title: Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia.
abstract: We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: pocklingtonaj@cardiff.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pocklington
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Elliott
authors.initials: E
authors.lastname: Rees
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: James T R
authors.initials: JT
authors.lastname: Walters
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: David H
authors.initials: DH
authors.lastname: Kavanagh
authors.affiliation: Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Chambert
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.affiliation: Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moran
authors.affiliation: Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: odonovanmc@cardiff.ac.uk.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology*; D051379:Mice; D012559:Schizophrenia / Q000175:diagnosis* / Q000235:genetics*; D015398:Signal Transduction / Q000502:physiology*