Schizophrenia genetic variants
July 5, 2014

Johns Hopkins Researchers Locate Genetic Variant Associated With Schizophrenia

redOrbit Staff & Wire Reports - Your Universe Online

According to a new study appearing in the July 3 edition of the journal Cell Stem Cell, researchers from the Johns Hopkins University School of Medicine have uncovered a new genetic variant that could result in certain people having a predisposition to schizophrenia.

While there are many genetic variants that could increase the risk of developing a psychiatric disorder, they are insufficient to cause these diseases, the researchers explained. Now, however, the Johns Hopkins researchers have described a new strategy that could reveal how these so-called “subthreshold” genetic risks could impact the development of a person’s nervous system by interacting with other risk factors.

“This is an important step toward understanding what physically happens in the developing brain that puts people at risk of schizophrenia,” senior author Dr. Guo-li Ming explained in a statement Thursday. Dr. Ming is a professor of neurology and neuroscience in the Johns Hopkins University School of Medicine’s Institute for Cell Engineering who worked on the study along with her husband, Dr. Hongjun Song.

In their study, Dr. Ming, Dr. Song and their colleagues explained that they used a multifaceted approach to find out why copy number variants in an area of the genome labeled 15q11.2 are prominent risk factors not just for schizophrenia, but for autism as well. Deletion of this part of a genome is associated with an increased risk of schizophrenia, but possessing extra copies results in an elevated risk of autism.

Their research focused on using a method which allows a patient’s skin cell to be reprogrammed into induced pluripotent stem cells (iPSCs), which can in turn be coaxed into creating any other type of cell. Using this technology, the study authors obtained stem cells from people with schizophrenia who were missing part of 15q11.2 on one of their chromosomes, ultimately coaxing them into neural progenitor cells, which are found in the developing brain.

By observing the process, the researchers found deficiencies during nerve development that could be linked to the gene CYFIP1, which maintains the structure of a nerve cell. By blocking the expression of this gene in developing mouse embryos, they found defects in the formation of the brain’s cerebral cortex, which plays a key role in consciousness.

The next step was to determine how this gene could interact with other factors, and they discovered that mutations in a pair of genes within a particular cellular pathway linked to CYFIP1 resulted in a significant increase in schizophrenia risk. According to the study authors, their research supports the belief that multiple factors in a single pathway could interact with one another to impact a patient’s potential risk for psychiatric disorders.

“The reason, the team found, is that CYFIP1 plays a role in building the skeleton that gives shape to each cell, and its loss affects spots called adherens junctions where the skeletons of two neighboring cells connect,” the university explained. A lack of CYFIP1 protein also caused some of the mice neurons to wind up in the brain’s wrong layer.

“During development, new neurons get in place by ‘climbing’ the tendrils of neural progenitor cells,” explained Ming. “We think that disrupted adherens junctions don’t provide a stable enough anchor for neural progenitors, so the ‘rope’ they form doesn’t quite get new neurons to the right place.”

The study authors also said that they discovered that CYFIP1 is part of a complex of proteins known as WAVE, which is essential to the construction of the cellular skeleton. Since many people with a CYFIP1 deletion do develop schizophrenia, they suspected that the condition was more likely to come about in men and women possessing a second defect in the WAVE complex – specifically, a variation in the signaling gene ACTR2/Arp2 that, when combined with the CYFIP1 deletion, increased schizophrenia risk more than either genetic change alone.


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