How Specific Gene Variants May Raise Bipolar Disorder Risk

cpgv level
In this data visualization, each horizontal line is an individual. Those with bipolar disorder were more likely to be on the lower end of the CPG2 protein expression scale, and more likely to have gene variants that reduced expression. Credit: Rathje, Nedivi, et. al.

A new study by researchers at The Picower Institute for Learning and Memory at MIT finds that the protein CPG2 is significantly less abundant in the brains of people with bipolar disorder (BD) and shows how specific mutations in the SYNE1 gene that encodes the protein undermine its expression and its function in neurons.

Led by Elly Nedivi, professor in MIT’s departments of Biology and Brain and Cognitive Sciences, and former postdoc Mette Rathje, the study goes beyond merely reporting associations between genetic variations and psychiatric disease. Instead, the team’s analysis and experiments show how a set of genetic differences in patients with bipolar disorder can lead to specific physiological dysfunction for neural circuit connections, or synapses, in the brain.
The mechanistic detail and specificity of the findings provide new and potentially important information for developing novel treatment strategies and for improving diagnostics, Nedivi said.

“It’s a rare situation where people have been able to link mutations genetically associated with increased risk of a mental health disorder to the underlying cellular dysfunction,” said Nedivi, senior author of the study online in Molecular Psychiatry. “For bipolar disorder this might be the one and only.”

The researchers are not suggesting that the CPG2-related variations in SYNE1 are “the cause” of bipolar disorder, but rather that they likely contribute significantly to susceptibility to the disease. Notably, they found that sometimes combinations of the variants, rather than single genetic differences, were required for significant dysfunction to become apparent in laboratory models.

“Our data fit a genetic architecture of BD, likely involving clusters of both regulatory and protein-coding variants, whose combined contribution to phenotype is an important piece of a puzzle containing other risk and protective factors influencing BD susceptibility,” the authors wrote.

CPG2 in the Bipolar Brain

During years of fundamental studies of synapses, Nedivi discovered CPG2, a protein expressed in response to neural activity, that helps regulate the number of receptors for the neurotransmitter glutamate at excitatory synapses. Regulation of glutamate receptor numbers is a key mechanism for modulating the strength of connections in brain circuits. When genetic studies identified SYNE1 as a risk gene specific to bipolar disorder, Nedivi’s team recognized the opportunity to shed light into the cellular mechanisms of this devastating neuropsychiatric disorder typified by recurring episodes of mania and depression.

For the new study, Rathje led the charge to investigate how CPG2 may be different in people with the disease. To do that, she collected samples of postmortem brain tissue from six brain banks. The samples included tissue from people who had been diagnosed with bipolar disorder, people who had neuropsychiatric disorders with comorbid symptoms such as depression or schizophrenia, and people who did not have any of those illnesses. Only in samples from people with bipolar disorder was CPG2 significantly lower. Other key synaptic proteins were not uniquely lower in bipolar patients.

“Our findings show a specific correlation between low CPG2 levels and incidence of BD that is not shared with schizophrenia or major depression patients,” the authors wrote.

From there they used deep-sequencing techniques on the same brain samples to look for genetic variations in the SYNE1 regions of BD patients with reduced CPG2 levels. They specifically looked at ones located in regions of the gene that could regulate expression of CPG2 and therefore its abundance.
Meanwhile, they also combed through genomic databases to identify genetic variants in regions of the gene that code CPG2. Those mutations could adversely affect how the protein is built and functions.

Examining Effects

The researchers then conducted a series of experiments to test the physiological consequences of both the regulatory and protein coding variants found in BD patients.

To test effects of non-coding variants on CPG2 expression, they cloned the CPG2 promoter regions from the human SYNE1 gene and attached them to a ‘reporter’ that would measure how effective they were in directing protein expression in cultured neurons. They then compared these to the same regions cloned from BD patients that contained specific variants individually or in combination. Some did not affect the neurons’ ability to express CPG2 but some did profoundly. In two cases, pairs of variants (but neither of them individually), also reduced CPG2 expression.

Previously Nedivi’s lab showed that human CPG2 can be used to replace rat CPG2 in culture neurons, and that it works the same way to regulate glutamate receptor levels. Using this assay they tested which of the coding variants might cause problems with CPG2’s cellular function. They found specific culprits that either reduced the ability of CPG2 to locate in the “spines” that house excitatory synapses or that decreased the proper cycling of glutamate receptors within synapses.

