead KS, Perry W, Shafer K, Braff DL. Cognitive functions in schizotypal personality disorder. Schizophr Res 1999; 37: 123–132. | Article | PubMed | ChemPort |

Nuechterlein KH, Asarnow RF, Subotnik KL, Fogelson DL, Payne DL, Kendler KS et al. The structure of schizotypy: relationships between neurocognitive and personality disorder features in relatives of schizophrenic patients in the UCLA Family Study. Schizophr Res 2002; 54: 121–130. | Article |

Asarnow RF, Nuechterlein KH, Asamen J, Fogelson D, Subotnik KL, Zaucha K et al. Neurocognitive functioning and schizophrenia spectrum disorders can be independent expressions of familial liability for schizophrenia in community control children: the UCLA Family Study. Schizophr Res 2002; 54: 111–120. | Article |

Dickey CD, McCarley RW, Shenton ME. The brain in schizotypal personality disorder: a review of structural MRI and CT findings. Harv Rev Psychiatry 2002; 10: 1–15. | Article |

Strauss JS, Carpenter Jr WT, Bartko JJ. The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull 1974; Winter: 61–69.

Crow TJ. Molecular pathology of schizophrenia: more than one disease process? BMJ 1980; 280: 66–68. | ChemPort |

Andreasen NC, Olsen S. Negative v positive schizophrenia. Definition and validation. Arch Gen Psychiatry 1982; 39: 789–794. | PubMed | ChemPort |

Crow TJ. The two-syndrome concept: origins and current status. Schizophr Bull 1985; 11: 471–486. | ChemPort |

Berrios GE. Positive and negative symptoms and Jackson. A conceptual history. Arch Gen Psychiatry 1985; 42: 95–97. | ChemPort |

Sommers AA. 'Negative symptoms': conceptual and methodological problems. Schizophr Bull 1985; 11: 364–379. | ChemPort |

Tandon R, Greden JF. Negative symptoms of schizophrenia: the need for conceptual clarity. Biol Psychiatry 1991; 30: 321–325. | Article | ChemPort |

Peralta V, Cuesta MJ, De Leon J. Positive and negative symptoms/syndromes in schizophrenia: reliability and validity of different diagnostic systems. Psychol Med 1995; 25: 43–50. | ChemPort |

Jablensky A. Symptoms of schizophrenia. In: Henn F, Sartorius N, Helmchen H, Lauter H (eds). Contemporary Psychiatry. Vol 3. Specific Psychiatric Disorders. Springer Verlag: Berlin, 2001, pp. 3–36.

Carpenter Jr WT, Heinrichs DW, Wagman AMI. Deficit and non-deficit forms of schizophrenia: the concept. Am J Psychiatry 1988; 145: 578–583. | PubMed | ISI |

Kirkpatrick B, Buchanan RW, Breier A, Carpenter Jr WT. Case identification and stability of the deficit syndrome of schizophrenia. Psychiatry Res 1993; 47: 47–56. | Article | ChemPort |

Kirkpatrick B, Ross DE, Walsh D, Karkowski L, Kendler KS. Family characteristics of deficit and nondeficit schizophrenia in the Roscommon family study. Schizophr Res 2000; 45: 57–64. | Article | PubMed | ChemPort |

Buchanan RW, Strauss ME, Kirkpatrick B, Holstein C, Breier A, Carpenter Jr WT. Neuropsychological impairments in deficit vs nondeficit forms of schizophrenia. Arch Gen Psychiatry 1994; 51: 804–811. | ChemPort |

Buchanan RW, Strauss ME, Breier A, Kirkpatrick B, Carpenter Jr WT. Attentional impairments in deficit and nondeficit forms of schizophrenia. Am J Psychiatry 1997; 154: 363–370. | PubMed | ChemPort |

Addington J, Addington D, Maticka-Tyndale E. Cognitive functioning and positive and negative symptoms in schizophrenia. Schizophr Res 1991; 5: 123–134. | Article | PubMed | ChemPort |

Ross DE. The deficit syndrome and eye tracking disorder may reflect a distinct subtype within the syndrome of schizophrenia. Schizophr Bull 2000; 26: 855–866. | PubMed | ChemPort |

