Schizophrenia genes stunt brain development

In the largest study of its kind, scientists have identified a number of schizophrenia-related gene variants that alter expression of certain genes in the human brain. The scientists found that altering the expression of a few of these genes stunted brain development in animal models. This suggests that changes in expression levels of particular genes might affect the human brain and the development of schizophrenia, according to a September 26, 2016 study in Nature Neuroscience.

More the 100 gene loci are known to have schizophrenia-associated variants, yet scientists don’t know how these common variants confer risk. Post-mortem gene expression studies of patients with schizophrenia have detected subtle abnormalities in multiple brain regions, including the prefrontal and temporal cortices, hippocampus, and several specific cell types.

To investigate this further, researchers from the CommonMind Consortium—a public-private partnership that generates genomic data on psychiatric disorders—performed post-mortem RNA sequencing of the dorsolateral prefrontal cortex from 258 patients with schizophrenia as well as 279 control subjects. (Incidentally, this created the largest publicly available resource to date of schizophrenia-related gene expression and genetic regulation.)

“As we move from gene discovery—which for risk genes can be done in any tissue—to the human brain, we are able to explore changes in the molecular machinery of the cell, such as gene expression and epigenetic mechanisms, that are impacted by these genetic risk factors,” explained Thomas Lehner, PhD, Director of the Office of Genomics Research Coordination at the National Institute of Mental Health (NIMH), in Bethesda, MD. NIMH helped to build the CommonMind Consortium and fund this study, which involved a team of 56 researchers supported by 15 NIMH grants.

The researchers performed RNA sequencing to determine that of the 108 gene loci known to be associated with schizophrenia, about 20 could potentially regulate brain gene expression. Of these 20 loci, 5 variants modulated expression of only 1 gene: FURIN, TSNARE1, CNTN4, CLCN3, and SNAP91.

The researchers experimentally altered expression of these 5 genes in zebrafish, and found that the alterations in 3 of them—FURIN, TSNARE1, and CNTN4—resulted in neuroanatomical deficits in brain development. For example, depleting the furin protein in zebrafish stunted head growth by 24%.

To further elucidate this observation, the researchers knocked down the FURIN gene in human neural progenitor cells, which significantly decreased their migration. Taken together, these findings support the hypothesis that changes in expression levels of these genes might disrupt the developing brain in schizophrenia.

“This study paves the way for connecting genetic influences on cellular function with changes in macroscopic circuits of the brain that may ultimately lead to disease,” the authors concluded.