The findings show how genetic variations associated with BD disrupt the levels and function of a protein crucial to synaptic activity and therefore the health of neural connections. It remains to be shown how these cellular deficits manifest as biopolar disorder.

Nedivi’s lab plans further studies including assessing behavioral implications of difference-making variants in lab animals. Another is to take a deeper look at how variants affect glutamate receptor cycling and whether there are ways to fix it. Finally, she said, she wants to continue investigating human samples to gain a more comprehensive view of how specific combinations of CPG2-affecting variants relate to disease risk and manifestation.

Materials provided by Picower Institute at MIT.

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Can Early Symptoms Predict Bipolar Disorder? Evidence Shows Differing Patterns of Risk Factors

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A picture of pink pills in a bubble pill container. Credit to flickr.com user Kris A. Used with permission under a Creative Commons license.

Two patterns of antecedent or “prodromal” psychiatric symptoms may help to identify young persons at increased risk of developing bipolar disorder (BD), according to a new analysis in the Harvard Review of Psychiatry.

Early signs of BD can fall into a relatively characteristic “homotypic” pattern, consisting mainly of symptoms or other features associated with mood disorders; or a “heterotypic” pattern of other symptoms including anxiety and disruptive behavior. Environmental risk factors and exposures can also contribute to BD risk, according to the analysis by Ciro Marangoni, MD, at the Department of Mental Health, Mater Salutis Hospital, Legnato, Italy; Gianni L. Faedda, MD, Director of the Mood Disorder Center of New York, NY, and Co-Chairman of a Task Force of the International Society for Bipolar Disorders on this topic; and Professor Ross J. Baldessarini, MD, Director of the International Consortium for Bipolar & Psychotic Disorders Research of the Mailman Research Center at McLean Hospital in Belmont, Mass.

The authors reviewed and analyzed data from 39 studies of prodromal symptoms and risk factors for later development of BD. Their analysis focused on high-quality evidence from prospective studies in which data on early symptoms and risk factors were gathered before BD was diagnosed.

BD is commonly preceded by early depression or other symptoms of mental illness, sometimes years before BD develops, as indicated by onset of mania or hypomania. Nevertheless, the authors note that “the prodromal phase of BD remains incompletely characterized, limiting early detection of BD and delaying interventions that might limit future morbidity.”

The evidence reviewed suggested two patterns of early symptoms that “precede and predict” later BD. A homotypic pattern consisted of affective or mood-associated symptoms that are related to, but fall short of, standard diagnostic criteria for BD: for example, mood swings, relatively mild symptoms of excitement, or major depression, sometimes severe and with psychotic symptoms.
The authors note that homotypic symptoms have “low sensitivity” — that is, most young people with these mood symptoms do not later develop BD. However, this symptom pattern also had “moderate to high specificity” — homotypic symptoms do occur in many patients who go on to develop BD.

The heterotypic pattern consisted of other types of prodromal symptoms, such as early anxiety and disorders of attention or behavior. This pattern had low sensitivity and specificity: relatively few patients with such symptoms develop BD, while many young people without heterotopic symptoms do develop BD.

The study findings also associate several other factors with an increased risk of developing BD, including preterm birth, head injury, drug exposures (especially cocaine), physical or sexual abuse, and other forms of stress. However, for most of these risk factors, both sensitivity and specificity are low.

Although many elements of the reported patterns of prodromal symptoms and risk factors have been identified previously, the study increases confidence that they are related to the later occurrence of BD. The researchers note that the findings of high-quality data from prospective studies are “encouragingly similar” to those of previous retrospective and family-risk studies.

“There was evidence of a wide range of [psychiatric] symptoms, behavioral changes, and exposures with statistically significant associations with later diagnoses of BD,” the authors conclude. With further study, the patterns of prodromal symptoms and risk factors may lead to new approaches to identifying young persons who are likely to develop BD, and might benefit from early treatment. The investigators add that predictive value might be even higher with combinations of multiple risk factors, rather than single predictors.

Materials provided by Wolters Kluwer Health

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Scientists Link Bipolar Disorder to Unexpected Brain Region

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A painted black brain on a rainbow background. Credit to flickr.com user Anders Sandberg. Used with permission under a Creative Commons license.

While bipolar disorder is one of the most-studied neurological disorders—the Greeks noticed symptoms of the disease as early as the first century—it’s possible that scientists have overlooked an important part of the brain for its source.