Nkam I, Thibaut F, Denise P, Van Der Elst A, Ségard L, Brazo P et al. Saccadic and smooth-pursuit eye movements in deficit and non-deficit schizophrenia. Schizophr Res 2001; 48: 145–153. | Article | ChemPort |

Hong LE, Avila MT, Adami H, Elliot A, Thaker GK. Components of the smooth pursuit function in deficit and nondeficit schizophrenia. Schizophr Res 2003; 63: 39–48. | Article |

Arango C, Kirkpatrick B, Buchanan RW. Neurological signs and the heterogeneity of schizophrenia. Am J Psychiatry 2000; 157: 560–565. | Article | ChemPort |

Galderisi S, Maj M, Mucci A, Cassano GB, Invernizzi G, Rossi A et al. Historical, psychopathological, neurological, and neuropsychological aspects of deficit schizophrenia: a multicenter study. Am J Psychiatry 2002; 159: 983–990. | Article |

Blanchard JJ, Horan WP, Collins LM. Examining the latent structure of negative symptoms: is there a distinct subtype of negative symptom schizophrenia? Schizophr Res 2005; 77: 151–165. | Article |

Bakker SC, Hoogendoorn MLC, Selten J-P, Verduijn W, Pearson PL, Sinke RJ et al. Neuregulin 1: genetic support for schizophrenia subtypes. Mol Psychiatry 2004; 9: 1061–1063 (letter). | Article | PubMed | ISI | ChemPort |

Hong LE, Wonodi I, Avila MT, Buchanan RW, McMahon RP, Mitchell BD et al. Dihydropyrimidinase-related protein 2 (DRP-2) gene and association to deficit and nondeficit schizophrenia. Am J Med Genet B Neuropsychiatry Genet 2005; 136B: 8–11. | Article |

Lorr M, Klett CJ, McNair DM. Syndromes of Psychosis. Pergamon: New York, 1963.

Liddle PF. The symptoms of chronic schizophrenia. A re-examination of the positive-negative dichotomy. Br J Psychiatry 1987; 151: 145–151. | PubMed | ChemPort |

Johnstone EC, Frith CD. Validation of three dimensions of schizophrenic symptoms in a large unselected sample of patients. Psychol Med 1996; 26: 669–679. | ChemPort |

Grube BS, Bilder RM, Goldman RS. Meta-analysis of symptom factors in schizophrenia. Schizophr Res 1998; 31: 113–120. | Article | ChemPort |

Smith DA, Mar CM, Turoff BK. The structure of schizophrenic symptoms: a meta-analytic confirmatory factor analysis. Schizophr Res 1998; 31: 57–70. | Article | ChemPort |

Arndt S, Andreasen NC, Flaum M, Miller D, Nopoulos P. A longitudinal study of symptom dimensions in schizophrenia. Prediction and patterns of change. Arch Gen Psychiatry 1995; 52: 352–360. | PubMed | ChemPort |

Gureje O, Aderibigbe YA, Obikoya O. Three syndromes in schizophrenia: validity in young patients with recent onset of illness. Psychol Med 1995; 25: 715–725. | ChemPort |

Emsley RA, Niehaus DJH, Mbanga NI, Oosthuizen PP, Stein DJ, Maritz JS et al. The factor structure for positive and negative symptoms in South African Xhosa patients with schizophrenia. Schizophr Res 2001; 47: 149–157. | Article | ChemPort |

Ratakonda S, Gorman JM, Yale SA, Amador XF. Characterization of psychotic conditions. Use of the domains of psychopathology model. Arch Gen Psychiatry 1998; 55: 75–81. | Article | PubMed | ChemPort |

Kay SR, Fizbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276. | PubMed | ISI | ChemPort |

Overall JE, Gorham DR. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacol Bull 1988; 24: 97–99.

