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This article is part of the Research Topic

Genetics and Epigenetics of Psychiatric Diseases

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2019.00389

Interrogating the evolutionary paradox of schizophrenia: A novel framework and evidence supporting recent negative selection of schizophrenia risk alleles

  • 1Department of Psychiatry, Melbourne Medical School, University of Melbourne, Australia
  • 2Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King's College London, United Kingdom
  • 3Melbourne Neuropsychiatry Centre, The Univeristy of Melbourne, Australia
  • 4Department of Psychiatry, University of Calgary, Canada

Schizophrenia is a psychiatric disorder with a worldwide prevalence of ~1%. The high heritability and reduced fertility among schizophrenia patients have raised an evolutionary paradox: why has negative selection not eliminated schizophrenia associated alleles during the evolution process? To address this question, we examined evolutionary markers, known as modern-human-specific sites and archaic-human-specific sites, using existing genome-wide association study data from 34,241 individuals with schizophrenia and 45,604 healthy controls included in the Psychiatric Genomics Consortium. By testing the distribution of schizophrenia single nucleotide polymorphisms (SNPs) with risk and protective effects in the human-specific sites, we observed a negative selection of risk alleles for schizophrenia in modern humans relative to archaic humans (e.g., Neanderthal and Denisovans). Such findings indicate that risk alleles of schizophrenia have been gradually removed from the modern human genome due to negative selection pressure. This novel evidence contributes to our understanding of the genetic origins of schizophrenia.

Keywords: Schizophrenia, evolution, GWAS, Neanderthal, negative selection

Received: 06 Nov 2018; Accepted: 10 Apr 2019.

Edited by:

Cunyou Zhao, Southern Medical University, China

Reviewed by:

Tom Dickins, Middlesex University, United Kingdom
Annemie Ploeger, University of Amsterdam, Netherlands
Jian-Huan Chen, Jiangnan University, China  

Copyright: © 2019 Liu, Everall, Pantelis and Bousman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Chenxing Liu, Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia,