Document Detail

How and why genetic linkage has not solved the problem of psychosis: review and hypothesis.
MedLine Citation:
PMID:  17202538     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: The author examined the chromosomal linkage method as an approach to the genetic basis of schizophrenia and bipolar disorder. METHOD: Comparisons were conducted of recent meta-analyses of genome scans of schizophrenia and bipolar disorder and of the three largest (N>300) sibling pair studies of schizophrenia and schizoaffective disorder and a comparable study of bipolar illness. RESULTS: Recent meta-analyses have not identified consistent sites of linkage. The three largest studies of schizophrenia fail to agree on a single locus, no commonality with bipolar illness has been demonstrated, and there is no replicable support for any of the current candidate genes. DISCUSSION: An alternative to the concept that DNA sequence variation lies in "multiple genes of small effect" is the hypothesis that the variation is epigenetic but related to the genetic transition ("the speciation event") that separated Homo sapiens from a prior hominid species. This hypothesis draws attention to the chromosomal rearrangement (the Xq21.3/Yp translocation) that occurred some 6 million years ago in the hominid lineage and subsequent rearrangements, including a paracentric inversion, that have taken place within the translocated segment. Here it is argued that the most recent of these events is relevant to specifically human characteristics, including language. The gene pair protocadherin X and Y within this region is under new selective pressure and is in a novel (epigenetic) situation with respect to X inactivation. CONCLUSIONS: Epigenetic variation associated with chromosomal rearrangements that occurred in the hominid lineage and that relates to the evolution of language could account for predisposition to schizophrenia and schizoaffective and bipolar disorder and failure to detect such variation by standard linkage approaches.
Timothy J Crow
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  The American journal of psychiatry     Volume:  164     ISSN:  0002-953X     ISO Abbreviation:  Am J Psychiatry     Publication Date:  2007 Jan 
Date Detail:
Created Date:  2007-01-04     Completed Date:  2007-03-12     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0370512     Medline TA:  Am J Psychiatry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13-21     Citation Subset:  AIM; IM    
Department of Psychiatry, SANE Prince of Wales Centre for Research on Schizophrenia and Depression, Warneford Hospital, Oxford OX3 7JX, UK.
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MeSH Terms
Bipolar Disorder / genetics
Chromosome Mapping
Epigenesis, Genetic / genetics
Genetic Variation
Hominidae / genetics
Humans / genetics
Language Development
Linkage (Genetics)*
Meta-Analysis as Topic
Psychotic Disorders / genetics*
Reproducibility of Results
Research Design* / standards,  statistics & numerical data
Schizophrenia / genetics
Translocation, Genetic

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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