McGuffin P, Farmer AE, Harvey IH. A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Arch Gen Psychiatry 1991a; 48: 764–770. | PubMed | ISI | ChemPort |

Rey E-R, Bailer J, Bräuer W, Händel M, Laubenstein D, Stein A. Stability trends and longitudinal correlations of negative and positive syndromes within a three-year follow-up of initially hospitalized schizophrenics. Acta Psychiatry Scand 1994; 90: 405–412. | ChemPort |

Lindenmayer J-P, Grochowski S, Hyman RB. Five factor model of schizophrenia: replication across samples. Schizophr Res 1995; 14: 229–234. | Article | ChemPort |

Serretti A, Rietschel M, Lattauda E, Krauss H, Schulze TG, Müller DJ et al. Major psychoses symptomatology: factor analysis of 2241 psychotic subjects. Eur Arch Psychiatry Clin Neurosci 2001; 251: 193–198. | Article | ChemPort |

Cardno AG, Jones LA, Murphy KC, Asherson P, Scott LC, Williams J et al. Factor analysis of schizophrenic symptoms using the OPCRIT checklist. Schizophr Res 1996; 22: 233–239. | Article | PubMed | ChemPort |

Lenzenweger MF, Dworkin RH. The dimensions of schizophrenia phenomenology. Not one or two, at least three, perhaps four. Br J Psychiatry 1996; 168: 432–440. | ChemPort |

White L, Harvey PD, Opler L, Lindenmayer JP, The PANSS Study Group. Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. Psychopathology 1997; 30: 263–274. | PubMed | ChemPort |

McGrath JA, Nestadt G, Liang KY, Lasseter VK, Wolyniec PS, Fallin MD et al. Five latent factors underlying schizophrenia: analysis and relationship to illnesses in relatives. Schizophr Bull 2004; 30: 855–873.

Cuesta MJ, Peralta V. Integrating psychopathological dimensions in functional psychoses: a hierarchical approach. Schizophr Res 2001; 52: 215–229. | Article | ChemPort |

Farmer AE, McGuffin P, Spitznagel EL. Heterogeneity in schizophrenia: a cluster-analytic approach. Psychiatry Res 1983; 8: 1–12. | Article | ChemPort |

Dollfus S, Everitt B, Ribeyre JM, Assouly-Besse F, Sharp C, Petit M. Identifying subtypes of schizophrenia by cluster analyses. Schizophr Bull 1996; 22: 545–555. | ChemPort |

McCutcheon AL. Latent Class Analysis. Sage Publications: Beverly Hills, California, 1987.

Sham PC, Castle DJ, Wessely S, Farmer AE, Murray RM. Further exploration of a latent class typology of schizophrenia. Schizophr Res 1996; 20: 105–115. | Article | ChemPort |

Murray V, McKee I, Miller PM, Young D, Muir WJ, Pelosi AJ et al. Dimensions and classes of psychosis in a population cohort: a four-class, four-dimension model of schizophrenia and affective psychoses. Psychol Med 2005; 35: 499–510. | Article | ChemPort |

Woodbury MA, Clive J, Garson A. Mathematical typology: a grade of membership technique for obtaining disease definition. Comput Biomed Res 1978; 11: 277–298. | Article | ChemPort |

Manton KG, Woodbury MA, Tolley DH. Statistical Applications Using Fuzzy Sets. John Wiley: New York, 1994.

Manton KG, Korten A, Woodbury MA, Anker M, Jablensky A. Symptom profiles of psychiatric disorders based on graded disease classes: an illustration using data from the WHO International Pilot Study of Schizophrenia. Psychol Med 1994; 24: 133–144. | PubMed | ISI | ChemPort |

Lewis SW, Reveley AM, Reveley MA, Chitkara B, Murray RM. The familial/sporadic distinction as a strategy in schizophrenia research. Br J Psychiatry 1987; 151: 306–313. | ChemPort |

Kendler KS, Hayes P. Familial and sporadic schizophrenia: a symptomatic, prognostic, and EEG comparison. Am J Psychiatry 1982; 139: 1557–1562. | ChemPort |

Gottesman II, McGuffin P, Farmer AE. Clinical genetics as clues to the 'real' genetics of schizophrenia (A decade of modest gains while playing for time). Schizophr Bull 1987; 13: 23–47. | ChemPort |

Lyons MJ, Kremen WS, Tsuang MT, Faraone SV. Investigating putative genetic and environmental forms of schizophrenia: methods and findings. Int Rev Psychiatr 1989; 1: 259–276.

