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Please use this identifier to cite or link to this item: http://hdl.handle.net/2262/61577

Title: Rethinking the genetic architecture of schizophrenia
Author: MITCHELL, KEVIN
Author's Homepage: http://people.tcd.ie/kemitche
Keywords: Neuroscience
Heterogeneous
polygenic
schizophrenia
Issue Date: 2011
Publisher: Cambridge University Press
Citation: Mitchell K.J. and Porteous, D.J., Rethinking the genetic architecture of schizophrenia, Psychological Medicine, 41, 1, 2011, 19-32
Series/Report no.: Psychological Medicine;
41;
1;
Abstract: Background. For many years, the prevailing paradigm has stated that in each individual with schizophrenia (SZ) the genetic risk is due to a combination of many genetic variants, individually of small effect. Recent empirical data are prompting a re-evaluation of this polygenic, common disease–common variant (CDCV) model. Evidence includes a lack of the expected strong positive findings from genome-wide association studies and the concurrent discovery of many different mutations that individually strongly predispose to SZ and other psychiatric disorders. This has led some to adopt a mixed model wherein some cases are caused by polygenic mechanisms and some by single mutations. This model runs counter to a substantial body of theoretical literature that had supposedly conclusively rejected Mendelian inheritance with genetic heterogeneity. Here we ask how this discrepancy between theory and data arose and propose a rationalization of the recent evidence base. Method. In light of recent empirical findings, we reconsider the methods and conclusions of early theoretical analyses and the explicit assumptions underlying them. Results. We show that many of these assumptions can now be seen to be false and that the model of genetic heterogeneity is consistent with observed familial recurrence risks, endophenotype studies and other populationwide parameters. Conclusions. We argue for a more biologically consilient mixed model that involves interactions between diseasecausing and disease-modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms.
Description: PUBLISHED
URI: http://hdl.handle.net/2262/61577
Related links: http://dx.doi.org/10.1017/S003329171000070X
Appears in Collections:Genetics (Scholarly Publications)

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