January 27, 2016

expert reaction to genetic association to schizophrenia

A study published in the journal Nature has reported an association between varying levels of protein brought about by different forms of a specific gene and schizophrenia in humans. The authors suggest that higher levels of the protein might lead to a number of connections between nerve cells, which is characteristic of individuals with schizophrenia.

Prof. Judith Pratt, Research Professor, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, said:

“In this elegant genetic study, Sekar and colleagues demonstrate that a genetic  variation in complement component 4 (C4A) of the MHC region is associated with schizophrenia and that this is independent of other genetic variations in this very large region. They go some way to providing evidence of the biology of gene function using C4 mutant mice, demonstrating that these mice show impaired synaptic pruning in visual system development.

“Clearly this is an important step forward.  Nevertheless, there are a number of caveats here 1) the mice do not have the two forms of C4 present in humans and so determining the importance of C4A or C4B is not possible from this study (as noted in the News and Views article). 2) The selection of investigating development of the visual system is puzzling, given that other circuitry development would be more relevant to schizophrenia (e.g. Cortico-thalamo-cortical and hippocampal pathways). Hence it remains to be determined whether ‘impaired synaptic pruning’ occurs in these neural systems.  3) This is not the first demonstration of a biological role of a risk variant – many other low penetrance and high penetrance genes have been examined for biological function in brain. These include Neuregulin, Disc1, nicotinic receptors and many of these have shown functions relevant to impaired synaptic transmission.

“Finally, it must be remembered that the GWAS variants discovered to date, each contribute a small degree of risk to the overall risk of developing schizophrenia and the MHC locus is no exception.  Assembling the biological information of these gene products into converging biological mechanisms is the real challenge for the future.”

Prof. Jeremy Hall, Professor of Psychiatry and Neurosciences, Cardiff University, said:

“This is a fantastic paper that goes from a highly complex genetic association with schizophrenia to a specific pathway and mechanism. The work highlights an association of schizophrenia with functional genetic variation in the complement immune pathway that is known to play a role in regulating the development of neuronal connections in the brain and suggests convergence with other pathways of genetic risk for the disorder affecting neuronal synapses. Very excitingly this work also highlights the potential of drugs targeting the immune system as potential therapies in schizophrenia.”

Prof. Mike Owen, Director of the MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, said:

“This is a very elegant piece of work which built on data produced by the Psychiatric Genomics Consortium Schizophrenia Working Group who published a paper in 2014 indicating the 108 regions of the genome associated with risk for schizophrenia.

“Basically, using some very sophisticated genetics on a very complex region of the genome, the authors have shown that one of these 108 associations is driven by the gene encoding C4 which is part of the innate immune system. C4 is part of the complement pathway which as well as being involved in immunity is also believed to be involved in synaptic pruning. Synaptic pruning is the processes by which unnecessary connections between nerve cells are eliminated during development extending through early life and adolescence. It has long been suspected that a defect in synaptic pruning might underlie schizophrenia.

“C4 is expressed in the brain and the versions of the gene associated with schizophrenia are expressed at higher levels than other versions. Evidence from mouse experiments suggested that this might result in increased pruning in humans though extrapolation between species requires caution.

“This study adds to previous findings from genetic studies pointing to a role for genes that encode synaptic proteins in schizophrenia and points to a particular developmental mechanism, synaptic pruning, as playing a role.

“The possibility that excessive synaptic pruning plays a role in schizophrenia has always been intriguing but largely unsupported by convincing evidence. But these findings change that, and might also help explain why the symptoms of schizophrenia tend to become manifest in adolescence and early adulthood when synaptic pruning is taking place. New research will be needed to understand exactly how C4 plays a role in synaptic pruning and schizophrenia and how this process interacts with other genes and proteins that have been implicated in the disorder. Treatment implications are unclear at the present time but this new work points the finger at a particular process and implicates a set of potential new targets which will need to be explored in experimental systems.

‘Schizophrenia risk from complex variation of complement component 4’ by Sekar et al. published in Nature on Wednesday 27^th January. 

Declared interests

Prof. Pratt: Research funding from MRC, Servier and Astrazeneca

Prof. Hall: None declared

Prof. Owen: I am a member of the Schizophrenia Working Group of the Psychiatric Genetics Consortium which is a co-author of the study.