Roy M-A, Crowe RR. Validity of the familial and sporadic subtypes of schizophrenia. Am J Psychiatry 1994; 151: 805–814. | ChemPort |

Gorwood P, Leboyer M, Jay M, Payan C, Feingold J. Gender and age at onset in schizophrenia: impact of family history. Am J Psychiatry 1995; 152: 208–212. | ChemPort |

Alda M, Ahrens B, Lit W, Dvorakova M, Labelle A, Zvolsky P et al. Age at onset in familial and sporadic schizophrenia. Acta Psychiatry Scand 1996; 93: 447–450. | ChemPort |

Roy M-A, Flaum MA, Gupta S, Jaramillo L, Andreasen NC. Epidemiological and clinical correlates of familial and sporadic schizophrenia. Acta Psychiatry Scand 1994; 89: 324–328. | ChemPort |

Lewis SW, Murray RM. Obstetric complications, neurodevelopmental deviance, and risk of schizophrenia. J Psychiatry Res 1987; 21: 413–421. | Article | ChemPort |

Schwarzkopf SB, Nasrallah HA, Olson SC. Perinatal complications and genetic loading in schizophrenia: preliminary findings. Psychiatry Res 1989; 27: 233–239. | Article | ChemPort |

O'Callaghan E, Larkin C, Kinsella A, Waddington JL. Obstetric complications, the putative familial-sporadic distinction, and tardive dyskinesia in schizophrenia. Br J Psychiatry 1990; 157: 578–584. | PubMed | ChemPort |

Shur E. Season of birth in high and low genetic risk schizophrenics. Br J Psychiatry 1982; 140: 410–415. | ChemPort |

O'Callaghan E, Gibson T, Colohan HA, Walshe D, Buckley P, Larkin C et al. Season of birth in schizophrenia: evidence for confinement of an excess of winter births to patients without a family history of mental disorder. Br J Psychiatry 1991; 158: 764–769. | ChemPort |

Reveley AM, Reveley MA, Murray RM. Cerebral ventricular enlargement in non-genetic schizophrenia: a controlled twin study. Br J Psychiatry 1984; 144: 89–93. | ChemPort |

Schwarzkopf SB, Nasrallah HA, Olson SC, Bogerts B, McLaughlin JA, Mitra T. Family history and brain morphology in schizophrenia: an MRI study. Psychiatry Res 1991; 40: 49–60. | Article | ChemPort |

Bartels M, Mann K, Friedrich W. Tardive dyskinesia: marked predominance of nongenetic schizophrenia. Biol Psychiatry 1985; 20: 94–119. | Article |

McCreadie RG, Hall DJ, Berry IJ, Robertson LJ, Ewing JI, Geals MF. The Nithdale schizophrenia surveys: X. Obstetrical complications, family history and abnormal movements. Br J Psychiatry 1992; 161: 799–805.

Griffiths TD, Sigmundsson T, Takei N, Frangou S, Birkett PB, Sharma T et al. Minor physical anomalies in familial and sporadic schizophrenia: the Maudsley family study. J Neurol Neurosurg Psychiatry 1998; 64: 56–60. | ChemPort |

Walker E, Shaye J. Familial schizophrenia. A predictor of neuromotor and attentional abnormalities in schizophrenia. Arch Gen Psychiatry 1982; 39: 1153–1156. | PubMed | ChemPort |

Jones PB, Owen MJ, Lewis SW, Murray RM. A case-control study of family history and cerebral cortical abnormalities in schizophrenia. Acta Psychiatry Scand 1993; 87: 6–12. | ChemPort |

Malaspina D, Harkavy-Friedman J, Corcoran C, Mujica-Parodi L, Printz D, Gorman JM et al. Resting neural activity distinguishes subgroups of schizophrenic patients. Biol Psychiatry 2004; 56: 931–937. | Article |

Weiss KM, Chakraborty R, Majumder PP. Problems in the assessment of relative risk of chronic disease among biological relatives of affected individuals. J Chron Dis 1982; 35: 539–551. | Article | ChemPort |

