Scientists dig deeper into the genetics of schizophrenia by evaluating microRNAs

Researchers at Columbia University Medical Center have illuminated a window into how abnormalities in microRNAs, a family of molecules that regulate expression of numerous genes, may contribute to the behavioral and neuronal deficits associated with schizophrenia and possibly other brain disorders.

In the May 11 issue of Nature Genetics, Maria Karayiorgou, M.D., professor of psychiatry, and Joseph A. Gogos, M.D., Ph.D., associate professor of physiology and neuroscience at Columbia University Medical Center explain how they uncovered a previously unknown alteration in the production of microRNAs of a mouse modeled to have the same chromosome 22q11.2 deletions previously identified in humans with schizophrenia.

“We’ve known for some time that individuals with 22q11.2 microdeletions are at high risk of developing schizophrenia,” said Karayiorgou, who was instrumental in identifying deletions of 22q11.2 as a primary risk factor for schizophrenia in humans several years earlier. “By digging further into this chromosome, we have been able to see at the gene expression level that abnormalities in microRNAs can be linked to the behavioral and cognitive deficits associated with the disease.”

The investigators modeled mice to have the same genetic deletion as the one observed in some individuals with schizophrenia and examined what happens in the expression of over 30,000 genes in specific areas of the brain. When they discovered that the gene family of microRNAs was affected, they suspected that the Dgcr8 gene was responsible. The Dgcr8 gene is one of the 27 included in the 22q11.2 microdeletion and has a critical role in microRNA production, so this was a logical hypothesis. Indeed, when they produced a mouse deficient for the Dgcr8 gene, and tested it on a variety of cognitive, behavioral and neuroanatomical tests, they observed the same deficits often observed in people with schizophrenia.

“Our studies show that alterations in microRNA processing result in synaptic and behavioral deficits,” said Dr. Gogos. Drs. Karayiorgou and Gogos have partnered together to decipher the role of individual genes from 22q11 in the development of schizophrenia by using human genetics and animal model approaches.

The significance of this work is that it implicates a completely novel, previously unsuspected group of susceptibility genes and brings investigators a step closer to understanding the biological mechanisms of this disorder. Implication of such a large family of genes (the most recent estimate puts the number of human microRNAs at at least 400 that influence the expression of as many as a third of all genes) could partly account for the genetic complexity associated with this devastating disorder and explain some of the difficulties that the researchers have encountered in their efforts to pinpoint individual genes.

“Our hope is that the more we know about the genes involved in schizophrenia, the more targeted treatment can be,” said Dr. Gogos.

“Much in the way that cancer patients who have tested for a particular gene, such as BRAC1, can be tested and then treated with protocols designed specifically for them, we want to be able to know enough about the schizophrenic brain to target treatments to individual patients.”

The next step for the researchers is to find the many genes whose expression is controlled by the identified deficient microRNAs, which could in turn be involved in the pathogenesis of schizophrenia. Much more study and identification of other genetic variants must be done to further illuminate the disease’s genetic underpinnings, according to Drs. Karayiorgou and Gogos.

Source: Columbia University

Related stories:

Protein on 'speed' linked to ADHD
A genetic change in the dopamine transporter – one of the brain's dopamine-handling proteins – makes it behave as if amphetamine is present and "run backward," Vanderbilt University Medical Center investigators report this week in The Journal of Neuroscience.
Researchers Pinpoint Gene Mutations Responsible for 10 Percent of Schizophrenia
Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations that account for at least 10 percent of the non-familial cases of the disease. Researchers describe specific genetic mutations present in individuals who have schizophrenia, but not present in their biological parents who do not have the disease.
A new gene trigger for pregnancy disorder identified
The COMT gene – known already for its role in schizophrenia – has been found to play a role in preeclampsia, according to a report in today’s advance on-line issue of Nature.
Human brain appears 'hard-wired' for hierarchy
Human imaging studies have for the first time identified brain circuitry associated with social status, according to researchers at the National Institute of Mental Health (NIMH) of the National Institutes of Health. They found that different brain areas are activated when a person moves up or down in a pecking order – or simply views perceived social superiors or inferiors. Circuitry activated by important events responded to a potential change in hierarchical status as much as it did to winning money.
Concentrating on different aspects of pain leads to breakthrough in migraine genetics
Migraine is the most common cause of episodic headache, and by far the most common neurological cause of a doctor’s visit. It affects some 15% of the population, including some 41 million people in Europe, and places a considerable burden on healthcare in both the developed and the developing world.
Researchers link genetic errors to schizophrenia
A team of researchers at the University of Washington and Cold Spring Harbor Laboratories has uncovered genetic errors that may shed light on the causes of schizophrenia. The scientists found that deletions and duplications of DNA are more common in people with the mental disorder, and that many of those errors occur in genes related to brain development and neurological function. The findings, which were replicated by a team at the National Institute of Mental Health, appear in the March 27 online edition of the journal Science.
Brain scientist shedding light on learning, memory
Neurons spoke to Dr. Joe Z. Tsien when he was a sophomore college student searching for some meaningful extracurricular activity.
Royal jelly makes bee queens, boosts nurture case
New Australian National University research may explain why eating royal jelly destines honeybee larvae to become queens instead of workers – and in the process adds new weight to the role of environmental factors in the nature/nurture divide.

News discussion:

Medicine & Health news