The Genetic Deconstruction of Psychosis
2Department of Psychological Medicine, The School of Medicine,
Cardiff University, Heath Park, Cardiff CF14 4XN, UK;3School
of Psychiatry and Clinical Neurosciences, The University of
Western Australia, Perth, Australia
Psychiatric research, including the search for predisposing
genes, has tended to proceed under the assumptions that
and Statistical Manual of Mental Disorders, Fourth Edi-
tion, and International Statistical Classification of Dis-
eases, 10th Revision, are discrete disease entities with
distinct etiology and pathogenesis and that these disease
entities can be identified by current ‘‘operational’’ diagnos-
tic conventions. However, recent findings emerging from
genetic studies show increasing evidence for an overlap
in genetic susceptibility across the traditional binary clas-
sification of psychosis. Moreover, the emerging evidence
suggests the possibility of relatively specific relationships
between genotype and psychopathology. For example, var-
iation in Disrupted in Schizophrenia 1 (DISC1) and Neu-
regulin 1 (NRG1) may confer susceptibility to a form of
illness with mixed features of schizophrenia and mania.
The elucidation of genotype-phenotype relationships is at
an early stage, but current findings highlight the need to
consider alternative approaches to classification and con-
ceptualization for psychiatric research rather than continu-
ing to rely heavily on the traditional categorical approach.
We can expect that, over the coming years, molecular ge-
netics will catalyze a reappraisal of psychiatric nosology as
well as contribute in a major way to our understanding of
pathophysiology and to the development of improved treat-
ments. However, our understanding of the brain mecha-
nisms that link specific gene actions and products to the
subjective experience of psychopathological symptoms is
likely to be bridged by employing intermediate (or endo-)
phenotypes in the domains such as cognition, neurophysi-
ology, or neuroanatomy rather than relying upon clinical
Key words: schizophrenia/bipolar disorder/genetics/
The majority of genetic studies into the psychoses over
the last 2 decades have been predicated on the double as-
sumption that (a) schizophrenia and bipolar disorder, as
defined in Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV),1and International
Statistical Classification of Diseases, 10th Revision2, are
discrete, ‘‘natural’’ disease entities with distinct etiology
and pathogenesis and (b) these disease entities can be
identified by current operational diagnostic conventions,
which are based on reported subjective symptoms and, to
a lesser extent, on deteriorating performance of expected
social roles. Data from genetic epidemiology have been
called upon to justify the validity of this approach, often
referred to as the ‘‘Kraepelinian dichotomy.’’
It is important to note that this widely held notion is
incorrect. Kraepelin’s seminal work, which aggregated 3
previously described syndromes—hebephrenia, catato-
nia, and paranoid dementia—into the clinical entity of
dementia praecox and delimited the latter from manic-
depressiveinsanity,paranoia, andlate paraphreniaintro-
duced order in the previously chaotic field of nosology
and laid down the foundation for the current classifica-
tions of psychotic disorders. It is not widely known that,
in contrast to the narrowly defined manic-depressive psy-
grouping, consisting of 9 clinical ‘‘forms,’’ also including
what today would be termed schizoaffective disorder and
mood-incongruent affective psychoses. However, in
1920, he wrote that ‘‘we cannot distinguish satisfactorily
between these two illnesses and this brings home the sus-
picion that our formulation of the problem may be incor-
rect . the affective and schizophrenic forms of mental
disorder do not represent the expression of particular
pathological processes, but rather indicate the areas of
our personality in which these processes unfold.’’3
and refine his ideas about psychiatric diagnoses, and his
thinking had in many ways moved on from the dichoto-
mous classification by the end of his life. However, it is
relation to modern nosological practice. A discussion of
this sort, although of historical interest, is not of direct
relevance. Unfortunately, the dichotomous, categorical
view of the psychoses has been reified in the Diagnostic
1To whom correspondence should be addressed; tel: þ44 (0)-29-
? The Author 2007. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved.
For permissions, please email: firstname.lastname@example.org.
Schizophrenia Bulletin vol. 33 no. 4 pp. 905–911, 2007
Advance Access publication on June 5, 2007
38. Raybould R, Green EK, MacGregor S, et al. Bipolar disorder
and polymorphisms in the dysbindin (dystrobrevin binding
protein 1) gene (DTNBP1). Biol Psychiatry. 2005;57:696–701.
39. Breen G, Prata D, Osborne S, et al. Association of the dysbin-
din gene with bipolar affective disorder. Am J Psychiatry.
40. Fanous AH, van den Oord EJ, Riley BP, et al. Relationship
between a high-risk haplotype in the DTNBP1 (dysbindin)
gene and clinical features of schizophrenia. Am J Psychiatry.