Eaves LJ, Kendler KS, Schulz SC. The familial sporadic classification: its power for the resolution of genetic and environmental etiologic factors. J Psychiatry Res 1986; 20: 115–130. | Article | ChemPort |

Brzustowicz LM, Honer WG, Chow EWC, Hogan J, Hodgkinson K, Bassett AS. Use of a quantitative trait to map a locus associated with severity of positive symptoms in familial schizophrenia to chromosome 6p. Am J Hum Genet 1997; 61: 1388–1396. | Article | PubMed | ChemPort |

Pulver AE, Mulle J, Nestadt G, Swartz KL, Blouin J-L, Dombroski B et al. Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes. Mol Psychiatry 2000; 5: 650–653. | Article | PubMed | ISI | ChemPort |

Chiu YF, McGrath JA, Thornquist MH, Wolyniec PS, Nestadt G, Swartz KL et al. Genetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q. Mol Psychiatry 2002; 7: 658–664. | Article | PubMed | ISI | ChemPort |

Fanous AH, Neale MC, Straub RE, Webb BT, O'Neill AF, Walsh D et al. Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF: a family based association study. Am J Med Genet B Neuropsychiatry Genet 2004; 125B: 69–78. | Article |

Fanous A, van den Oord E, Riley B, Aggen SH, Neale MC, O'Neill FA et al. Relationship between a high-risk haplotype in the dystrobrevin-binding protein 1 (DTNBP1) gene and clinical features of schizophrenia. Am J Psychiatry 2005; 162: 1–9. | Article |

Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM et al. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet 2006; 15: 1563–1568. | Article | ChemPort |

Murphy KC. The behavioural phenotype in velo-cardio-facial syndrome. J Intellect Disabil Res 2004; 48: 524–530. | Article | ChemPort |

Liu H, Abecasis GR, Heath SC, Knowles A, Demars S, Chen YJ et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 16859–16864. | Article | PubMed | ChemPort |

Swillen A, Vogels A, Devriendt K, Fryns JP. Chromosome 22q11 deletion syndrome: update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications. Am J Med Genet C Semin Med Genet 2000; 97: 128–135. | Article | ChemPort |

Horowitz A, Shifman S, Rivlin N, Pisanté A, Darvasi A. A survey of the 22q11 microdeletion in a large cohort of schizophrenia patients. Schizophr Res 2005; 73: 263–267. | Article |

Sporn A, Addington A, Reiss AL, Dean M, Gogtay N, Potocnik U et al. 22q11 deletion syndrome in childhood onset schizophrenia: an update. Mol Psychiatry 2004; 9: 225–226 (letter). | Article | PubMed | ChemPort |

Bassett AS, Chow EWC, Abdel Malik P, Gheorghiu M, Husted J, Weksberg R. The schizophrenia phenotype in 22q11 deletion syndrome. Am J Psychiatry 2003; 160: 1580–1586. | Article | PubMed | ISI |

van Amelsvoort T, Henry J, Morris R, Owen M, Linszen D, Murphy K et al. Cognitive deficits associated with schizophrenia in velo-cardio-facial syndrome. Schizophr Res 2004; 70: 223–232. | Article |

Chow EWC, Zipursky RB, Mikulis DJ, Bassett AS. Structural brain abnormalities in patients with schizophrenia and 22q11 deletion syndrome. Biol Psychiatry 2002; 51: 208–215. | Article |

Schaer M, Schmitt JE, Glaser B, Lazeyras F, Delavelle J, Eliez S. Abnormal patterns of cortical gyrification in velo-cardio-facial syndrome (deletion 22q11.2): an MRI study. Psychiatry Res Neuroim 2006; 146: 1–11. | Article |

Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CAM et al. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9: 1415–1423. | Article | PubMed | ISI | ChemPort |

Cannon TD, Hennah W, van Erp TGM, Thompson PM, Lönnqvist J, Huttunen M et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short-and long-term memory. Arch Gen Psychiatry 2005; 62: 1205–1213. | Article | ChemPort |

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM et al. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16: 1399–1402. | Article |

Cromwell RL, Elkins IJ, McCarthy ME, O'Neil TS. Searching for the phenotypes of schizophrenia. Acta Psychiatry Scand 1994; 90 (Suppl 384): 34–39.

