Rethinking the genetic architecture of schizophrenia
Citation:
Mitchell K.J. and Porteous, D.J., Rethinking the genetic architecture of schizophrenia, Psychological Medicine, 41, 1, 2011, 19-32Download Item:
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.
Author's Homepage:
http://people.tcd.ie/kemitcheDescription:
PUBLISHED
Author: MITCHELL, KEVIN
Publisher:
Cambridge University PressType of material:
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Series/Report no:
Psychological Medicine;41;
1;
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Full text availableKeywords:
Neuroscience, Heterogeneous, polygenic, schizophreniaMetadata
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