41. Chumakov I, Blumenfeld M, Guerassimenko O, et al. Genetic
and physiological data implicating the new human gene G72
and the gene for D-amino acid oxidase in schizophrenia. Proc
Natl Acad Sci USA. 2002;99:13675–13680.
42. Detera-Wadleigh SD, McMahon FJ. G72/G30 in schizophre-
nia and bipolar disorder: review and meta-analysis. Biol Psy-
43. Williams NM, Green EK, Macgregor S, et al. Variation at the
DAOA/G30 locus influences susceptibility to major mood
episodes but not psychosis in schizophrenia and bipolar disor-
der. Arch Gen Psychiatry. 2006;63:366–373.
44. Blackwood DH, Fordyce A, Walker MT, et al. Schizophrenia
and affective disorders—cosegregation with a translocation at
chromosome 1q42 that directly disrupts brain-expressed
genes: clinical and P300 findings in a family. Am J Hum
45. Millar JK, Wilson-Annan JC, Anderson S, et al. Disruption
of two novel genes by a translocation co-segregating with
schizophrenia. Hum Mol Genet. 2000;9:1415–1423.
46. Sachs NA, Sawa A, Holmes SE, Ross CA, DeLisi LE,
Margolis RL. A frameshift mutation in Disrupted in Schizo-
phrenia 1 in an American family with schizophrenia and
schizoaffective disorder. Mol Psychiatry. 2005;10:758–764.
47. Green E, Norton N, Peirce T, et al. Evidence that a DISC1
frame-shift deletion associated with psychosis in a single fam-
ily may not be a pathogenic mutation. Mol Psychiatry.
48. Ekelund J, Hovatta I, Parker A, et al. Chromosome 1 loci in
Finnish schizophrenia families. Hum Mol Genet. 2001;10:1611–
49. Ekelund J, Hennah W, Hiekkalinna T, et al. Replication
of 1q42 linkage in Finnish schizophrenia pedigrees. Mol
50. Macgregor S, Visscher PM, Knott SA, et al. A genome scan
and follow-up study identify a bipolar disorder susceptibility
locus on chromosome 1q42. Mol Psychiatry. 2004;9:1083–1090.
51. Devon RS, Anderson S, Teague PW, et al. Identification of
polymorphisms within Disrupted in Schizophrenia 1 and Dis-
rupted in Schizophrenia 2, and an investigation of their asso-
ciation with schizophrenia and bipolar disorder. Psychiatr
of polymorphisms in the 5# upstream region of human DISC1
gene with schizophrenia. Neurosci Lett. 2004;368:41–45.
53. Hennah W, Varilo T, Kestila M, et al. Haplotype transmis-
sion analysis provides evidence of association for DISC1 to
schizophrenia and suggests sex-dependent effects. Hum Mol
54. Hodgkinson CA, Goldman D, Jaeger J, et al. Disrupted in
schizophrenia 1 (DISC1): association with schizophrenia,
schizoaffective disorder, and bipolar disorder. Am J Hum
55. Thomson PA, Wray NR, Millar JK, et al. Association be-
tween the TRAX/DISC locus and both bipolar disorder and
schizophrenia in the Scottish population. Mol Psychiatry.
56. Callicott JH, Straub RE, Pezawas L, et al. Variation in
DISC1 affects hippocampal structure and function and
increases risk for schizophrenia. Proc Natl Acad Sci USA.
57. Kendell R, Jablensky A. Distinguishing between the validity
and utility of psychiatric diagnoses. Am J Psychiatry.
58. Kendler KS. Reflections on the relationship between psychi-
atric genetics and psychiatric nosology. Am J Psychiatry.
59. Hallmayer JF, Kalaydjieva L, Badcock J, et al. Genetic evi-
dence for a distinct subtype of schizophrenia characterized by
pervasive cognitive deficit. Am J Hum Genet. 2005;77:468–476.
60. Jablensky A. Subtyping schizophrenia: implications for ge-
netic research. Mol Psychiatry. 2006;11:815–836.
61. Harrison PJ, Owen MJ. Genes for schizophrenia? Recent
findings and their pathophysiological implications. Lancet.
62. Levinson DF, Mowry BJ, Escamilla MA, Faraone SV. The
Lifetime Dimensions of Psychosis Scale (LDPS): descrip-
tion and interrater reliability. Schizophr Bull. 2002;28:683–
63. Craddock N, Jones I, Kirov G, et al. The Bipolar Affective
Disorder Dimension Scale (BADDS)—a dimensional scale
for rating lifetime psychopathology in bipolar spectrum disor-
ders. BMC Psychiatry. 2004;4:19.
The Genetic Deconstruction of Psychosis