Ginsburg BE, Werick TM, Escobar JI, Kugelmass S, Treanor JJ, Wendtland L. Molecular genetics of psychopathologies: a search for simple answers to complex problems. Behav Genet 1996; 26: 325–333. | Article | PubMed | ChemPort |

Almasy L, Blangero J. Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet Neuropsychiatry Genet 2001; 105: 42–44. | Article | ChemPort |

Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br J Psychiatry 1973; 122: 15–30. | PubMed | ChemPort |

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645. | Article | PubMed | ISI |

Keating M, Dunn C, Atkinson D, Timothy K, Vincent GM, Leppert M. Consistent linkage of the long-QT syndrome to the Harvey ras-1 locus on chromosome 11. Am J Hum Genet 1991; 49: 1335–1339. | PubMed | ISI | ChemPort |

Leppert M, Burt R, Hughes JP, Samowitz W, Nakamura Y, Woodward S et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. New Engl J Med 1990; 322: 904–908. | ChemPort |

Lalouel JM, Le Mignon L, Simon M, Fauchet R, Bourel M, Rao DC 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. | PubMed | ISI | ChemPort |

Greenberg DA, Delgado-Escueta AV, Widelitz H, Sparkes RS, Treiman L, Maldonado HM et al. Juvenile myoclonic epilepsy (JME) may be linked to the BF and HLA loci on human chromosome 6. Am J Med Genet 1988; 31: 185–192. | Article | PubMed | ISI | ChemPort |

Holzman PS, Solomon CM, Levin S, Waternaux CS. Pursuit eye movement dysfunctions in schizophrenia. Family evidence for specificity. Arch Gen Psychiatry 1984; 41: 136–139. | ChemPort |

Holzman PS. Behavioral markers of schizophrenia useful for genetic studies. J Psychiatry Res 1992; 26: 427–445. | Article | ChemPort |

Sponheim SR, Iacono WG, Thuras PD, Beiser M. Using biological indices to classify schizophrenia and other psychotic patients. Schizophr Res 2001; 50: 139–150. | Article | ChemPort |

Braff DL, Geyer MA, Light GA, Sprock J, Perry W, Cadenhead KS et al. Impact of prepulse characteristics on the detection of sensorimotor gating deficits in schizophrenia. Schizophr Res 2001; 49: 171–178. | Article | PubMed | ChemPort |

Joober R, Zarate J-M, Rouleau G-A, Skamene E, Boksa P. Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle. Neuropsychopharmacology 2002; 27: 765–781. | Article | ChemPort |

Kumari V, Das M, Zachariah E, Ettinger U, Sharma T. Reduced prepulse inhibition in unaffected siblings of schizophrenia patients. Psychophysiology 2005; 42: 588–594. | Article |

Adler LE, Freedman R, Ross RG, Olincy A, Waldo MC. Elementary phenotypes in the neurobiological and genetic study of schizophrenia. Biol Psychiatry 1999; 46: 8–18. | Article | PubMed | ChemPort |

Myles-Worsley M, Coon H, McDowell J, Brenner C, Hoff M, Lind B et al. Linkage of a composite inhibitory phenotype to a chromosome 22q locus in eight Utah families. Am J Med Genet Neuropsychiatry Genet 1999; 88: 544–550. | Article | ChemPort |

Freedman R, Adams CE, Adler LE, Bickford PC, Gault J, Harris JG et al. Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia. Am J Med Genet C Semin Med Genet 2000; 97: 58–64. | Article | ChemPort |

Bramon E, McDonald C, Croft RJ, Landau S, Filbey F, Gruzelier JH et al. Is the P300 wave an endophenotype for schizophrenia? A meta-analysis and a family study. NeuroImage 2005; 27: 960–968. | Article | PubMed |

McCarley RW, Niznikiewicz MA, Salisbury DF, Nestor PG, O'Donnell BF, Hirayasu Y et al. Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects. Eur Arch Psychiatry Clin Neurosci 1999; 249(Suppl 4): IV/69–IV/82.

