Here at the BHRC we are very interested in increasing our understanding of brain dysfunction. As a result, when we see headlines like the ones that have appeared in the news recently, like The Guardian story Schizophrenia breakthrough as genetic study reveals link to brain changes we really start to get excited.
After a read through of the original study we realised that some of the details might be a little hard to follow for non-neuroscientists, so we have had a go at putting together the main findings.
To summarise, researchers from Harvard Medical School and the Broad Institute in the USA have discovered a genetic link between the immune system and the development of schizophrenia. So what does this mean?
Your genome is made up of billions of genes. Those genes physically exist as combinations of the four nucleotides A, C, T, and G. Each nucleotide is like a puzzle piece; it has a very specific shape and can only fit together with its corresponding piece. A fits with T, and C fits with G. A single gene can be hundreds of thousands of nucleotides long. The pattern of nucleotides dictates what the gene will ultimately do and so a change or difference in this pattern can have all sorts of effects.
It is normal to have a certain amount of variation in genes between people. These variations are what make us individuals. But some variations are more dramatic than others, and in some cases can alter the intended effect of the gene.
Genetic variations in an area of the genome associated with the immune system have long been accepted as a genetic factor in schizophrenia. Until now, however, it has been unclear exactly what these variations might do, or even if they have any effect at all.
In the current study, the researchers conducted a genome wide association study (GWAS). These studies examine the genomes of a large number of people to try to identify if any genetic variations are associated with a particular trait, which in this case was schizophrenia. This GWAS included the genomes of more than 64,000 people. What the researchers found was that a specific kind of change, called a SNP, occurred at a very high rate in genes associated with the Major Histocompatibility Complex, or MHC, which is part of the immune system.
SNPs, or Single nucleotide polymorphisms to give them their full name, are changes which switch out a single nucleotide for a different one. Depending on where they end up in the genetic code these tiny substitutions can be harmless, disastrous or somewhere in-between.
The main role of the MHC is to produce molecules which help the immune cells of the body to destroy invading organisms, infected cells, and dysfunctional cells. The MHC does this by producing proteins which attach to these unwanted cells, thereby tagging them to tell the immune cells that they should be destroyed. The gene within the MHC which was most impacted by SNPs in the DNA of people with schizophrenia is called complement component 4, or C4 for short. The researchers believe that C4 may play a role in this tagging process in the brain.
C4 produces two proteins in humans, C4A and C4B, which are both expressed by neurons. These proteins might be important for a process known as synaptic pruning which occurs a number of times throughout a person's life. During synaptic pruning the immune cells of the brain, microglia, identify and destroy any unnecessary connections between neurons. This allows the brain to work smoothly, and minimises the energy cost of running the brain. Microglia identify which synapses, or whole neurons, to destroy using the same tagging process we described earlier. Although scientists were aware that complement component 3 was important in this process, it was unclear whether C4 was also important. However, when the researchers examined the brains of mice who lacked C4 they found excessive branching, which suggests that C4 is also important in the pruning process.
So, have these genetic alterations identified in the GWAS changed the amount of C4 in the brains of people with schizophrenia? And if they have, what effect could this have?
The researchers examined the post-mortem brains of 35 individuals with schizophrenia and compared the levels of C4 in those brains with the levels of C4 in other post-mortem brains. What they found was that the concentration of C4A was 1.4 times higher in the brains of people with schizophrenia. This suggests that the mutations in the C4 gene might have caused excessive pruning in these peoples brains.
Synaptic pruning itself is a very important process, without which other issues such as autism spectrum disorder tend to arise. However, the excessive pruning which may occur in people with schizophrenia could be the cause of the abnormal rates of cell death which are related to the disorder. The neurons of people with schizophrenia also tend to display very limited branching and reduced numbers of synapses compared to other neurons, which may contribute to the symptoms they develop.
While this finding does not explain all of the cellular issues we observe with schizophrenia, such as excessive glutamate signalling or the dysfunction of certain neurons, it is a major step forward in understanding the disorder as a whole. The more we know about the underlying causes of a disorder the more prepared we are to develop treatments and potential cures.
The wide-ranging nature of the symptoms of schizophrenia has made it difficult to understand and treat, but this new research may highlight a common factor that has the potential to impact the way that we treat schizophrenia as a whole, and provides real hope for the development of a cure in the future.