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Disruptions to Prenatal Gene Network Linked to Schizophrenia Development

NEW YORK (GenomeWeb News) – Researchers have traced gene mutations found in people with schizophrenia to networks involved in fetal brain development, as they reported in Cell today.

Schizophrenia, a highly heritable disease, has been linked to a number of individually rare genetic mutations. Patients with the sporadic, non-familial form of schizophrenia are especially likely to have de novo mutations behind their disease.

Through exome sequencing of patients from otherwise healthy families, their parents, and, when possible, unaffected siblings, researchers led by the University of Washington's Mary-Claire King and Jon McClellan homed in on de novo mutations associated with schizophrenia. They then mapped the genes harboring those mutations onto transcriptional profiles of the brain that had been built at various developmental time points. Many of the genes affected in schizophrenia have roles in neuronal migration, synaptic transmission, and other crucial processes, especially during prenatal development, the researchers found.

"Processes critical for the brain's development can be revealed by the mutations that disrupt them," said King, a professor of genome sciences and medicine at the University of Washington, in a statement. "Mutations can lead to loss of integrity of a whole pathway, not just of a single gene. Our results implicate networked genes underlying a pathway responsible for orchestrating neurogenesis in the prefrontal cortex in schizophrenia."

She and her colleagues noted that their findings support the neurodevelopmental hypothesis of schizophrenia. That hypothesis, put forward a quarter century ago, posits that disruptions to prenatal cortical development lie behind the development of schizophrenia.

In this study, King, McClellan, and their colleagues performed exome sequencing on nearly 400 people, in sets of trios or quads that included a person with schizophrenia, that person's parents, and, possibly, a healthy sibling. Their exomes were sequenced on the Illumina HiSeq 2000 to a median depth of coverage of at least 100x.

By comparing the 105 probands' exome sequences to those of their parents, the researchers uncovered 103 de novo mutations, 57 of which were predicted to be damaging.

The 84 unaffected siblings, by comparison, harbored 67 de novo mutations, of which slightly more than half were predicted to be damaging.

King, McClellan, and their colleagues traced the interactions of the 54 genes harboring de novo mutations in the probands to find networks involved in the development of schizophrenia. As a control, they conducted similar analyses on de novo mutations identified in the unaffected siblings.

Of those proband-identified deleterious mutations, 18 mapped to an interconnected protein-protein interaction network with a number of edges and nodes. The sibling-identified mutations, by contrast, mapped to a network with fewer edges and nodes, as did the benign mutations identified in the probands.

Then by examining RNA sequencing data collected from different brain regions during a number of life stages as part of the BrainSpan Atlas, the researchers were able to pinpoint the activation of that network to the prenatal frontal cortex, particularly the dorsolateral and ventrolateral prefrontal cortex, which are linked to cognitive control and decision-making, respectively.

Previous studies, the researchers noted, have hinted at a role for the prefrontal cortex in schizophrenia. Neuroimaging and postmortem brain studies, for instance, have indicated that anatomical and functional deficits may be present there in people with schizophrenia.

The merged PPI networks active in both regions included 50 of the 54 genes uncovered harboring de novo mutations in the patients with schizophrenia; in addition, the network included 126 connections among those genes.

Those 50 genes play critical roles in neurogenesis and synaptic integrity, the researchers said. For example, ITGA3 and LAMA2 are involved in neuronal migration, while MKI67 is linked to cellular proliferation, and others like ADCY9 and CACNA1I have roles in neurotransmitter signaling and synaptic transmission.

"These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia," wrote King, McClellan, and their colleagues.

They further noted that their findings could help identify biology-specific treatments for the disease. "Medications targeting glutamate and T-type calcium channel pathways are potential therapeutic mechanisms suggested by mutant genes in our patients," they said, adding that "[l]arge-scale collaborative efforts in genomics and neurobiology are needed to reveal additional therapeutic targets based on the genes and biological mechanisms underlying brain circuitry."

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