Michie PT, Innes-Brown H, Todd J, Jablensky AV. Duration mismatch negativity in biological relatives of patients with schizophrenia spectrum disorders. Biol Psychiatry 2002; 52: 749–758. | Article | PubMed |

Baldeweg T, Klugman A, Gruzelier J, Hirsch SR. Mismatch negativity potentials and cognitive impairment in schizophrenia. Schizophr Res 2004; 69: 203–217. | Article |

Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ, Lim KO et al. Early-stage visual processing and cortical amplification deficits in schizophrenia. Arch Gen Psychiatry 2005; 62: 495–504. | Article |

Umbricht D, Krljes S. Mismatch negativity in schizophrenia: a meta-analysis. Schizophr Res 2005; 76: 1–23. | Article |

Holzman PS, Kringlen E, Matthysse S, Flanagan SD, Lipton RB, Cramer G et al. A single dominant gene can account for eye tracking dysfunctions and schizophrenia in offspring of discordant twins. Arch Gen Psychiatry 1988; 45: 641–647. | ChemPort |

Levy DL, Lajonchere CM, Dorogusker B, Min DK, Lee S, Tartaglini A et al. Quantitative characterization of eye tracking dysfunction in schizophrenia. Schizophr Res 2000; 42: 171–185. | Article | PubMed | ChemPort |

Tregellas JR, Tanabe JI, Miller DE, Ross RG, Olincy A, Freedman R. Neurobiology of smooth pursuit eye movement deficits in schizophrenia: an fMRI study. Am J Psychiatry 2004; 161: 315–321. | Article | PubMed |

Matthysse S, Holzman PS, Gusella JF, Levy DL, Harte CB, Jørgensen Å et al. Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: Additional evidence. Am J Med Genet B Psychiatry Genet 2004; 128B: 30–36. | Article |

Clementz BA, McDowell JE, Zisook S. Saccadic system functioning among schizophrenia patients and their first-degree relatives. J Abnorm Psychol 1994; 103: 277–287. | Article | ChemPort |

Malone SM, Iacono WG. Error rate on the antisaccade task: heritability and developmental change in performance among preadolescent and late-adolescent female twin youth. Psychophysiology 2002; 39: 664–673. | Article |

Levy DL, O'Driscoll G, Matthysse S, Cook SR, Holzman PS, Mendell NR. Antisaccade performance in biological relatives of schizophrenia patients: a meta-analysis. Schizophr Res 2004; 71: 113–125. | Article |

Louchart-de la Chapelle S, Nkam I, Houy E, Belmont A, Ménard J-F, Roussignol A-C et al. A concordance study of three electrophysiological measures in schizophrenia. Am J Psychiatry 2005; 162: 466–474. | Article |

Price GW, Michie PT, Johnston J, Innes-Brown H, Kent A, Clissa P et al. A multivariate electrophysiological endophenotype, from a unitary cohort, shows greater research utility than any single feature in the Western Australian Family Study of Schizophrenia. Biol Psychiatry, Pre-publication version available online 20 December 2005, http:///www.sciencedirect.com/science/article/B6T4S-4HVDJK7-3/2/da823e5eacd44ad891541fe0c0c3acfe.

Marcelis M, Suckling J, Woodruff P, Hofman P, Bullmore E, van Os J. Searching for a structural endophenotype in psychosis using computational morphometry. Psychiatry Res Neuroim 2003; 122: 153–167. | Article |

McDonald C, Bullmore ET, Sham PC, Chitnis X, Wickham H, Bramon E et al. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004; 61: 974–984. | Article |

Faraone SV, Seidman LJ, Kremen WS, Kennedy D, Makris N, Caviness VS et al. Structural brain abnormalities among relatives of patients with schizophrenia: implications for linkage studies. Schizophr Res 2003; 60: 125–140. | Article |

Davatzikos C, Shen D, Gur RC, Wu X, Liu D, Fan Y et al. Whole-brain morphometric study of schizophrenia revealing a spatially complex set of focal abnormalities. Arch Gen Psychiatry 2005; 62: 1218–1227. | Article |

