Dozens of new spontaneous genetic mutations playing a major role in the development of schizophrenia have been identified, contributing to the growing number of genetic variants that make up the illness.
The discovery was made by researchers from Columbia University Medical Center (CUMC) who conducted the largest and most comprehensive study of its kind. Findings were published in the journal Nature Genetics.
Many of the mutations identified affect genes during early-to-mid fetal development—an interesting find considering the onset of schizophrenia is usually around adolescence to early adulthood. Findings show the function of the mutated gene, as well as when the gene is expressed, are significant factors for identifying schizophrenia risk.
The findings show that in pregnancy, environmental factors such as infection or malnutrition can contribute to the development of schizophrenia. “Our findings provide a mechanism that could explain how prenatal environmental insults during the first and second trimester of pregnancy increase one’s risk for schizophrenia,” said study leader Maria Karayiorgou, MD, professor of psychiatry at CUMC, and acting chief in the division of Psychiatric and Medical Genetics at New York State Psychiatric Institute. “Patients with these mutations were much more likely to have had behavioral abnormalities, such as phobias and anxiety in childhood, as well as worse disease outcome.”
A previous study looked at 53 families, and found that spontaneous mutations (or de novo mutations) are genetic errors that patients with schizophrenia have but their parents do not. Researchers found these mutations played a major role in cases of sporadic schizophrenia. These mutations were found in the part of the genome known as the exome.
The current study consisted of 231 patient “trios” from the United States and South Africa. “Trios” consist of a patient with schizophrenia and his/her parents who do not have the illness. Researchers compared the exomes from the patient to the parents to identify if the mutations leading to schizophrenia were de novo or heritable.
Many mutated genes with diverse functions were identified. Researchers believe that several hundred genetic locations could play a factor in the development of schizophrenia. “The chance that two patients have exactly the same mutation or combination of mutations is rather small,” Karayiorgou said. “What is intriguing is that despite this variability, people with schizophrenia tend to have, more or less, the same phenotype—that is, the same clinical presentation. Our hypothesis is that many neural circuits are extremely important in schizophrenia and that these circuits are vulnerable to a number of influences. So, when any of the genes involved in these circuits are mutated, the end result is the same.”
“Although the genetics of schizophrenia are extremely complex, a coherent picture of the disease is beginning to emerge,” said study co-director Joseph Gogos, MD, PhD, and associate professor of physiology and neuroscience at Columbia University Medical Center. “Our studies show that dozens, and perhaps hundreds, of different spontaneous mutations can raise one’s risk for schizophrenia. On the surface this is daunting, but using these new findings to understand how these mutations affect the same neural circuits, including during early fetal development, raises hopes that it may be possible to develop effective prevention and treatment strategies for the disease.”