Psychological Medicine

Review Article

Rethinking the genetic architecture of schizophrenia

K. J. Mitchella1 c1 and D. J. Porteousa2 c2

a1 Smurfit Institute of Genetics, Trinity College Dublin, Ireland

a2 Medical Genetics Section, University of Edinburgh Molecular Medicine Centre, Institute of Genetics and Molecular Medicine, Edinburgh, UK

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 population-wide parameters.

Conclusions We argue for a more biologically consilient mixed model that involves interactions between disease-causing and disease-modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms.

(Received December 21 2009)

(Revised March 09 2010)

(Accepted March 15 2010)

(Online publication April 12 2010)

Correspondence

c1 Address for correspondence: Dr K. J. Mitchell, Smurfit Institute of Genetics, Trinity College Dublin, Ireland. (Email: Kevin.Mitchell@tcd.ie)

c2 (Email: David.Porteous@ed.ac.uk)

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