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown for the first time that ensembles of genes within the striatum—a part of the brain that coordinates many primary aspects of our behavior, such as motor and action planning, motivation, and reward perception—could be deeply involved in the disorder. Most modern studies of bipolar disorder have concentrated on the brain’s cortex, the largest part of the brain in humans, associated with higher-level thought and action.

“This is the first real study of gene expression in the striatum for bipolar disorder,” said Ron Davis, chair of the Department of Neuroscience at TSRI, who directed the study. “We now have a snapshot of the genes and proteins expressed in that region.”

The study, published recently online ahead of print in the journal Molecular Psychiatry, also points to several pathways as potential targets for treatment.

Bipolar disorder is a mental illness that affects about 2.6 percent of the U.S. adult population—some 5.7 million Americans—with a sizable majority of these cases classified as severe. The disease runs in families, and more than two-thirds of people with bipolar disorder have at least one close relative with the illness or with unipolar major depression, according to the National Institute of Mental Health.

In the new research, tissue samples from 35 bipolar and non-bipolar control subjects were analyzed. The number of genes differentially expressed in tissue samples from the two groups turned out to be surprisingly small—just 14 in all. However, co-expression network analysis also revealed two modules of interconnected genes that were particularly rich in genetic variations associated with bipolar disorder, suggestive of a causal role in the disorder. One of these two modules was particularly striking, as it seemed to be highly specific to the striatum.

“Our finding of a link between bipolar disorder and the striatum at the molecular level complements studies that implicate the same brain region in bipolar disorder at the anatomical level, including functional imaging studies that show altered activity in the striatum of bipolar subjects during tasks that involve balancing reward and risk,” said TSRI Research Associate Rodrigo Pacifico, who was first author of the new study. Analyzing reactions to risk was important because bipolar patients may act impulsively and engage in high-risk activities during periods of mania.

Pathway analysis also found changes in genes linked to the immune system, the body’s inflammatory response, and cells’ energy metabolism. Davis noted, “We don’t know if these changes are a cause of the disease or the result of it. But they provide additional gene markers in bipolar disorder that could potentially lead to the future development of diagnostics or treatments.”

The study, “Transcriptome Sequencing Implicates Dorsal Striatum-Specific Gene Network, Immune Response and Energy Metabolism Pathways in Bipolar Disorder,” was supported by funding from the State of Florida.

Text</a< from the Scripps Research Institute.

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Gene Breakthrough on Lithium Treatment for Bipolar Disorder

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Credit to flickr.com user Berkeley Lab. Used with permission under a Creative Commons license.

Genes linked to schizophrenia in psychiatric patients suffering from bipolar disorder are the reason why such patients don’t respond to the “gold standard” treatment for bipolar – the drug lithium – according to international research led by the University of Adelaide.

Lithium has been widely used as a treatment for bipolar disorder since the 1950s because of its mood stabilising effect. It has unique protective properties against both manic and depressive episodes, and an ability to decrease the risk of suicide.

However, about 30% of patients are only partially responsive, more than a quarter show no clinical response at all, and others have significant side-effects to lithium.

Until now, researchers have not understood why these patients have not responded to the common treatment, while others have responded well to the drug.

Published in the journal JAMA Psychiatry>, an international consortium of researchers led by the University of Adelaide’s Professor Bernhard Baune reports a major discovery that could affect the future quality of treatment for people with this significant mental health condition.

Known as the international Consortium on Lithium Genetics, the group has studied the underlying genetics of more than 2500 patients treated with lithium for bipolar disorder.

“We found that patients clinically diagnosed with bipolar disorder who showed a poor response to lithium treatment all shared something in common: a high number of genes previously identified for schizophrenia,” says Professor Baune, Head of the Discipline of Psychiatry at the University of Adelaide and lead author on the paper.

“This doesn’t mean that the patient also had schizophrenia – but if a bipolar patient has a high ‘gene load’ of schizophrenia risk genes, our research shows they are less likely to respond to mood stabilisers such as lithium.

“In addition, we identified new genes within the immune system that may play an important biological role in the underlying pathways of lithium and its effect on treatment response,” Professor Baune says.

Understanding the underlying biology of people’s response to lithium treatment is a key area of research and urgent clinical need in mental health.

“These findings represent a significant step forward for the field of translational psychiatry,” Professor Baune says.

“In conjunction with other biomarkers and clinical variables, our findings will help to advance the highly needed ability to predict the response to treatment prior to an intervention. This research also provides new clues as to how patients with bipolar disorder and other psychiatric disorders should be treated in the future.”

Text provided by the University of Adelaide.

