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Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders

Tarjinder Singh, James T. R. Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M. McIntosh, Georg Kirov, Daniel Geschwind, Robin M. Murray, Marta Di Forti, Elvira Bramon, INTERVAL Study, UK10K Consortium, Aarno Palotie, Michael C. O’Donovan, Michael J. Owen, Jeffrey C. Barrett
doi: https://doi.org/10.1101/069344
Tarjinder Singh
1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, Cambridge, UK.
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James T. R. Walters
2MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
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Mandy Johnstone
3Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.
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David Curtis
4University College London (UCL) Genetics Institute, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
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Jaana Suvisaari
5National Institute for Health and Welfare (THL), Helsinki FI-00271, Finland
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Minna Torniainen
5National Institute for Health and Welfare (THL), Helsinki FI-00271, Finland
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Elliott Rees
2MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
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Conrad Iyegbe
6Institute of Psychiatry, King’s College London, 16 De Crespigny Park, London SE5 8AF, UK.
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Douglas Blackwood
3Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.
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Andrew M. McIntosh
3Division of Psychiatry, The University of Edinburgh, Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.
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Georg Kirov
2MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
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Daniel Geschwind
7UCLA David Geffen School of Medicine, Los Angeles, California 90095, USA.
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Robin M. Murray
6Institute of Psychiatry, King’s College London, 16 De Crespigny Park, London SE5 8AF, UK.
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Marta Di Forti
6Institute of Psychiatry, King’s College London, 16 De Crespigny Park, London SE5 8AF, UK.
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Elvira Bramon
8Division of Psychiatry, University College London, Charles Bell House, Riding House Street, London W1W 7EJ, UK.
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Aarno Palotie
9Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki FI-00014 Finland.
10Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge MA 02132, USA.
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Michael C. O’Donovan
2MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
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Michael J. Owen
2MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.
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Jeffrey C. Barrett
1Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1HH, Cambridge, UK.
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Abstract

By meta-analyzing rare coding variants in whole-exome sequences of 4,264 schizophrenia cases and 9,343 controls, de novo mutations in 1,077 trios, and array-based copy number variant calls from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in a subset of 3,230 “highly constrained” genes previously identified as having near-complete depletion of protein truncating variants. Furthermore, rare variant enrichment analyses demonstrate that this burden is concentrated in known autism spectrum disorder risk genes, genes diagnostic of severe developmental disorders, and the autism-implicated sets of promoter targets of CHD8, and mRNA targets of FMRP. We further show that schizophrenia patients with intellectual disability have a greater enrichment of rare damaging variants in highly constrained genes and developmental disorder genes, but that a weaker but significant enrichment exists throughout the larger schizophrenia population. Combined, our results demonstrate that schizophrenia risk loci of large effect across a range of variant types implicate a common set of genes shared with broader neurodevelopmental disorders, suggesting a path forward in identifying additional risk genes in psychiatric disorders and further supporting a neurodevelopmental etiology to the pathogenesis of schizophrenia.

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Posted August 16, 2016.
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Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders
Tarjinder Singh, James T. R. Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M. McIntosh, Georg Kirov, Daniel Geschwind, Robin M. Murray, Marta Di Forti, Elvira Bramon, INTERVAL Study, UK10K Consortium, Aarno Palotie, Michael C. O’Donovan, Michael J. Owen, Jeffrey C. Barrett
bioRxiv 069344; doi: https://doi.org/10.1101/069344
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Rare schizophrenia risk variants are enriched in genes shared with neurodevelopmental disorders
Tarjinder Singh, James T. R. Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M. McIntosh, Georg Kirov, Daniel Geschwind, Robin M. Murray, Marta Di Forti, Elvira Bramon, INTERVAL Study, UK10K Consortium, Aarno Palotie, Michael C. O’Donovan, Michael J. Owen, Jeffrey C. Barrett
bioRxiv 069344; doi: https://doi.org/10.1101/069344

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