“If we hadn’t known that these were two different diseases, and had put all the mutations into a single analysis, it would have come up with very similar networks,” said Dennis Vitkup, Ph.D., associate professor at Columbia University Medical Center.
“It shows how closely the autism and schizophrenia genetic networks are intertwined,” he added.
The study provides new insight into the molecular causes of schizophrenia. It also suggests that mutations associated with schizophrenia, autism, and probably many other psychiatric disorders, most likely come together in certain molecular processes.
Using an unbiased collection of hundreds of mutations linked to schizophrenia, the Columbia researchers applied a computational approach to discover hidden relationships among seemingly unrelated genes.
The researchers gathered the strongest mutations that had been observed in schizophrenia research.
The program uncovered two genetic networks. Genes in the first network are involved mainly in axon guidance, synapse function, and cell migration. Genes in the second network are involved in chromosomal organization and remodeling.
Parts of both networks are extremely active during fetal development, suggesting that changes in the brain that cause schizophrenia in early adulthood may begin very early in life.
Vitkup then compared his schizophrenia networks with networks found in neurodevelopmental disorders such as autism. One schizophrenia network is closely related to an autism network he described in a previous study. Both networks include genes involved in axon guidance, synapse function and cell migration.
“Our recent mutational analysis showed that this overlap includes primarily genes that are important for early fetal development. This is not surprising, because some cases of schizophrenia and likely many cases of autism have neurodevelopmental origin,” said Maria Karayiorgou, M.D., of Columbia.
This raises an intriguing question: How can mutations in the same or related genes cause two separate disorders?
“I like to use the analogy of car brakes,” said Vitkup. “Different mechanical malfunctions of the brake mechanism can have very different functional consequences, from rapid acceleration to stalling.”
Vitkup looked at large mutations called copy number variants (CNVs) that can lead to either schizophrenia or autism.
In CNVs involved in the growth of dendrites, or dendritic spines, found at the ends of neurons, he discovered that a decrease in growth was more common in schizophrenia and an increase in growth more common in autism. “That’s consistent with what’s been found by postmortem brain studies,” he said.
Vitkup predicts that many more genes involved in schizophrenia and autism will eventually be identified — possibly up to 1,000 genes for each disorder — but a significant fraction of them will likely fall into the networks and pathways identified in the current study.
“Until a few years ago, people were looking for just a handful of genes responsible for autism and schizophrenia, so the idea that many hundreds of genes are involved is a big change in thinking,” said Vitkup.
“Our study and the studies of our collaborators suggest that in the search for the causes of complex genetic disorders, it will be more productive to look for common pathways and gene circuits than for a handful of causal genes. This type of network analysis gives us a way to begin to make sense of what’s happening.”
“To uncover all of the processes and molecular pathways involved in schizophrenia and related disorders, more gene searches are clearly necessary,” he said. “By looking at individuals with schizophrenia who are born into families with no history of the disorder, we can identify de novo mutations that are likely to have caused their disorder.”
The research is published in the online edition of the journal Nature Neuroscience.