By tracing spontaneous mutations and reverse engineering the outlines of a disrupted prenatal gene network in schizophrenia, researchers are able to detect areas of damage to the brain. Some people with the brain disorder may suffer from impaired birth of new neurons, or neurogenesis, in the front of their brain during prenatal development, suggests the study, which was funded by the National Institutes of Health.
"Processes critical for the brain's development can be revealed by the mutations that disrupt them," explained Mary-Claire King, Ph.D., University of Washington (UW), Seattle, a grantee of the NIH's National Institute of Mental Health (NIMH). "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."
King, and collaborators at UW and seven other research centers participating in the NIMH genetics repository, report on their discovery August 1, 2013 in the journal Cell
"By linking genomic findings to functional measures, this approach gives us additional insight into how early development differs in the brain of someone who will eventually manifest the symptoms of psychosis," said NIMH Director Thomas R. Insel, M.D.
Earlier studies had linked spontaneous mutations to non-familial schizophrenia and traced them broadly to genes involved in brain development, but little was known about convergent effects on pathways. King and colleagues set out to explore causes of schizophrenia by integrating genomic data with newly available online transcriptome resources that show where in the brain and when in development genes turn on. They compared spontaneous mutations in 105 people with schizophrenia with those in 84 unaffected siblings, in families without previous histories of the illness.Unlike most other genes, expression levels of many of the 50 mutation-containing genes that form the suspected network were highest early in fetal development, tapered off by childhood, but conspicuously increased again in early adulthood - just when schizophrenia symptoms typically first develop. This adds to evidence supporting the prevailing neurodevelopmental model of schizophrenia. The implicated genes play important roles in migration of cells in the developing brain, communication between brain cells, regulation of gene expression, and related intracellular workings.