Scientists produce the strongest evidence yet about the causes of schizophrenia: risk mutations disturb a delicate chemical balance in the brain that is essential for development and function.
An international research team led by Cardiff University has produced the most compelling genetic evidence to date explaining how schizophrenia develops. The findings, published in the journal Neuron, show that mutations linked to the disorder disrupt the fine-tuned chemical balance between excitatory and inhibitory signaling in the brain—an equilibrium that is central to healthy brain development and normal cognitive function.
In the largest study of chromosomal copy number variants (CNVs) related to schizophrenia so far, researchers compared genetic data from 11,355 people diagnosed with schizophrenia to 16,416 control participants. Their analyses reveal that disease-associated CNVs disproportionately affect genes involved in both excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission. Disruption of this excitatory–inhibitory balance provides a coherent biological framework for understanding how diverse genetic faults can produce a common clinical outcome.
The new work builds on earlier landmark studies from the Cardiff team and collaborators. Those studies first implicated glutamatergic signaling in schizophrenia; the current study confirms those findings and, for the first time at this scale, provides strong genetic evidence that impaired GABAergic signaling is also directly involved in disease risk.
“We’re beginning to piece together what goes wrong in schizophrenia,” says lead author Dr Andrew Pocklington from Cardiff’s MRC Centre for Neuropsychiatric Genetics and Genomics. “This study brings together multiple genetic signals and points directly to disruptions in the balancing mechanisms between excitation and inhibition in the brain. Establishing a reliable biological model of schizophrenia is vital for guiding future research and for the development of better, more targeted treatments.”
Professor Hugh Perry, chair of the Medical Research Council Neuroscience and Mental Health Board, commented that the work clarifies how combinations of genetic faults can interfere with the brain’s chemical balance. “These results, produced by an international consortium of scientists, bring us closer to predicting individual risk and to developing treatments that target the underlying biology rather than only managing symptoms,” he said.
The research focused on CNVs, a type of genetic mutation in which large segments of DNA are deleted or duplicated. By comparing CNV patterns in patients and unaffected individuals, the investigators were able to identify which biological pathways are most frequently affected in schizophrenia. The results show specific enrichment for genes involved in synaptic signaling complexes—particularly those mediating glutamatergic and GABAergic neurotransmission—rather than a broad pattern of disruption across many unrelated biological systems.
These CNV effects are not unique to schizophrenia; similar disruptions have been associated with other neurodevelopmental conditions including intellectual disability, Autism Spectrum Disorder and ADHD. However, the present study clarifies that in schizophrenia the disrupted pathways converge on excitatory and inhibitory signaling mechanisms, offering a focused target for follow-up studies aimed at understanding disease mechanisms and translating findings into potential interventions.
Schizophrenia affects an estimated 1% of the global population. In the UK alone, studies estimate that around 635,000 people will be affected by schizophrenia at some point in their lives, and the societal costs of schizophrenia and psychosis are substantial. Symptoms can be severely disabling, impairing a person’s ability to work, maintain relationships, and manage everyday self-care.
Funding: Cardiff-based work was supported by the Medical Research Council (MRC) and the European Community’s Seventh Framework Programme. Additional contributions from collaborators at other institutions were supported by philanthropic funding to the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.
Source: Tomas Llewelyn Barrett – Cardiff University
Image Source: Image credit: Marco Castellani. Licensed under Creative Commons Attribution-Share Alike 2.0 Generic.
Original Research: “Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia” by Andrew J. Pocklington et al., published in Neuron. Published online June 3, 2015. doi:10.1016/j.neuron.2015.04.022
Abstract
Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia
Highlights
• First genetic evidence implicating disruption of GABAergic signaling in schizophrenia
• No significant CNV enrichment observed for biological processes outside the central nervous system
• Independent support for involvement of NMDAR and ARC synaptic complexes in schizophrenia
• Additional independent evidence reinforcing disruption of glutamatergic signaling
Summary
To gain new insight into schizophrenia pathogenesis, the authors leveraged the association between the disorder and chromosomal copy number burden. They combined data from multiple published CNV datasets to assemble a sample of 11,355 cases and 16,416 controls. Analyses revealed that schizophrenia-associated CNVs are significantly enriched for genes involved in GABAergic neurotransmission, providing the first strong genetic evidence that disrupted inhibitory signaling is causally relevant to the disorder. The study also replicates and expands previous findings of CNV enrichment among genes involved in glutamatergic signaling. Because inhibitory GABAergic and excitatory glutamatergic systems are tightly functionally linked, these convergent genetic findings identify a coherent set of pathogenic processes that form a firm foundation for mechanistic and translational research into schizophrenia.
“Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia” by Andrew J. Pocklington, Elliott Rees, James T.R. Walters, Jun Han, David H. Kavanagh, Kimberly D. Chambert, Peter Holmans, Jennifer L. Moran, Steven A. McCarroll, George Kirov, Michael C. O’Donovan, and Michael J. Owen. Neuron. Published online June 3, 2015. doi:10.1016/j.neuron.2015.04.022