Schizophrenia and Bipolar genetics: One Surprise and One Confirmation

This month, a very sophisticated genetic study took a look at the differentiation  of psychotic disorders from controls.  They looked at both schizophrenia and bipolar disorder.  They looked at which genes were more active in brain tissue, and  correlated this to a history of psychosis.  Specifically, they looked at increased gene activity, as a reflection of either genetic variations from birth, signalling by some genes to turn on other genes (like a promoter) , or response to environment to up-regulate “turn on” the gene.  They compared controls with subjects with a known history of psychosis. They correlated their data with previous research to strengthen their results.

Amazingly, they found a pattern across and within the five biggest genome studies yet done to date for either schizophrenia or bipolar, each involving thousands of patients and millions of gene variants. Note: these are respected studies, like the Stanley Medical Foundation, the worldwide schizophrenia consortium, and the worldwide bipolar consortium.  The number crunching was massive, so they had to use supercomputers at the University of Chicago. They characterized 24 different gene clusters, which they called modules, and only two of them were significant for psychosis.

They found one gene module (a cluster of genes that interacted together in a functional web) they called MA1 which had to do with neuron growth, development, signalling, and differentiation. This was expected.  It furthered the neurodevelopmental hypothesis that psychosis occurs when proper brain development (probably up to age 25) is influenced by altered, rare, or unusual gene–>protein signals making it vulnerable.  The theory goes:  triggers like stress, drugs, and brain injury can tip off the “first break” in a vulnerable brain cortex (n.b. these data show that it is abnormal development of the cerebral cortex which leads to psychosis.)  Using consortium genetic variant studies (GWAS) for psychosis they confirmed that the gene variations in their MA1 module had previously been found in psychotic disorders.  This was confirmation.  The vulnerability genes, so to speak, are ones you are born with, due to discrete changes (SNPs* or CNVs*) in the DNA sequence.

They also found a surprise.  The other module (MA3) deals with heavy metal handling in the brain!  It also deals with oxidation or inflammation pathways.  Apparently, these genes were more active because of current demands put on them, NOT because of any inherited genetic variations in DNA sequence.   These genes are likely more active to respond to some brain insult like heavy metal load, inflammation, or oxidative damage.  This supports a theory that psychosis is due to infection or environmental toxin!  This was a provocative and unexpected finding.

It is tempting to conclude that psychosis occurs in either 1) a “neuroatypical” brain (caused by genetic variants) exposed to a toxin or infection, or 2)  a typical brain is exposed to heavy metal toxins or infection–the data about intrauterine exposure to the influenza, toxoplasmosis, CMV come to mind– or 3) a “neuroatypical” brain activated by stress and/or nonspecific environmental triggers.

The implications are uncertain, and future research will have to sort this out.

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