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Mapping genomic loci implicates genes and synaptic biology in schizophrenia

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  • Vassily Trubetskoy, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
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  • Antonio F Pardiñas, Cardiff University
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  • Ting Qi, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
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  • Georgia Panagiotaropoulou, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
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  • Swapnil Awasthi, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, Frankfurt, Germany.
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  • Tim B Bigdeli, SUNY-Downstate Medical Center,
  • Julien Bryois, Karolinska Univ Hosp Huddinge, Karolinska University Hospital, Karolinska Institutet
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  • Chia-Yen Chen, Biogen
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  • Charlotte A Dennison, Cardiff University
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  • Lynsey S Hall, Cardiff University
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  • Max Lam, Broad Institute of Harvard and MIT
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  • Kyoko Watanabe, Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands.
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  • Oleksandr Frei, University of Oslo, Norway; Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway; Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway. Electronic address: harald.breivik@medsin.uio.no.
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  • Tian Ge, Center for Genomic Medicine
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  • Janet C Harwood, Cardiff University
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  • Frank Koopmans, Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands.
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  • Sigurdur Magnusson, DeCODE Genetics/Amgen
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  • Alexander L Richards, Cardiff University
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  • Julia Sidorenko, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
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  • Yang Wu, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
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  • Jian Zeng, Queensland Centre for Mental Health Research, University of Queensland, St. Lucia, Queensland, Australia; Queensland Brain Institute, University of Queensland, St. Lucia, Queensland, Australia; National Centre for Register-based Research, Aarhus BSS, Aarhus University, Aarhus, Denmark.. Electronic address: j.mcgrath@uq.edu.au.
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  • Jakob Grove
  • Minsoo Kim, Family Medicine, University of California, Los Angeles, Los Angeles, California.
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  • Zhiqiang Li, Shanghai Jiao Tong Univ, Shanghai Jiao Tong University, Shanghai Peoples Hosp 1, Dept Lab Med
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  • Georgios Voloudakis, Friedman Brain Institute
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  • Wen Zhang, Friedman Brain Institute
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  • Mark Adams, Edinburgh Cancer Centre, University of Edinburgh, Edinburgh, UK.
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  • Ingrid Agartz, University of Oslo, Norway; Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway; Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway. Electronic address: harald.breivik@medsin.uio.no.
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  • Elizabeth G Atkinson, Massachusetts General Hospital Nuclear Magnetic Resonance Center, Department of Radiology, Massachusetts General Hospital, and Harvard Medical School
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  • Esben Agerbo
  • Mariam Al Eissa, Univ Coll London Hosp NHS Fdn Trust, University College London Hospitals NHS Foundation Trust, University of London, University College London, Inst Nucl Med
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  • Margot Albus, Comedicum Lindwurmhof
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  • Madeline Alexander, Center for Neuropsychiatric Depression Research (CNDR)
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  • Behrooz Z Alizadeh, University of Groningen, University Medical Centre Groningen, Department of Cardiology, Hanzeplein Groningen, The Netherlands.
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  • Köksal Alptekin, Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Psychiatry, Dokuz Eylul University School Of Medicine, Izmir, Turkey.
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  • Thomas D Als
  • Farooq Amin, Emory Univ, Emory University, Sch Med, CFERV
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  • Volker Arolt, University of Münster, Münster, Germany.
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  • Manuel Arrojo, Univ Hosp Santiago Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Dept Gastroenterol & Hepatol
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  • Lavinia Athanasiu, University of Oslo, Norway; Department of Pain Management and Research, Oslo University Hospital, Oslo, Norway; Department of Anaesthesiology, Oslo University Hospital, Oslo, Norway. Electronic address: harald.breivik@medsin.uio.no.
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  • Maria Helena Azevedo, Coimbra Herbarium, University of Coimbra
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  • Ditte Demontis
  • Manuel Mattheisen, Dalhousie University
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  • John J McGrath
  • Sandra Meier
  • Wei J Chen, National Health Research Institutes Taiwan, National Taiwan University
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  • Ole Mors
  • Preben B Mortensen
  • Anders D Børglum
  • Jian Yang, Westlake University, University of Queensland
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  • Indonesia Schizophrenia Consortium

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

OriginalsprogEngelsk
TidsskriftNature
Vol/bind604
Nummer7906
Sider (fra-til)502-508
Antal sider7
ISSN0028-0836
DOI
StatusUdgivet - apr. 2022

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