London: Researchers at Columbia University Medical Center have identified gene networks affected in schizophrenia.
They also uncovered an intriguing connection between schizophrenia and autism.
“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 the study’s senior author, Dennis Vitkup, PhD, associate professor in the Department of Biomedical Informatics, the Centre for Computational Biology and Bioinformatics, and the Columbia Initiative in Systems Biology at Columbia University Medical Center.
“It shows how closely the autism and schizophrenia genetic networks are intertwined,” he added.
Although it will take time to translate the findings into practical treatments, the study provides insight into the molecular causes of schizophrenia. It also suggests that mutations associated with schizophrenia, autism, and probably many other psychiatric disorders, are likely to converge on a set of interrelated molecular processes.
To discover potential connections among genes mutated in schizophrenia, Dr. Vitkup and colleagues developed a computational approach, called NETBAG+, to identify networks of genes likely to be responsible for the same genetic phenotype. They then gathered the strongest mutations that had been observed in schizophrenia by other researchers—including a set of de novo mutations recently described by a team of Columbia researchers led by Maria Karayiorgou, MD, and Joseph A. Gogos, MD, PhD—and fed them into the program.
The program uncovered two genetic networks. Genes in the first network are involved primarily 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 highly active during prenatal development, suggesting that changes in the brain that cause schizophrenia later in life are laid down very early in life.
Dr. Vitkup also compared his schizophrenia networks with networks found in neurodevelopmental disorders such as autism. One schizophrenia network is strongly related to an autism network he described in a study published last year. Both networks contain genes involved in axon guidance, synapse function, and cell migration.
Dr. Vitkup looked at large mutations called copy number variants (CNVs) that can lead to either schizophrenia or autism. CNVs involve long stretches of the genome containing several genes that have been either duplicated or deleted. Duplication of a region increases the “dosage” of its genes; deletion of a region decreases the dosage.
In CNVs involved in the growth of dendrites, or dendritic spines, at the ends of neurons, he found decrease in growth to be more common in schizophrenia and increase in growth more common in autism.
“That’s consistent with what’s been found by postmortem brain studies,” he said.
Dr. Vitkup predicts that many more genes involved in schizophrenia and autism will eventually be found—possibly up to 1000 genes for each disorder—but a significant fraction of them will likely fall into the networks and pathways identified in the current study.
A paper reporting their finding has been published in the online edition of the journal Nature Neuroscience.