A biological link between a gene associated with schizophrenia and differences in the brains of people with the psychiatric disorder has been reported in Nature.The researchers highlight that while many genes are known to be associated with schizophrenia, very little is known about the link between those genes and the disorder’s symptoms. People with schizophrenia have fewer synapses – the junctions between neurons – than normal, and the researchers found that the C4 gene plays a role in ‘pruning’ synapses in the brain; a process that occurs during adolescence when schizophrenia usually develops.
Dr. Monsheel Sodhi, Assistant Professor, Departments of Pharmacy Practice and Psychiatry, Center for Biomolecular Sciences, University of Illinois at Chicago (webpage):
Expertise: The genetics and pharmacogenetics of schizophrenia and mood disorders.
“There is a paucity of effective treatments for schizophrenia and unfortunately there have been few biological or medical breakthroughs since the disorder was first described. While the genetic and neurodevelopmental bases of schizophrenia have been established for decades, the identification of abnormally regulated genes that participate in the molecular pathways leading to schizophrenia has been hindered by inadequate technology and small sample sizes.
“Recent studies of the entire human genome in schizophrenia (genome-wide association, GWA) have detected over 100 genetic loci that are associated with schizophrenia risk. However, these studies may lack power because the schizophrenia populations tested contain groups of individuals with several distinct subtypes of the syndrome. Therefore, these studies have required ever increasing sample numbers to detect ‘small’ effects. The new study by Sekar and colleagues uses a research design known as the candidate gene approach, where a gene that has a biologically plausible reason for association with schizophrenia was tested.
“Inflammation and its effects on brain function have been previously associated with major psychiatric illnesses, including schizophrenia. Driven by the hypothesis that complement C4 genes express immune factors that are important in inflammatory pathways, the authors analyzed the association of schizophrenia with specific genes encoding complement C4. The authors tested variations in the C4 genes in nearly 65,000 people and their findings suggest that C4 genes play a key role in the abnormal brain development associated with schizophrenia.
“In mice, C4 gene products were shown to mediate synapse elimination, or ‘pruning’, during brain development after birth. The density of synapses has been shown to be depleted in the brains of schizophrenia patients, and may explain the disorganized thought and working memory deficits in some patients with the disorder. In postmortem human subjects, analyses of gene expression in the brain showed that schizophrenia patients had relatively higher expression levels of C4, with associated reductions in the density of synapses in key brain regions. Therefore, excessive activity of C4 genes could underpin the reduced numbers of synapses in the brains of individuals with schizophrenia.
“Brain imaging and more detailed clinical evaluation of patients with the variations in the C4 genes that are associated with schizophrenia risk, in addition to studies of behavior in transgenic animals with altered C4 gene expression, will consolidate the role of C4 genes in the cause and pathology of schizophrenia. Moreover, greater understanding of the molecular pathways of these abnormally regulated genes could facilitate the identification of novel targets for the development of improved antipsychotic drugs.”
Dr. Stephen Warren, William Patterson Timmie Professor of Human Genetics & Charles Howard Candler Chair in Human Genetics, Emory University School of Medicine (webpage):
Expertise: The genetic and epigenetic influences on autism, schizophrenia, and bipolar disorder.
“This is a transformational report on many levels and the work seems solid. Like all such studies, independent replication of the findings will be critical.
“The paper has a credible explanation for the strong correlation in schizophrenia association studies with the region of the genome under investigation: the HLA locus. This correlation has been known for some time and seemingly ignored since the HLA locus encodes for regulation of the immune system, and a mechanism of immunity influencing schizophrenia risk was unclear.
“The link between having fewer synapses and schizophrenia has been known for some time although its importance has been controversial (i.e. was it a cause or a consequence of schizophrenia?). This new data on the influence of C4 expression on synaptic pruning points to it being a contributing cause and could, for the first time, establish a molecular explanation for the peculiar age-of-onset aspects of schizophrenia. Clearly the C4 explanation does not fully explain schizophrenia risk and it is also clear that genetic variation alone is insufficient to solely cause schizophrenia.
“The link between synaptic pruning and schizophrenia would also fit the link between autism susceptibility and schizophrenia susceptibility. Certain genetic variants have been found to increase risk of either autism or schizophrenia in different families, suggesting an underlying common link. Considerable work on autism and autism-like syndromes, such as fragile X syndrome, all point to the synapse and specifically the density of synapses as important. Based upon this paper, it seems also true for schizophrenia.”
