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Study found missing section protected against psychiatric illness

By Amanda Gardner
HealthDay Reporter

MONDAY, Sept. 29 (HealthDay News) -- New research suggests that a missing section of DNA in a certain gene may hold the key to whether a person does or does not develop bipolar disorder.

"[Our] findings show that a natural, common mutation in the GRIK4 gene protects against bipolar disorder," said Ben Pickard, lead author of a study in this week's issue of the Proceedings of the National Academy of Sciences and a member of the department of medical genetics at the University of Edinburgh in Scotland. "If a natural mutation can result in protection, then this may offer clues as to how future drug treatments might be directed. . . Another benefit from this work is that in the future, when we possess a greater knowledge of psychiatric illness mutations, we may be able to predict which individuals are at risk of illness before they develop it or tailor appropriate medicine to subsets of patients."

"These findings are important, because they link an important brain receptor to bipolar disorder, which may help researchers devise new drug treatments targeting kainate and related receptors, added Keith A. Young, an associate professor of psychiatry and behavioral science at the Texas A&M Health Science Center College of Medicine and co-director of the Central Texas Veterans Health Care System Neuropsychiatry Research Program.

According to Young, the GRIK4 gene provides the genetic coding for the glutamate neurotransmitter receptor known as the KA1 kainate receptor. These kainate receptors are considered "excitatory," because they generally make neurons more prone to firing signaling messages. The glutamate transmitter has been linked to different psychiatric disorders.

"Excitatory receptors neurons have long been thought to being involved in psychotic disorders, since drugs that attach to some glutamate receptors can mimic symptoms of psychosis, such as hallucinations," Young explained.

The authors of this study had previously identified two different regions of the GRIK4 gene as involved in both bipolar disorder and schizophrenia. Previous research had also suggested that underactivity in the brain's glutamate signaling system might underlie several different mental illnesses.

This study investigated the gene in more detail.

As it turns out, absence of this section of the gene lowered the risk of developing bipolar disorder, as demonstrated by computer modeling.

The deletion seems to be responsible for generating more glutamate receptors, thereby increasing glutamate signaling. "If kainate signaling can be stimulated, then that, too, might protect against bipolar disorder, Pickard said. "However, one problem with modulating glutamate activity like this is that too much glutamate is also harmful."

"This paper provides some of the best evidence for a protective genetic variation being involved in mediating risk for developing bipolar disorder," Young said. "Perhaps people aren't just falling out of the nest because they are weighed down by risk alleles, rather, there's probably a kind of balancing act between risk and protective alleles, which will add complexity to trying to understand how genes affect mental illness."

Young also noted that a major drug trials looking at drugs for major depression has identified the GRIK4 gene as an important predictor of how a person will respond to treatment with the antidepressants known as selective serotonin reuptake inhibitors (SSRIs).

"This may be important for bipolar disorder, whose symptoms overlap with major depression," Young said. "There may be interactions between the KA1 receptor and the serotonin system that could be involved in mediating the GRIK4 genetic effects."

More information

The National Institute of Mental Health has more on bipolar disorder.
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