Rethinking the genetic architecture of schizophrenia

Kevin J. Mitchell, David J. Porteous

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)19-32
Number of pages14
JournalPsychological Medicine
Volume41
Issue number1
Early online date12 Apr 2010
DOIs
Publication statusPublished - Jan 2011

Keywords

  • Heterogeneous
  • polygenic
  • schizophrenia

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