Schizophrenia risk is increased with a particular gene mutation

An article posted on February 23rd by the Los Angeles Times:

By Shari Roan

Schizophrenia is a severe, complicated illness. There are no obvious explanations for what causes the condition, which causes hallucinations and delusions. Genes are known to play a big role. The condition is often clustered in families.

Scientists announced a significant step in understanding the genetics of the disease this week. A large nationwide consortium of scientists led by Jonathan Sebat of UC San Diego has identified a gene mutation that is strongly linked to the disorder. Understanding the signaling pathway of this mutation creates a target for future therapies.

Previous research has shown a number of rare gene mutations that increase the risk of schizophrenia. In the new study, researchers looked for specific gene variants, called copy number variants, in 8,290 people with schizophrenia and 7,431 healthy people. Among the discoveries was a duplication in the tip of chromosome 7q. This duplication was found in people with schizophrenia at a rate 14 times that of healthy people.

The duplication affects a particular gene called the vasoactive intestinal peptide receptor 2 gene, which is known to play a role in behavior and learning. In people with schizophrenia, the expression of this gene is much higher, the researchers found. The VIPR2 gene mutation, therefore, will be an important target in developing medications that might alter the symptoms of the illness.

"This discovery might be the best target yet to come out of genetic studies of mental illness," Sebat said in a new release. The research was published online in the journal Nature.

Image courtesy of the National Library of Medicine.

Gene-Environment Interactions Could Influence Several Psychiatric Disorders; 'Schizophrenia Gene' May Also Trigger Anxiety, Depression

A December 3rd media release from Johns Hopkins University:

BALTIMORE, Dec. 3 (AScribe Newswire) -- Male mice born with a genetic mutation that's believed to make humans more susceptible to schizophrenia develop behaviors that mimic other major psychiatric illnesses when their mothers are exposed to an assault to the immune system while pregnant, according to new Johns Hopkins research.

What was most surprising to researchers was that the mental illnesses the mice developed didn't look like schizophrenia, which they were genetically predisposed to, but more like mood and anxiety disorders, suggesting that one gene mutation can lead to different mental illnesses when influenced by the same environmental factor.

"Psychiatric diseases have genetic roots, but genes alone do not explain the entire disease," says Mikhail V. Pletnikov, M.D., Ph.D. [pictured], an associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's leader. "When we study genes in conjunction with environmental challenges, we can better understand how diseases develop."

Pletnikov hopes his research, which appears in the December issue of the journal Biological Psychiatry, may be a small step toward eventually finding ways to prevent mental illnesses in humans. "The main goal here is to understand how gene-environment interactions take place on the molecular level so that you can find suitable drug targets, ultimately stopping these diseases before they happen," he says. "It all can start before birth."

Pletnikov and his team studied a mutant human form of the Disrupted-in-Schizophrenia 1 gene (mhDISC1), breeding mice in the laboratory with this mutation. This genetic variation is believed to be associated with vulnerability to major mental illnesses in humans. The mhDISC1 mice were impregnated, and at the ninth day of gestation (the equivalent to the middle or end of the first trimester in a human pregnancy), one group was given a drug to stimulate the immune system, forcing it to react as if it had been exposed to a virus like influenza or a parasite like toxoplasma. The rest of the pregnant mice - whose fetuses also had the mutated gene- were kept as a control group and their immune systems were left unchallenged.

The study found that prenatal immune stimulation in mhDISC1 mice produced behavioral abnormalities that were not present in the unchallenged mice: elevated anxiety, depression-like responses, an altered pattern of sociability and a weakened response to stress. The unchallenged mice did not show those behaviors, even though they also had the mutant gene. Pletnikov says the findings suggest that the same mutation, in this case mhDISC1, can lead to different illnesses, depending on interactions with environmental factors.

This may provide an explanation, he says, for why the extended Scottish family in which scientists first discovered this genetic mutation had members who suffered not solely from schizophrenia but also from major depression and bipolar disorder. "This one gene mutation can lead to very different clinical manifestations," Pletnikov says.

Along with the behavior differences, Pletnikov and his team also found that parts of the brain, including the amygdala and the hypothalamus, were smaller in the mice that had been prenatally challenged. A similar abnormality can be found in those same areas of the brain in humans with major depression and bipolar disorder.

