Schizophrenia genetic networks identified: Connection to autism found

Although schizophrenia is highly genetic in origin, the genes involved in the disorder have been difficult to identify. In the past few years, researchers have implicated several genes, but it is unclear how they act to produce the disorder. A new study by researchers at Columbia University Medical Center identifies affected gene networks and provides insight into the molecular causes of the disease.

The paper was published today in the online edition of the journal .

Using an unbiased collection of hundreds of associated with schizophrenia, the Columbia researchers applied a sophisticated to uncover hidden relationships among seemingly unrelated genes. The analysis revealed that many of the genes mutated in schizophrenia are organized into two main networks, which take part in a few key processes, including axon guidance, synapse function, neuron mobility, and chromosomal modification.

The study also uncovered an intriguing connection between schizophrenia and . "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 Center for and , 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 , are likely to converge on a set of interrelated molecular processes.

Computer analysis uncovers genetic networks

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.

Connection to autism

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.

"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 Dr. Karayiorgou.

The close relationship between involved in autism and schizophrenia raises an intriguing question: How can mutations in the same or related genes cause two different disorders?

"I like to use the analogy of car brakes," said Dr. Vitkup. "Different mechanical malfunctions of the brake mechanism can have very different functional consequences, from rapid acceleration to stalling."

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 , 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.

"Evidence of functional convergence among risk genes is consistent with the notion that schizophrenia and autism are both primarily diseases of neuronal communication. However, they have distinct clinical features and the challenge remains to identify the critical neural circuits and mechanisms that differentiate them," said Dr. Joseph A. Gogos. "This is a step in that direction."

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.

"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," Dr. Vitkup said. "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."

Study points way to future approaches to gene discovery

"To uncover all of the processes and molecular pathways involved in schizophrenia and related disorders, more gene searches are clearly necessary," said Dr. Vitkup.

Until recently, the hunt for disease was focused primarily on analyses of common genetic mutations, using so-called genome-wide association studies (GWAS). But according to Drs. Vitkup, Karayiorgou, and Gogos, a complementary, possibly less expensive, approach may be more fruitful. "By looking at individuals with schizophrenia who are born into families with no history of the disorder," Dr. Vitkup said, "we can identify de novo mutations that are likely to have caused their disorder."

Drs. Karayiorgou and Gogos recently used this approach to uncover many dozens of new schizophrenia mutations from several hundred families; nearly every mutation was unique to one patient.

"Our study demonstrates that through network-based analyses of rare de novo mutations, it is possible to implicate relevant molecular processes," said Dr. Vitkup. "Applying similar methods to larger cohorts of patients, we should be able to delineate all of the pathways and underlying complex psychiatric disorders such as ."

More information: The paper is titled, "Diverse types of genetic variation converge on functional gene networks involved in schizophrenia."

Related Stories

Scientists find gene linked to schizophrenia

Apr 12, 2010

An international study led by Université de Montréal scientists suggests that gene mutations may predispose some individuals to schizophrenia and provides new clues about the causes of this ambiguous disorder. ...

Understanding Schizophrenia

Nov 16, 2011

(Medical Xpress) -- Genetic mutations that cause schizophrenia could be linked to systems in the brain responsible for learning and memory, a major University study suggests.

Genes found for schizophrenia are involved in brain signaling

May 10, 2010

By analyzing the genomes of patients with schizophrenia, genetics researchers have discovered numerous copy number variations—deletions or duplications of DNA sequences—that increase the risk of developing schizophrenia. ...

Recommended for you

New ALS associated gene identified using innovative strategy

15 hours ago

Using an innovative exome sequencing strategy, a team of international scientists led by John Landers, PhD, at the University of Massachusetts Medical School has shown that TUBA4A, the gene encoding the Tubulin Alpha 4A protein, ...

Can bariatric surgery lead to severe headache?

16 hours ago

Bariatric surgery may be a risk factor for a condition that causes severe headaches, according to a study published in the October 22, 2014, online issue of Neurology, the medical journal of the American Academy of Neurol ...

Bipolar disorder discovery at the nano level

16 hours ago

A nano-sized discovery by Northwestern Medicine scientists helps explain how bipolar disorder affects the brain and could one day lead to new drug therapies to treat the mental illness.

Brain simulation raises questions

20 hours ago

What does it mean to simulate the human brain? Why is it important to do so? And is it even possible to simulate the brain separately from the body it exists in? These questions are discussed in a new paper ...

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

PleonasticAxiom
5 / 5 (1) Nov 11, 2012
Wow! This is fascinating!