New Insights Into the Genetics of Schizophrenia

A bold new model has been developed for this mysterious disorder.

Posted Oct 03, 2014

Let’s dive in. Schizophrenia is a psychiatric condition where the brain starts to go awry, typically in young adulthood, with symptoms manifesting as paranoia, delusions, hallucinations, and disorganized behavior (among other symptoms). The disease is progressive, leading to neuron death, and many of the afflicted are unable to lead normal lives after diagnoses. There are treatments including antipsychotic medication and either supportive or cognitive enhancing type of psychotherapies, and for some people they work very well. For others, however, current treatment either doesn’t work or the side effects of the medications are too awful to tolerate.

To anyone working in the field, its been obvious all along that the diagnosis of schizophrenia is a conglomeration of symptoms that seems to encompass several distinct disorders. In fact, researchers often call it “the schizophrenias.” The type and severity of psychosis will differ from person to person, as well as the severity of the disorganization. Some folks seem to have symptoms similar to bipolar disorder (with manias and depression on top of the deteriorating mental condition over time and chronic psychotic symptoms) whereas others seem to have no pathological mood fluctuations. Some people seem to be psychotic all the time, whereas in others it seems to wax and wane, often dependent upon stressful life events. Schizophrenia is about 80% inherited, but the rest is due to environmental factors (perhaps exposure to cannabis at a critical time period in adolescent brain development, or maternal exposure to certain infections while pregnant, paternal age, or even choline or omega 3 deficiency…there are many possible causative factors in addition to the risk genes).  

Because schizophrenia is so devastating and highly inherited, researchers have been searching for the schizophrenia “gene” for a long time. Finding the gene could mean more targeted treatments and aggressive early intervention in those who have the highest risk, so that perhaps the disease wouldn’t progress. What they’ve found so far in very large genome-wide association studies is not a single gene, but sets of different ones that together confer greatly increased risk of developing the disorder. It’s difficult to find these gene networks, because the ways genes interact is extremely complex, changes during development, and in many cases is poorly understood. For the first time, researchers were able to combine three large sets of data of folks from varying populations with and without schizophrenia that had not only information about the genes, but more specific information about patients’ symptoms.

Using an immense amount of data crunching, researchers found what small genetic differences were in common between different folks with symptoms of schizophrenia, then more precisely define which of these hundreds of risk genes were more or less risky.  They found one set in 9 different people where every single person had schizophrenia (100% risk), and others that conferred far less risk…but there were 42 different sets of genes that had risk for schizophrenia of >70%. By crunching even more numbers for these high risk sets of genes, they found that some of these sets “grouped” together in what is called a genotypic network. Then they overlapped the data from the risky genetic networks with the symptoms of the sick individuals to come out with eight different distinct diseases, now all known as “schizophrenia.”

To clarify what this number crunching means, we need a basic understanding of genes, proteins, and expression. While we have the same genes in all cells of our body (for the most part), obviously different genes are expressed in our eyeballs than in our feet, or we would look mighty strange and have a hard time walking. Different genes are also expressed at different times in our development, causing us to grow and change. Genes can produce proteins that are then spliced and folded differently depending on where the cells are and other genes and proteins that are expressed, just as 3 yards of green silk can make a pretty dress or a large, expensive sack. Using the same analogy, the quality and perfection of the dress can also be affected all down the line of production…a faulty dress pattern, an inefficient seamstress, or sick silkworms.  A genotypic network would include all these disparate genes that have to work together to create the correct protein of correct shape at the right time and place. Problems in the network could lead to similar symptoms (schizophrenia) with different specific genes being responsible.

The researchers found certain phenotypes that corresponded to certain genotypes. For example, severe progressive disease with continuous hallucinations, disorganization, and delusions (such as mind-reading or thoughts being inserted in the brain) corresponded to certain gene sets, whereas blunted emotional response, disorganized speech and thought, and paranoia without hallucinations corresponded to other gene sets.  Some of these symptoms (such as hallucinations) are known as “positive” symptoms as they are “added” compared to normal human experience, whereas other symptoms (like social withdrawal or blunted emotional response) are known as “negative” symptoms. The severity and progression of the disease also varied among the sets, from very severe process to moderate to mild. The eight final disorders of schizophrenia included severe process positive and negative, positive and negative, negative, positive, severe process positive, moderate process disorganized negative, moderate process positive and negative, and moderate process continuous positive. 

While not a particularly exciting nomenclature, just being able to find these genes and link them to clusters of disease is an amazing feat. It means we can examine how useful antipsychotic medication is for someone affected with a certain type to use it in those where it is likely to be helpful, and avoid using it where it would do more harm than good. We could work out novel pharmaceuticals based on the actual physiologic deficits predicted by the genes. We could see which gene clusters/schizophrenia seem to be associated with high levels of cannabis use or are related to problems with cerebral inhibition which *might* be fixed by choline supplementation.   

If this research holds true on reexamination, we might be taking the first steps toward isolating the pathology of a major psychiatric disorder, as infectious disease doctors did a hundred and fifty years ago with the development of germ theory.

Image of John Nash from Wikimedia commons

Image from Wikimedia commons

Copyright Emily Deans MD

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