Previous studies have suggested that the prenatal immune response to a microbe - be it a major illness or just transient flu-like symptoms barely noticed by the pregnant woman - may be responsible for the increased incidence of adult psychopathology in humans. But this hypothesis, Pletnikov says, has been difficult to prove. Using this mouse model, he suggests, is a valuable way to study the relationship between gene-environment interactions and mental illness, and should be replicated to find more of these interactions to gain a better understanding of these relationships.

Future studies, he says, will try to sort out whether different timing or stimulating different parts of the immune system might lead to specific types of mental illness, as well as explore the consequences of other environmental adverse events such as stress or drug abuse.

Other Johns Hopkins researchers on the study include Bagrat Abazyan, M.D.; Jun Nomura, Ph.D.; Geetha Kannan; Koko Ishizuka, Ph.D.; Kellie L. Tamashiro, Ph.D.; Frederick Nucifora, Ph.D.; Vladimir Pogorelov, Ph.D.; Chunxia Yang; Carlos Pardo, M.D.; Susumu Mori, Ph.D.; Atsushi Kamiya, M.D., Ph.D.; Akira Sawa, M.D., Ph.D.; and Christopher A. Ross, M.D., Ph.D.

The study was supported by the National Institute of Mental Health, Autism Speaks, the National Alliance for Research on Schizophrenia and Depression, the Mortimer W. Sackler Foundation, the Cell Science Research Foundation and the National Institutes of Health/National Institute on Drug Abuse-Intramural Research Program.

For more information: http://www.hopkinsmedicine.org/psychiatry/research/neurobiology/research_labs/behavioral_pletnikov.html

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CONTACT: Stephanie Desmon, Johns Hopkins Medicine Media Relations and Public Affairs, 410-955-8665, sdesmon1@jhmi.edu

Image credit

Largest effort to find gene-environment interactions underlying schizophrenia risk

An article posted on July 16th by news-medical.net:

At the 23rd ECNP Congress 2010 in Amsterdam, Professor Dr. Jim van Os, Chairman of the Department of Psychiatry and Neuropsychology at Maastricht University Medical Centre, The Netherlands, will present the EU-GEI project, involving more than 7,500 patients and their families, which brings together a multidisciplinary research team from 15 countries in the largest effort to date to find gene-environment interactions underlying schizophrenia risk. In particular, he will explain the development of tools that will make it possible to monitor, and possibly modify, vulnerability at the behavioural level, thus preventing transition to overt illness.

Schizophrenia and related psychotic disorders are the most mysterious and costliest of mental disorders in terms of human suffering and societal expenditure, representing a major challenge to scientists. Until recently, researchers had relatively few starting points in trying to unravel the causes of psychosis and to identify better treatments. While epidemiological research has characterised powerful environmental effects on schizophrenia risk, twin and family studies have established that more than half of the vulnerability for schizophrenia is of genetic origin. However, despite enormous investments, it has proven extremely difficult to identify molecular genetic variants underlying schizophrenia liability. According to the model of gene-environment interaction, genes influencing schizophrenia risk may do so indirectly by making individuals more sensitive to the effects of causal environmental risk factors (e.g. urbanisation, migration, cannabis use, childhood trauma). Now, for the first time, a focused scientific collaboration has been organised in Europe in order to elucidate the causes of schizophrenia, focussing on both genes and environments in the same research project.

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Rethinking Mental Disorders

An article posted May 20th on Care2.com:

By Kristina Chew

Psychiatric or mental disorders such as schizophrenia, bipolar disorder, depression and psychosis are better understood and treated as 'disorders of the brain' according to an article by Tom Insel, M.D., Director of the National Institute of Mental Health, and Philip Wang, M.D., Deputy Director of NIMH. The article, Rethinking Mental Illness, is published in the May 19th issue of the Journal of the American Medical Association. The authors note that, while there have been many 'insights gained from genetics and neuroscience'---such as twin studies that show high heritability for autism, schizophrenia, and bipolar disorder---such research explains only a 'fraction of the heritability' of mental disorders. (For instance, some182 genes have been identified as linked to eating disorders, and some 100 to autism.) These should rather be seen as 'disorders of brain circuits':

"The genetics of mental illness may really be the genetics of brain development, with different out comes possible, depending on the biological and environmental context."

