Schizophrenia is one of the world’s most devastating mental disorders and affects more than 21 million people globally.
A new study of identical twins shows for the first time that schizophrenia may be caused by not one distinct but an accumulation of gene mutations, some of which are not inherited from the twins’ parents. These de novo somatic mutations occur independently in every individual as we develop, grow and age.
The findings of Shiva Singh, collaborator Richard O’Reilly and their colleagues from Western University and Christina Castellani from Johns Hopkins University School of Medicine were recently published by the journal Clinical and Translational Medicine.
In the study, the scientists proved that different patients may possess dissimilar sets of gene mutations making almost every patient genetically unique. These mutations affect a limited number of schizophrenia-related biochemical pathways in the brain necessitating novel strategies for personalized medicine based on patient-specific needs.
“The bottom line is no two patients affected with schizophrenia have identical mutations – every patient is different. Therefore, the same medication could not be used to treat these patients,” says Singh, a professor at Western’s Faculty of Science. “Any personalized medicine must be based on the biochemical pathways that are affected in each particular patient.”
Singh notes that it is now reasonable to scan a patient’s complete genome sequence, which is needed in order to identify the complete suite of genetic abnormalities underlying the patient’s schizophrenia.
This important medical discovery was made by utilizing two unique strategies. The first strategy was studying monozygotic, or identical, twins that developed from a single zygote with a focus on the rare pairs in which one has schizophrenia and the other is unaffected. Such monozygotic twins affected by schizophrenia are highly rare and therefore, highly informative. The second strategy was examining the complete DNA sequences of both twins and their parents. The aim was identifying any and all sequence differences.
The results showed for the first time that the genome sequences of monozygotic twins are not identical. Their differences arise through new (de novo) and independent mutations in the two individuals. Such mutations continue to accumulate and increase the genetic difference between such twins over time. Also, such mutations were much more common in the affected than in unaffected member of the twin pair. The differences were then mapped to the human genome which successfully identified specific genes that are ultimately affected by these mutations. It demonstrated the exceptional efficiency of the use of monozygotic twins in genetic analysis of complex multifactorial disorders and diseases like schizophrenia.
Once the mapping was complete, the next step was to determine if the genes affected actually accounted for schizophrenia in the affected twin and no schizophrenia in the unaffected twin. For this, the researchers relied on five decades of genetic research that has established that no single gene defect causes schizophrenia rather that a variety of mutations in more than 100 genes segregate with schizophrenia in different populations. This analysis established that many more schizophrenia-associated genes were mutated in the patient than the unaffected twin. Also, it allowed identification of all mutations in an individual patient for the first time. Interestingly, the genes affected belong to two critical pathways, Glutamate Receptor Signaling and Dopamine feedback pathways, which are known to be affected in this disease.
The results offer a novel strategy for personalized medicine focused on patient specific defective pathways. It will add a precision to the treatment of this devastating mental disorder that robs the life of individual patients, ruins families and causes major societal burden.
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