The genetic deconstruction of psychosis.
Psychiatric research, including the search for predisposing genes, has tended to proceed under the assumptions that schizophrenia and bipolar disorder, as defined in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and International Statistical Classification of Diseases, 10th Revision, are discrete disease entities with distinct etiology and pathogenesis and that these disease entities can be identified by current "operational" diagnostic conventions. However, recent findings emerging from genetic studies show increasing evidence for an overlap in genetic susceptibility across the traditional binary classification of psychosis. Moreover, the emerging evidence suggests the possibility of relatively specific relationships between genotype and psychopathology. For example, variation in Disrupted in Schizophrenia 1 (DISC1) and Neuregulin 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 conceptualization for psychiatric research rather than continuing to rely heavily on the traditional categorical approach. We can expect that, over the coming years, molecular genetics 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 treatments. However, our understanding of the brain mechanisms 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, neurophysiology, or neuroanatomy rather than relying upon clinical measures alone.
Owen
Michael J
MJ
Department of Psychological Medicine, The School of Medicine, Cardiff University, Cardiff, UK. owenmj@cardiff.ac.uk
Craddock
Nick
N
Jablensky
Assen
A
D002352:Carrier Proteins / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D039721:Diagnostic and Statistical Manual of Mental Disorders; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D015870:Gene Expression / Q000235:genetics; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics; D020890:Neuregulin-1; D011618:Psychotic Disorders / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics; D014427:Twins / Q000235:genetics
D002352:Carrier Proteins; C475071:DAOA protein, human; C412476:DISC1 protein, human; C432416:DTNBP1 protein, human; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D047908:Intracellular Signaling Peptides and Proteins; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D002394:Catechol O-Methyltransferase