Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Vassily Trubetskoy, Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
Antonio F. Pardiñas, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Ting Qi, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Georgia Panagiotaropoulou, Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
Swapnil Awasthi, Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
Tim B. Bigdeli, Department of Psychiatry and the Behavioral Sciences, SUNY Downstate Medical Center, New York, NY, USA.
Julien Bryois, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Chia-Yen Chen, Biogen, Cambridge, MA, USA.
Charlotte A. Dennison, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Lynsey S. Hall, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Max Lam, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kyoko Watanabe, Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Oleksandr Frei, NORMENT Centre, Division of Mental Health and Addiction, University of Oslo, Oslo, Norway.
Tian Ge, Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Janet C. Harwood, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Frank Koopmans, Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Faculty of Science, Amsterdam Neuroscience, Vrije Universiteit, Amsterdam, The Netherlands.
Sigurdur Magnusson, deCODE Genetics, Amgen, Reykjavik, Iceland.
Alexander L. Richards, MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Julia Sidorenko, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Yang Wu, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Jian Zeng, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
Jakob Grove, The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
Minsoo Kim, Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Zhiqiang Li, Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China.
Georgios Voloudakis, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Friedman Brain Institute, Department of Genetics and Genomic Science and Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Wen Zhang, Department of Psychiatry, Pamela Sklar Division of Psychiatric Genomics, Friedman Brain Institute, Department of Genetics and Genomic Science and Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.Follow
Mark Adams, Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
Ingrid Agartz, NORMENT Centre, Division of Mental Health and Addiction, University of Oslo, Oslo, Norway.
Elizabeth G. Atkinson, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Esben Agerbo, The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.
Mariam Al Eissa, Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK.
Margot Albus, Comedicum Lindwurmhof, Munich, Germany.
Madeline Alexander, Center for Depression, Anxiety and Stress Research, McLean Hospital, Belmont, MA, USA.

Abstract

Schizophrenia has a heritability of 60-80%, 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.

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Nature

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