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Children at High Risk for Bipolar Disorder Genetically Vulnerable to Stress

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Genetic alterations that regulate stress have been found in children at high risk for bipolar disorder, according to research done by scientists at The University of Texas Health Science Center at Houston (UTHealth). The study was published in Translational Psychiatry, a Nature Publishing Group journal.

 

Researchers have long known that children who experience stressors in their lives are more likely to develop bipolar disorder. Parents with bipolar may struggle with their disorders, thus placing stress on their children. But this study shows that children at a high risk for developing bipolar–due to having family members with a history of psychiatric illness–are genetically vulnerable to stress.

The scientists at UTHealth took blood samples from eighteen children, consisting of a set of bipolar patients, a set of apparently neurotypical patients with bipolar parents, and a set of neurotypical controls with parents that have no history of mental illness. The blood samples revealed that, compared with the control group, bipolar children and unaffected kids with bipolar parents have genetic alterations that regulate the response to stress.

So, children with bipolar parents are more vulnerable to stress, and when stressed, tend to develop the disorder. This may sound like bad news all around, but there is a positive approach to this study. Future research may reveal the effects of reducing stress, as well as whether medication might be able to reverse the genetic alterations in children before bipolar disorder matures.

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Bipolar Genes Linked to Autism

Many psychiatric diseases share genetic roots. A new study, run by researchers at three different laboratories, suggests that rare genetic variations linked to bipolar disorder are also linked to schizophrenia and especially autism.

The study, by researchers at Johns Hopkins School of Medicine, Cold Spring Harbor Laboratory, and the University of Iowa Carver College of Medicine, is among the first to demonstrate the overlap between bipolar disorder and autism.

Despite bipolar disorder’s demonstrated inheritability, pinpointing genes relating to the disease has been exorbitantly difficult. But advances made in medical science recently have allowed scientists to start to figure out which genetic variations affect patients with bipolar disorder.

The researchers behind the study linking autism with bipolar disorder combined a case-control approach with “family-based exome sequencing” to try to discover which genetic variations contribute to bipolar. Case-control approaches look at genetic variants in people who have the disorder compared to people who don’t to figure out which genes increased susceptibility to the disease. The key to this approach is large pools of data.

Family-based exome sequencing is more difficult to perform. Scientists compare all the expressed genes in a genome (known as the exome). The researchers first examine the DNA that encodes proteins (known as exons), and then put that DNA into sequence using computers. This allows technicians to see variants that “travel with” the disease, especially in cases where the disorder is passed from parent to child.

This two-pronged approach identified 84 rare variants in 82 genes that traveled with bipolar disorder. The research team then examined these

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84 variants in three case-control datasets of 3,541 individuals with bipolar disorder and 4,774 control patients to figure out which variants predicted the disorder.

 

Nineteen genes were over-represented in bipolar disorder patients compared to the controls. However, while the data on these genes wasn’t enough to specifically pinpoint the genetic culprits of bipolar disorder, several of the genes were linked to autism and schizophrenia, with autism being especially prominent.

The findings suggest that schizophrenia, bipolar disorder, and autism have similar roots, and are simply different manifestations of similar diseases. The researchers from the study hope that by linking these diseases and finding which genes are responsible, new treatments will be discovered for all of them.

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New Research Pinpoints Bipolar Disorder Gene

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Credit to flickr.com user Berkeley Lab. Used with permission under a Creative Commons license.

A new study published in the Molecular Psychiatry journal reports that researchers have found a mutation in a gene that causes bipolar disorder in as many as ten percent of cases. This is fantastic news! Finally, the causes of bipolar disorder are starting to be pinpointed.

The gene, G protein receptorkinase 3 (GRK3), regulates neurotransmitters such as dopamine. The mutation happens in a section of the gene called the promoter, which turns GRK3 on and off. Scientists at the University of California, San Diego (UCSD) School of Medicine hypothesize that what causes bipolar disorder is that the mutation makes the gene hypersensitive to dopamine.

The study took place over a year, and screened DNA samples from more than 400 families with bipolar disorder. The researchers found six mutations in the promoter region of GRK3. Most notable was that the P-5 mutation happened three times more frequently in people who suffer from bipolar disorder than those who don’t.

Research has long pointed to several genes being the causes of bipolar disorder. But this is the first time a single gene has been determined as a cause. Bipolar disorder is characterized by extreme highs and lows. Few therapies work to treat the mental illness, and those that do work aren’t effective for all people who suffer from it. The scientists involved in this study hope that specific therapies that target genes on a molecular level will be developed.

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