A new study of identical twins shows for the first time that schizophrenia may be caused by not one distinct gene mutation, but an accumulation of mutations, some of which are not inherited from the twins’ parents. These mutations occur independently as individuals develop, grow and age.
“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,” Science professor Shiva Singh explained. “Any personalized medicine must be based on the biochemical pathways that are affected in each particular patient.”
The findings of Singh, Schulich School of Medicine & Dentrisy professor Richard O’Reilly and colleagues from Western, along with 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.
Researchers studied monozygotic – or identical – twins who 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 rare. Researchers also examined the DNA sequences of both twins and their parents to identify sequence differences.
The results showed the genome sequences of monozygotic twins are not identical. Their differences arise through new and independent mutations in the two individuals. Such mutations continue to accumulate and increase the genetic difference between such twins over time. Such mutations were much more common in the affected than in the unaffected member of the twin pair.
Once the mapping was complete, 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.