De novo mutations in schizophrenia implicate synaptic networks

Menachem Fromer, Andrew J. Pocklington, David H. Kavanagh, Hywel J. Williams, Sarah Dwyer, Padhraig Gormley, Lyudmila Georgieva, Elliott Rees, Priit Palta, Douglas M. Ruderfer, Noa Carrera, Isla Humphreys, Jessica S. Johnson, Panos Roussos, Douglas D. Barker, Eric Banks, Vihra Milanova, Seth G. Grant, Eilis Hannon, Samuel A. Rose, Kimberly Chambert, Milind Mahajan, Edward M. Scolnick, Jennifer L. Moran, George Kirov, Aarno Palotie, Steven A. McCarroll, Peter Holmans, Pamela Sklar, Michael J. Owen (), Shaun M. Purcell and Michael C. O’Donovan
Additional contact information
Menachem Fromer: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Andrew J. Pocklington: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
David H. Kavanagh: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Hywel J. Williams: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Sarah Dwyer: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Padhraig Gormley: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Lyudmila Georgieva: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Elliott Rees: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Priit Palta: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Douglas M. Ruderfer: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Noa Carrera: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Isla Humphreys: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Jessica S. Johnson: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Panos Roussos: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Douglas D. Barker: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Eric Banks: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Vihra Milanova: Medical University, Sofia 1431, Bulgaria
Seth G. Grant: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, UK
Eilis Hannon: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Samuel A. Rose: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Kimberly Chambert: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Milind Mahajan: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Edward M. Scolnick: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Jennifer L. Moran: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
George Kirov: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Aarno Palotie: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK
Steven A. McCarroll: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Peter Holmans: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Pamela Sklar: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Michael J. Owen: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK
Shaun M. Purcell: and Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai
Michael C. O’Donovan: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK

Nature, 2014, vol. 506, issue 7487, 179-184

Abstract: Abstract Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case–control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders.

Date: 2014
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DOI: 10.1038/nature12929

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