Other advances in the field of genetics contribute to a reconceptualization of mental disorders. Epigenetics looks at the inherited changes in gene expression caused that are caused by something other than than changes in the underlying DNA sequence; Insel and Wang note that:

"The same twin studies that point to high heritability also demonstrate the limits of genetics: environmental factors must be important for mental disorders......The advent of epigenomics [the study of the factors that control genes], which can detect the molecular effects of experience, may provide a powerful approach for understanding the critical effects of early-life events and environment on adult patterns of behavior."

Further, the authors write that the behavioral and cognitive symptoms that indicate 'mental illness' may actually be the 'late stages' of neurological processes that, if detected at early stages, might be better and more fully treated:

"As a result, interventions, rather than being ameliorative or rehabilitative, could become preemptive or even preventive. But this transformation in diagnosis and treatment, which can be informed by recent progress in cardiovascular disease and cancer, will depend on an intense focus on the genetics and circuitry underlying mental illness to ensure new approaches to detecting risk, validating diagnosis, and developing novel interventions that may be based on alter ing plasticity or retuning circuitry rather than neurotransmitter pharmacology."

As an example, in the past several years, autism has gone from being seen as a psychiatric, and even psychogenic, disorder, to a neurological/neurodevelopmental one, with significant consequences in how autism is conceived of, treated and, too, perceived by the public. Autism was once thought to be caused by bad parenting, by 'refrigerator mothers' who were emotionally withdrawn and 'cold,' and therefore did not 'bond' with their children, who 'withdrew into autism'; the damage wrought to families and individuals by these misconceptions is unmeasurable. Seeing autism as a neurodevelopmental disorder---due, perhaps, to 'abnormalities' in synapses in the brain does change how autistic individuals are see by others.

Similarly, understanding that an eating disorder such as anorexia nervosa is biologically based rather than simply putting the blame on parents, on our society's and culture's equating being thin with success, has significant changes on treatment and, again, understanding, and this can make a huge difference in people's (parents, for sure) lives. Societal factors do play a role, but seeing anorexia as biologically based---a recent study of brain imaging has found neurocircuit dysregulation in anorexics---can have real changes for people's lives and, hopefully, for the ultimate outcomes of those diagnosed with these conditions.

Also see:

NIMH Builds New Framework for Understanding Mental Illness

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Gene linked to schizophrenia: Canadian study

An article posted on April 13th by AFP:

MONTREAL — People with a specific mutated gene may be prone to schizophrenia, according to a Canadian study published Monday in a US scientific journal.

The study led by University of Montreal researchers found new mutations in the so-called "SHANK3 gene" in [schizophrenia] patients.

"That these new mutations occur in schizophrenia is rather unexpected and may explain why the identification of the genes linked to this disease has been so difficult," senior author Guy Rouleau [pictured] said in a statement.

"Our findings show that a significant number of schizophrenia cases are the result of new genetic mutations in the SHANK3 gene," he said in the study published in the US Proceedings of the National Academy of Science.

Schizophrenia is a mental disorder that affects about one percent of people worldwide. It is most commonly manifested as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking.

It often leads to significant social or occupational dysfunction.

SHANK3 proteins are involved in maintaining the physical structure of nerve cells, and mutations in the gene result in specific abnormalities in cell shapes.

These deformations have been observed in schizophrenia patients.

Lead study author Julie Gauthier said the SHANK3 gene had "previously been linked to autism," which suggests "a molecular genetic link between these two neurodevelopmental disorders."

It also means that SHANK3 "may have a role in other brain disorders," she said.

Posting of this article is for the purposes of research into schizophrenia.

Scientists identify age-associated defects in schizophrenia

A March 1st news release from The Scripps Research Institute:

Gene network-based analysis reveals unexpected results

LA JOLLA, CA – March 1, 2010 –The underlying causes of the debilitating psychiatric disorder schizophrenia remain poorly understood. In a new study published online in Genome Research March 2, 2010, however, scientists report that a powerful gene network analysis has revealed surprising new insights into how gene regulation and age play a role in schizophrenia.

Researchers are actively working to identify the direct cause of schizophrenia, likely rooted in interactions between genes and the environment resulting in abnormal gene expression in the central nervous system. Scientists have been studying expression changes in schizophrenia on an individual gene basis, yet this strategy has explained only a portion of the genetic risk.

