Schizophrenia and Autism Linked

Megan Brooks

November 16, 2012

Investigators at Columbia University Medical Center in New York City found several cohesive gene networks affected in schizophrenia and determined that these gene networks overlap with autism.

"Very interestingly, the networks that we find for schizophrenia and for autism are quite similar," senior author Dennis Vitkup, PhD, told Medscape Medical News.

"This suggests that these 2 diseases, and probably many other psychiatric diseases, overlap in terms of the processes they perturb; they perturb some processes important for early brain development," added Dr. Vitkup.

The study was published online November 11 in Nature Neuroscience.

Fruitful Approach

Dr. Vitkup and colleagues say a "pressing challenge" of human genetics is to combine diverse disease-related genetic variations to find pathways and networks affected in common disorders.

"The main statistical challenge of the genome data," Dr. Vitkup said, "is the number of gene mutations identified that are potentially involved in schizophrenia; because there are so many, you hardly ever see recurrence."

The approach taken by his team, he said, is to seek a cohesive functional gene network that consists of all the genes perturbed by these mutations and then to look for the significance of that network.

"So we don't find the significance of every gene, but we find the significance for the whole network. That's what's novel here, and we believe it's a quite fruitful approach."

Using a computational algorithm they developed called NETBAG+, the researchers were able to integrate data from multiple types of genetic variation: de novo single nucleotide variants from recent studies, de novo copy number variants from published genome-wide scans, and genomic regions implicated by the genome-wide association studies. In total, the set contained 1044 genes.

The analysis revealed that many of the genes that are mutated in schizophrenia are organized into 2 main networks, which take part in a few key processes, including axon guidance, synaptic function, neuronal cell mobility, and chromosomal remodeling.

Connection to Autism

"The genes forming the networks are highly expressed in the brain, with higher brain expression during prenatal development," the researchers say. "The identified networks are functionally related to genes previously implicated in schizophrenia, autism and intellectual disability."

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

Knowing the pathway or networks affected in schizophrenia and autism begins to "show us the footprint of the disease," Dr. Vitkup commented.

He predicts that many more genes involved in schizophrenia and autism will eventually be found — possibly as many as 1000 genes for each disorder — and many will likely fall into the networks and pathways they've identified.

"If you just focus on individual genes — 1 gene out of 1000 — doesn't really mean much. But if you have a smaller number of pathways, then you can better identify the significance," he said.

"This research," he added, "helps us understand the pathways and biological processes that are affected, which can have clinical implications because it can help direct you toward drug targets or for prognostic purposes."

Important Research

Raimond L. Winslow, PhD, director, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, who was not involved in the research, called it a "very important paper, worth publishing."

"Identifying network-disease relationships rather than gene-disease relationships is the next step in understanding the molecular basis of human disease. Identifying gene networks associated with schizophrenia will yield significant advances towards understanding the functional basis of this disease," he told Medscape Medical News.

The research was supported in part by a grant from the Simons Foundation, a US National Centers for Biomedical Computing (MAGNet) grant to Columbia University, US National Institute of Mental Health grants, and the Lieber Center for Schizophrenia Research at Columbia University. The US National Institute of General Medical Sciences and the US National Alliance for Research in Schizophrenia and Depression also provided grant money for this research. The authors and Dr. Winslow have disclosed no relevant financial relationships.

Nat Neurosci. Published online November 11, 2012. Abstract