Davidson LL, Heinrichs RW. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res Neuroim 2003; 122: 69–87. | Article |

Garver DL, Nair TR, Christensen JD, Holcomb J, Ramberg J, Kingsbury S. Atrophic and static (neurodevelopmental) schizophrenic psychoses: premorbid functioning, symptoms and neuroleptic response. Neuropsychopharmacology 1999; 21: 82–92. | Article | ChemPort |

Nuechterlein KH, Asarnow RF, Subotnik KL, Fogelson DL, Ventura J, Torquato RD et al. Neurocognitive vulnerability factors for schizophrenia: convergence across genetic risk studies and longitudinal trait-state studies. In: Lenzenweger MF and Dworkin RH (eds). Origins and Development of Schizophrenia: Advances in Experimental Psychopathology. American Psychological Association: Washington, DC, 1998, pp 299–327.

Egan MF, Goldberg TE, Gscheidle T, Weirich M, Bigelow LB, Weinberger DR. Relative risk of attention deficits in siblings of patients with schizophrenia. Am J Psychiatry 2000; 157: 1309–1316. | Article | PubMed | ChemPort |

Chen WJ, Chang C-H, Liu SK, Hwang TJ, Hwu H-G. Sustained attention deficits in nonpsychotic relatives of schizophrenic patients: a recurrence risk ratio analysis. Biol Psychiatry 2004; 55: 995–1000. | Article |

Paulsen JS, Heaton RK, Sadek JR, Perry W, Delis DC, Braff D et al. The nature of learning and memory impairments in schizophrenia. J Int Neuropsychol Soc 1995; 1: 88–99. | ChemPort |

Turetsky BI, Moberg PJ, Mozley LH, Moelter ST, Agrin RN, Gur RC et al. Memory-delineated subtypes of schizophrenia: relationship to clinical, neuroanatonical, and neurophysiological measures. Neuropsychology 2002; 16: 481–490. | Article |

Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS et al. Executive subprocesses in working memory. Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 2003; 60: 889–896. | Article | PubMed | ISI | ChemPort |

Kremen WS, Seidman LJ, Faraone SV, Toomey R, Tsuang MT. Heterogeneity of schizophrenia: a study of individual neuropsychological profiles. Schizophr Res 2004; 71: 307–321. | Article |

Glahn DC, Therman S, Manninen M, Huttunen M, Kaprio J, Lönnqvist J et al. Spatial working memory as an endophenotype for schizophrenia. Biol Psychiatry 2003; 53: 624–626. | Article |

Dickinson D, Iannone VN, Wilk CM, Gold JM. General and specific cognitive deficits in schizophrenia. Biol Psychiatry 2004; 55: 826–833. | Article | PubMed |

Bruder GE, Wexler BE, Sage MM, Gil RB, Gorman JM. Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits. Schizophr Res 2004; 68: 137–147. | Article |

Hallmayer JF, Kalaydjieva L, Badcock J, Dragovic M, Howell S, Michie PT et al. Genetic evidence for a distinct subtype of schizophrenia characterized by pervasive cognitive deficit. Am J Hum Genet 2005; 77: 468–476. | Article | ChemPort |

Griffiths TD, Sigmundsson T, Takei N, Rowe D, Murray RM. Neurological abnormalities in familial and sporadic schizophrenia. Brain 1998; 121: 191–203. | Article |

Kinney DK, Yurgelun-Todd DA, Woods BT. Neurologic signs of cerebellar and cortical sensory dysfunction in schizophrenics and their relatives. Schizophr Res 1999; 35: 99–104. | Article | ChemPort |

Gourion D, Goldberger C, Bourdel M-C, Bayle FJ, Millet B, Olie J-P et al. Neurological soft-signs and minor physical anomalies in schizophrenia: differential transmission within families. Schizophr Res 2003; 63: 181–187. | Article |

Keshavan MS, Sanders RD, Sweeney JA, Diwadkar VA, Goldstein G, Pettegrew JW et al. Diagnostic specificity and neuroanatomical validity of neurological abnormalities in first-episode psychoses. Am J Psychiatry 2003; 160: 1298–1304. |

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