In the new work, a team of researchers led by Associate Professor Elizabeth Thomas [pictured] of The Scripps Research Institute has taken a novel approach to this problem, performing a gene network-based analysis that revealed surprising insight into schizophrenia development.

The group analyzed gene expression data from the prefrontal cortex, a region of the brain associated with schizophrenia, sampled post-mortem from normal individuals and schizophrenia patients ranging from 19 to 81 years old. However, instead of just looking at genes individually, Thomas and colleagues at the Scripps Translational Science Institute, Nicholas Schork and Ali Torkamani, considered interactions between genes, as well as groups of genes that showed similar patterns of expression, to identify dysfunctional cellular pathways in schizophrenia.

"Once gene co-expression networks are identified," said Thomas, "we can then ask how they are affected by factors such as age or drug treatment, or if they are associated with particular cell types in the brain."

The gene network analysis suggested that normal individuals and schizophrenia patients have an unexpectedly similar connectivity between genes, but the most surprising finding was a significant link between aging and gene expression patterns in schizophrenia. The team identified several groups of co-expressed genes that behaved differently in schizophrenia patients compared to normal subjects when age was considered.

A particularly striking age-related difference in co-expression was found in a group of 30 genes related to developmental processes of the nervous system. Normally these genes are turned off as a person ages, but in schizophrenia patients the genes remain active. This critical finding strongly suggests that age-related aberrant regulation of genes important for development can explain at least part of the manifestation of schizophrenia.

Thomas explained that these findings help to refine the developmental hypothesis of schizophrenia, which states that one or more pathogenic "triggers" occur during critical periods of development to increase risk of the disease. Specifically, this work indicates that abnormal gene expression in developmentally related genes might be a significant pathogenic trigger, occurring over a broader time-scale than expected.

"Rather than a pathological trigger occurring at a critical developmental time point," said Thomas, "the trigger is ongoing throughout development and aging."

Furthermore, Thomas noted that the new study supports early intervention and treatment of schizophrenia. Treatment approaches aimed at averting gene expression changes and altering the course of the disease could be specifically tailored to the age of the patient.

###

In addition to Thomas, Torkamani, and Schork, authors of the study, "Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia," include Brian Dean of the Mental Health Research Institute (Australia). See Genome Res doi:10.1101/gr.101956.109.

This work was supported by the Scripps Translational Science Institute Clinical Translational Science Award, the National Institutes of Health, and a Scripps Dickinson Fellowship.

Interested reporters may obtain copies of the manuscript from Peggy Calicchia, Editorial Secretary, Genome Research (calicchi@cshl.edu; +1-516-422-4012).


About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.

Contact: Keith McKeown
kmckeown@scripps.edu
858-784-8134
Scripps Research Institute


About Genome Research

Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.


About Cold Spring Harbor Laboratory Press

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its press, originating in 1933, is the largest of the laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

Photo by Dana Neibert.

Understanding What Causes Schizophrenia: A Developmental Perspective

An editorial published in the January 2010 edition of the American Journal of Psychiatry:

By John H. Gilmore, M.D.

Understanding what causes schizophrenia is becoming harder and harder. We know that schizophrenia has genetic causes, since the most significant risk factor is having a first-degree relative with schizophrenia. However, most people with schizophrenia do not have an affected relative, and while the overall genetic contribution to schizophrenia may be large, the contribution of specific genes is very small. Candidate gene studies and more recent genome-wide association studies have had inconsistent results and indicate, at best, individual genes increase risk by less than 2 times—from an average population rate of 1 in 100 to 1.5 in 100. Pre- and perinatal complications and environmental exposures appear to have somewhat stronger effects than individual genes, as prenatal exposure to infection or hypoxia increases risk of schizophrenia from 1 in 100 to 2–4 in 100 (1). Schizophrenia is likely the result of an interaction between genetic risk and environmental exposures, and recent studies have attempted to describe that interaction.

To read the entire editorial, please click here.

I thank Dr. David Whitehorn for bringing this article to my attention.

