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Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection

View ORCID ProfileAntonio F. Pardiñas, View ORCID ProfilePeter Holmans, View ORCID ProfileAndrew J. Pocklington, View ORCID ProfileValentina Escott-Price, View ORCID ProfileStephan Ripke, View ORCID ProfileNoa Carrera, View ORCID ProfileSophie E. Legge, View ORCID ProfileSophie Bishop, View ORCID ProfileDarren Cameron, View ORCID ProfileMarian L. Hamshere, View ORCID ProfileJun Han, View ORCID ProfileLeon Hubbard, View ORCID ProfileAmy Lynham, View ORCID ProfileKiran Mantripragada, View ORCID ProfileElliott Rees, View ORCID ProfileJames H. MacCabe, View ORCID ProfileSteven A. McCarroll, View ORCID ProfileBernhard T. Baune, View ORCID ProfileGerome Breen, View ORCID ProfileEnda M. Byrne, View ORCID ProfileUdo Dannlowski, View ORCID ProfileThalia C. Eley, View ORCID ProfileCaroline Hayward, View ORCID ProfileNicholas G. Martin, View ORCID ProfileAndrew M. McIntosh, View ORCID ProfileRobert Plomin, View ORCID ProfileDavid J. Porteous, View ORCID ProfileNaomi R. Wray, GERAD Consortium, View ORCID ProfileDavid A. Collier, View ORCID ProfileDan Rujescu, View ORCID ProfileGeorge Kirov, View ORCID ProfileMichael J. Owen, View ORCID ProfileMichael C. O’Donovan, View ORCID ProfileJames T. R. Walters
doi: https://doi.org/10.1101/068593
Antonio F. Pardiñas
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Peter Holmans
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Andrew J. Pocklington
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Valentina Escott-Price
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • ORCID record for Valentina Escott-Price
Stephan Ripke
bAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
cDepartment of Psychiatry and Psychotherapy, Charité, Campus Mitte, 10117 Berlin, Germany
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Noa Carrera
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Sophie E. Legge
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Sophie Bishop
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Darren Cameron
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Marian L. Hamshere
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Jun Han
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Leon Hubbard
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Amy Lynham
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Kiran Mantripragada
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Elliott Rees
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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James H. MacCabe
dDepartment of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King’s College London
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Steven A. McCarroll
eStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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  • ORCID record for Steven A. McCarroll
Bernhard T. Baune
fDiscipline of Psychiatry, University of Adelaide, Australia
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Gerome Breen
gMedical Research Council, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
hNIHR Biomedical Research Centre for Mental Health, Maudsley Hospital and Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Enda M. Byrne
iQueensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
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  • ORCID record for Enda M. Byrne
Udo Dannlowski
jDepartment of Psychiatry and Psychotherapy University of Muenster, Muenster, Germany
kDepartment of Psychiatry, University of Marburg, Marburg, Germany
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Thalia C. Eley
gMedical Research Council, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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Caroline Hayward
lMedical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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Nicholas G. Martin
mSchool of Psychology, University of Queensland
nQIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
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Andrew M. McIntosh
oDivision of Psychiatry, University of Edinburgh, Edinburgh, UK
pCentre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
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Robert Plomin
gMedical Research Council, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
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David J. Porteous
lMedical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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Naomi R. Wray
iQueensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
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qControl data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s disease (GERAD1) Consortium. As such, the investigators within the GERAD1 consortia contributed to the design and implementation of GERAD1 and/or provided control data but did not participate in analysis or writing of this report.
David A. Collier
gMedical Research Council, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK
rDiscovery Neuroscience Research, Eli Lilly and Company Ltd, Lilly Research Laboratories, Erl Wood Manor, Surrey, UK
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Dan Rujescu
sDepartment of Psychiatry, University of Halle, Halle, Germany
tDepartment of Psychiatry, University of Munich, Munich, Germany
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George Kirov
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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Michael J. Owen
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • ORCID record for Michael J. Owen
  • For correspondence: owenmj@cardiff.ac.uk odonovanmc@cardiff.ac.uk waltersjt@cardiff.ac.uk
Michael C. O’Donovan
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • For correspondence: owenmj@cardiff.ac.uk odonovanmc@cardiff.ac.uk waltersjt@cardiff.ac.uk
James T. R. Walters
aMRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
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  • For correspondence: owenmj@cardiff.ac.uk odonovanmc@cardiff.ac.uk waltersjt@cardiff.ac.uk
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Abstract

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation intolerant genes and suggest a mechanism by which common risk variants are maintained in the population.

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Posted August 09, 2016.
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Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection
Antonio F. Pardiñas, Peter Holmans, Andrew J. Pocklington, Valentina Escott-Price, Stephan Ripke, Noa Carrera, Sophie E. Legge, Sophie Bishop, Darren Cameron, Marian L. Hamshere, Jun Han, Leon Hubbard, Amy Lynham, Kiran Mantripragada, Elliott Rees, James H. MacCabe, Steven A. McCarroll, Bernhard T. Baune, Gerome Breen, Enda M. Byrne, Udo Dannlowski, Thalia C. Eley, Caroline Hayward, Nicholas G. Martin, Andrew M. McIntosh, Robert Plomin, David J. Porteous, Naomi R. Wray, GERAD Consortium, David A. Collier, Dan Rujescu, George Kirov, Michael J. Owen, Michael C. O’Donovan, James T. R. Walters
bioRxiv 068593; doi: https://doi.org/10.1101/068593
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Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection
Antonio F. Pardiñas, Peter Holmans, Andrew J. Pocklington, Valentina Escott-Price, Stephan Ripke, Noa Carrera, Sophie E. Legge, Sophie Bishop, Darren Cameron, Marian L. Hamshere, Jun Han, Leon Hubbard, Amy Lynham, Kiran Mantripragada, Elliott Rees, James H. MacCabe, Steven A. McCarroll, Bernhard T. Baune, Gerome Breen, Enda M. Byrne, Udo Dannlowski, Thalia C. Eley, Caroline Hayward, Nicholas G. Martin, Andrew M. McIntosh, Robert Plomin, David J. Porteous, Naomi R. Wray, GERAD Consortium, David A. Collier, Dan Rujescu, George Kirov, Michael J. Owen, Michael C. O’Donovan, James T. R. Walters
bioRxiv 068593; doi: https://doi.org/10.1101/068593

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