In the largest and most comprehensive study of its kind, researchers from Columbia University Medical Center have identified dozens of new spontaneous genetic mutations (de novo mutations) that play a significant role in the development of schizophrenia.
Although symptoms of schizophrenia typically appear during adolescence and early adulthood, many of the mutations occurred during early-to-mid fetal development.
The findings indicate that both the function of the mutated gene and the timing of expression are vital in determining the risk for schizophrenia.
The findings add to previous studies showing that environmental factors, such as malnutrition or infections during pregnancy, 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, M.D., professor of psychiatry at Columbia University Medical Center.
“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.”
In a previous study of 53 families, researchers found that spontaneous mutations — genetic errors that are present in patients but not in their parents — are linked to a significant amount of sporadic cases of schizophrenia. The mutations were found in the part of the genome that codes for proteins, known as the exome.
“Although the genetics of schizophrenia are extremely complex, a coherent picture of the disease is beginning to emerge,” said co-director of the study Joseph Gogos, M.D., Ph.D., 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.”
In the new study, whole-exome sequencing was performed on 231 patient “trios” from the United States and South Africa. Each trio included a patient and both of his or her parents, who were both unaffected by the disease.
By comparing the exomes of the patients with those of their parents, the researchers were able to identify de novo rather than inherited mutations that may contribute to schizophrenia.
The researchers identified many mutated genes with different functions. They also identified four new genes (LAMA2, DPYD, TRRAP, and VPS39) affected by recurrent de novo events within or across the two populations, a finding unlikely to have occurred by chance.
“The chance that two patients have exactly the same mutation or combination of mutations is rather small,” said Karayiorgou.
“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.”
The study is published in the online edition of the journal Nature Genetics.