Genes for Psychosis and Creativity

The abstract of a research report posted online on July 6th by the journal Psychological Science:

Genes for Psychosis and Creativity: A Promoter Polymorphism of the Neuregulin 1 Gene Is Related to Creativity in People With High Intellectual Achievement

By Szabolcs Kéri

Semmelweis University, Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest H1083, Balassa u. 6, Hungary

Abstract

Why are genetic polymorphisms related to severe mental disorders retained in the gene pool of a population? A possible answer is that these genetic variations may have a positive impact on psychological functions. Here, I show that a biologically relevant polymorphism of the promoter region of the neuregulin 1 gene (SNP8NRG243177/rs6994992) is associated with creativity in people with high intellectual and academic performance. Intriguingly, the highest creative achievements and creative-thinking scores were found in people who carried the T/T genotype, which was previously shown to be related to psychosis risk and altered prefrontal activation.

Posting of this abstract is for the purposes of research into psychosis.

Also see:

Genetic link between mental illness, creativity: Study

Understanding Complex Interactions Key to Preventing Alcohol Abuse

An article published in the July 17th edition of Psychiatric News:

A genetically associated characteristic — the level of response to alcohol — connects genetic vulnerabilities with the environment to reveal the complicated process through which alcohol use disorders develop.

By Jun Yan

Like other mental illnesses, alcohol use disorders (AUDs) develop through interactions of multiple genetic vulnerabilities and environmental factors over a long period. By understanding these interactions, psychiatrists can devise and apply targeted, effective, and efficient prevention methods.

These were the messages of Marc Schuckit, M.D. [pictured], in his Adolf Meyer Award lecture at APA's 2009 annual meeting in May in San Francisco. Schuckit is a professor of psychiatry at the University of California, San Diego, and director of the Alcohol and Drug Treatment Program and Alcohol Research Center at the Veterans Affairs San Diego Healthcare System.

His lecture, "How Alcoholism Develops: Identification of Genetic and Environmental Influences in a 25-Year Longitudinal Study," examined groundbreaking research by him and his colleagues on the intricate dynamics between genes and environment that reveal much about AUDs as well as other mental illnesses.

To read the entire article, please click here.

Photograph by David Hathcox

Canadian hospital pioneers mental-health treatment

An article published is yesterday's edition of The Globe and Mail:

By Anne McIlroy

A Canadian psychiatric hospital will be the first in the world to use a combination of genetic testing and brain imaging to help determine the best course of treatment for patients with schizophrenia, depression, bipolar disorder and other mental illnesses.

A few dozen patients will take part starting in the fall, and the experimental program will slowly ramp up to include 100 people, says James Kennedy, director of the neuroscience research department at the Centre for Addiction and Mental Health in Toronto. If it proves successful, the program will be a step toward giving psychiatrists more precise tools to assess patients with common psychiatric conditions.

“It is a small revolution, a great opportunity to change, in a fundamental way, how we treat patients,” says Dr. Kennedy, who along with his colleague, Sylvain Houle, is leading the new research initiative.

To read the entire article, please click here.

Also see:

CAMH combines genetics with brain imaging to personalize treatment for mental illness and addictions

I thank John Devlin for bringing this article to my attention.

Gene clues to schizophrenia risk

An article posted July 1st by BBC News:

Scientists have identified thousands of tiny genetic variations which together could account for more than a third of the inherited risk of schizophrenia.

They also showed the condition is genetically similar to bipolar disorder also known as manic depression.

The findings came from work by three separate teams, who analysed DNA from thousands of people.

The studies - the biggest ever into the genetics of schizophrenia - appear in the journal Nature.

The findings suggest that schizophrenia is much more complex than previously thought, and can arise not only from rare genetic variants, but common ones as well.

It is hoped the work could lead to new diagnostic tests and treatments for the condition.

To read the entire article, please click here.

Also see:

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Hoopla, and Disappointment, in Schizophrenia Research

Altered Gene Can Increase Risk Of Schizophrenia

An article posted on April 7th by ScienceDaily:

Rutgers geneticist Linda Brzustowicz [pictured] and her colleagues have identified a specific DNA change that is likely to increase risk for developing schizophrenia in some people. It provides a potential mechanism that may be a point of entry for drug therapy, consistent with the growing trend of personalized medicine.

The research findings are reported in the April issue of the American Journal of Psychiatry (AJP). An accompanying editorial highlights the significance of this work.