Dr. Dimitrios Avramopoulos, Associate Professor, Institute of Genetic Medicine and Department of of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine (webpage):
Expertise: Genetics of complex disorders; Genetics of psychiatric disorders (bipolar, Alzheimer’s, schizophrenia)
“This is a significant contribution towards understanding the mechanisms underlying genetic associations for schizophrenia. The approach is unusual and interesting and it supports that synaptic pruning may be one of many mechanisms involved in schizophrenia, although it falls short of proving it.
“Previous reports have implicated hundreds of genetic variants in over 100 genomic locations for schizophrenia risk, some of those near the C4 gene. This gene carries unusual structural variations and the authors find that these variations determine the expression of the C4 gene, and are predicted by schizophrenia-associated genetic variants.
“Then the authors use a large sample, with existing information on the schizophrenia-associated variants, to predict the gene’s structural variations and corresponding expression. They show that the predicted C4 expression correlates strongly with disease. It must be noted however that this does not demonstrate that expression of C4 drives the risk of developing schizophrenia, since the expression is predicted from schizophrenia-associated variants.
“The authors then characterize the function of C4 in the brain. Working on a brain region that is commonly used in studies of synaptic pruning (yet not known to be directly relevant to schizophrenia) they show that mice lacking functional C4 show a defect consistent with defective synaptic pruning. While this falls short of directly showing an effect of C4 on pruning, or that it happens in schizophrenia-relevant regions, or that it leads to disease, it is certainly encouraging and revives the defective pruning hypothesis for schizophrenia. This hypothesis is old, and although not much primary data has been published for 15 years it remains possible that synaptic pruning is one of the defects that alone or in combination can lead to schizophrenia.
“While it is important to understand the limitations, this remains an important study. Each genetic variant associated with schizophrenia points to a small part of the overall cause, as suggested by the small risk increase contributed by each genetic variant and the fact that millions of healthy people carry them. Once we understand the genetic contributions and the connections to the environment, breakthrough treatments and prevention will follow.”
Dr. Vishwajit Nimgaonkar, Professor of Psychiatry and Human Genetics, Director, Program for Genetics and Psychosis, University of Pittsburgh (webpage):
Expertise: Causation of severe psychiatric illnesses, including genetic and environmental factors.
“This paper represents a tour de force, as it seeks to explain a decades long enigma in schizophrenia research. We have known for a long time that genetic variation in the HLA region can increase risk for schizophrenia. As many genes in the HLA region regulate immune function, it was assumed that immune dysfunction would explain these findings. Through sophisticated and innovative analyses, the authors propose that a portion of the risk of schizophrenia associated with the HLA region could be explained by variation in the C4A gene.
“They analyzed a large number of post-mortem tissue samples and found that the expression of this gene is increased in brain tissues from patients with schizophrenia. The C4A gene has been previously investigated in relation to immunological functions, but the authors present data from animal models indicating that a structural analogue of the C4A gene, called C4, could regulate the number of synapses present on neurons in the brains of rodents.
“It is widely believed that the number of synapses in certain brain regions is reduced in post-mortem samples from patients with schizophrenia, when compared with comparison groups. As synaptic dysfunction has been noted in other studies, the authors point to a plausible link between the HLA genetic results and the post-mortem observations without invoking immune dysfunction.
“There are some caveats: (i) the C4 gene in rodents differs from the C4 gene in humans, so the analyses of synapses conducted in animal models also need to be conducted in human cells; and (ii) the authors’ analyses indicate that other genetic variants in the HLA region could act independently of the C4 genetic variation to cause schizophrenia, suggesting additional biological mechanisms of disease.”
Dr. Alan Anticevic, Assistant Professor of Psychiatry and of Psychology; Co-Director, Division of Neurocognition, Neurocomputation, and Neurogenetics, Yale University (webpage):
Expertise: The neural mechanisms behind cognitive and affective deficits in neuropsychiatric illness
“Identifying causal genetic mechanisms that predispose individuals for developing schizophrenia is one of the fundamental goals of clinical neuroscience. This work provides the foundation for mechanistically mapping such genetic mechanism to downstream neural circuit disruptions that can be ameliorated with rationally-guided treatments. More importantly, this type of work can potentially help us identify individuals at elevated risk, which would help us minimize the likelihood of conversion to full blown illness. This would be transformative for people suffering from this devastating disease and their families.”
Declared interests (see GENeS register of interests policy):
Dr. Dimitrios Avramopoulos: “I consult for Ono Pharma USA, Inc in relation to schizophrenia treatment.”
No further interests declared
‘Schizophrenia risk from complex variation of complement component 4‘ by McCarroll et al, published in Nature on Wednesday 27 January, 2015.