Brzustowicz, a professor of genetics at Rutgers, The State University of New Jersey, and board-certified psychiatrist, said that the research has demonstrated a functional DNA change that increases gene expression. This conclusion is based on its presence in the genes of a Canadian study population of 24 families where multiple individuals had been diagnosed with schizophrenia. The gene in question, NOS1AP, previously known as CAPON, is one which Brzustowicz has been studying for six years.

The paper also presents an innovative statistical method, Posterior Probability of Linkage Disequilibrium (PPLD). This is the work of co-author Veronica Vieland of The Research Institute at Nationwide Children's Hospital, Columbus, Ohio. The new analytical technique quantifies the statistical evidence for association, in this case between the altered gene and schizophrenia. The researchers evaluated 60 variants of the gene or single nucleotide polymorphisms (SNPs).

"Our use of the PPLD was really helpful in sorting the evidence. It showed that of the 60 SNPs we were evaluating, three had a much higher probability of association with the illness," Brzustowicz said. "This paved the way for our next step – doing a functional analysis using cells grown in culture – which is much more labor intensive. We had reduced our 60 candidates down to a short list of three, which greatly simplified this next step."

Each of the three candidate SNPs was introduced into separate cultures of identical cloned cells derived from human brain tissue. The cultures differed only in which of the SNP variants was introduced. The challenge was to measure the quantity of overexpression, that is, how much excess protein was being produced by each of the three variants.

To each culture the researchers also added DNA that contained the gene that produces the enzyme which makes a firefly glow, along with human regulatory DNA which would control the production of that enzyme. The three kinds of DNA (the SNP, the firefly and the human regulatory) were all joined together prior to insertion into the brain-derived cells. Thus, the amount of expression of each SNP would be reflected (via the regulatory DNA) in the intensity of the light produced. An instrument known as a luminometer measured the glow produced and showed a dramatic increase in gene expression in one variant over the others. These results echo the increased expression of NOS1AP that has been observed in postmortem brain samples from individuals with schizophrenia.

Bonnie Firestein, a professor in Rutgers' Department of Cell Biology and Neuroscience, though not an author on the AJP paper, is conducting complementary research. She is investigating the consequences of increased expression of the NOS1AP gene. Firestein is looking at this gene in cells in culture and examining how the overexpression of this protein alters the way neurons branch.

Identifying this specific functional genetic variant is an important step, but there are qualifiers. Schizophrenia is not a single-gene disorder, and there are environmental factors that are also important. "It is not as though, if you have this altered gene, you will get the disease," said Brzustowicz.

The frequency of this variant in the general population is more than 40 percent. Approximately 1 percent of the general population has schizophrenia but not all of those with the illness will have this altered gene. Brzustowicz estimates that the frequency of the altered gene in people with schizophrenia is going to be higher than the average in the general population. For example, the frequency of this variant in people with schizophrenia in the Canadian families is 55 percent.

To refine this estimate, Brzustowicz and her team will be looking at the altered gene's frequency in DNA samples from the National Institute of Mental Health collection of cell lines housed in the Rutgers University Cell and DNA Repository. The collection includes samples drawn from large populations of Asian, Caucasian, African American and Hispanic individuals with schizophrenia.

Adapted from materials provided by Rutgers University.

Gene 'has key schizophrenia role'

An article posted today by BBC News:

Two studies have pinpointed a single gene as key to the development and treatment of schizophrenia.

A US team from the Howard Hughes Medical Institute found that a mutated version of the DISC1 gene disrupts the growth and development of brain cells.

And a team from the University of Edinburgh showed that the gene affects how patients respond to treatment.

Both studies, published in the journals PLoS One and Cell, raise hopes of more effective treatment for schizophrenia.

To read the entire article, please click here.

Also see:

Disrupted in Schizophrenia 1 Regulates Neuronal Progenitor Proliferation via Modulation of GSK3(beta)/beta-Catenin Signaling

The DISC1 Pathway Modulates Expression of Neurodevelopmental, Synaptogenic and Sensory Perception Genes

I thank John Devlin and Dr. Roger Cann for bringing this article to my attention.

Loss of Brain Protein in Mice Leads to Schizophrenia-Like Behavior

Posted on February 19th by Genetic Engineering and Biotechnology News:

Disrupting the function of a key cranial molecule leads to microscopic brain abnormalities and schizophrenia in mice, according to a team from The Scripps Research Institute. Neuregulin is an important developmental protein that helps the brain form its distinct structures early in development.

They also found that the schizophrenic mice could recover normal behavior when treated with clozapine, a decades-old drug sometimes used to treat schizophrenia in people. They thus suggest that these mice might provide researchers with a good model for studying the disease. This study also provides support for the schizophrenia hypothesis that implicates glutamatergic neurons, because the mice had problems with their glutamatergic synapses.

The abnormalities found the mouse brains were similar to those seen in the autopsied brains of people who were diagnosed with schizophrenia, the scientists note. Also, genetic studies have linked inherited forms of this protein and its receptors to schizophrenia and numerous other mental health problems, they add.

In the study, the team effectively removed the function of neuregulin by eliminating the receptor to which it binds. Because this is such an important developmental protein, they expected that eliminating its receptor would severely impact the development of the mouse’s brain. As it turns out, the brains were normal overall, but the loss of neuregulin did affect the brain on a microscopic level.

Investigators revealed that when mice are deprived of neuregulin, their dendritic spines start to form but do not completely mature. Instead they fall apart while the brain itself matures. The effect of this loss is evident in behavior tests, where mice display hallmarks of schizophrenia, such as social interaction problems and reduced anxiety.

Loss of the spines also kept mice from adapting to and anticipating a startling noise, which is a classic sign of a schizophrenia-like state, the Scripps team explains.

The findings were published this week in the early edition of the journal Proceedings of the National Academy of Sciences.

Also see:

Scripps Research Study Shows How Microscopic Changes to Brain Cause Schizophrenic Behavior in Mice

Schizophrenia symptom linked to gene mutation

Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system

Photograph by Rasbak.

Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study

The summary of an article published in the January 17th edition of The Lancet:

By Paul Lichtenstein (a), Benjamin H. Yip (a), Camilla Björk (a), Yudi Pawitan (a), Tyrone D. Cannon (d), Patrick F. Sullivan (a,c), and Christina M. Hultman.

Background

Whether schizophrenia and bipolar disorder are the clinical outcomes of discrete or shared causative processes is much debated in psychiatry. We aimed to assess genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and their comorbidity.

Methods

We linked the multi-generation register, which contains information about all children and their parents in Sweden, and the hospital discharge register, which includes all public psychiatric inpatient admissions in Sweden. We identified 9,009,202 unique individuals in more than 2 million nuclear families between 1973 and 2004. Risks for schizophrenia, bipolar disorder, and their comorbidity were assessed for biological and adoptive parents, offspring, full-siblings and half-siblings of probands with one of the diseases. We used a multivariate generalised linear mixed model for analysis of genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and the comorbidity.

Findings

First-degree relatives of probands with either schizophrenia (n=35,985) or bipolar disorder (n=40,487) were at increased risk of these disorders. Half-siblings had a significantly increased risk (schizophrenia: relative risk [RR] 3·6, 95% CI 2·3—5·5 for maternal half-siblings, and 2·7, 1·9—3·8 for paternal half-siblings; bipolar disorder: 4·5, 2·7—7·4 for maternal half-siblings, and 2·4, 1·4—4·1 for paternal half-siblings), but substantially lower than that of the full-siblings (schizophrenia: 9·0, 8·5—11·6; bipolar disorder: 7·9, 7·1—8·8). When relatives of probands with bipolar disorder were analysed, increased risks for schizophrenia existed for all relationships, including adopted children to biological parents with bipolar disorder. Heritability for schizophrenia and bipolar disorder was 64% and 59%, respectively. Shared environmental effects were small but substantial (schizophrenia: 4·5%, 4·4%—7·4%; bipolar disorder: 3·4%, 2·3%—6·2%) for both disorders. The comorbidity between disorders was mainly (63%) due to additive genetic effects common to both disorders.

Interpretation

Similar to molecular genetic studies, we showed evidence that schizophrenia and bipolar disorder partly share a common genetic cause. These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities.

Funding

Swedish Council for Working Life and Social Research, and the Swedish Research Council.

Footnotes

(a) Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

(b) Department of Neuroscience, Psychiatry, Ulleråker, Uppsala University, Sweden

(c) Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

(d) Departments of Psychology and Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA

Correspondence to: Prof. Paul Lichtenstein, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, 17177 Stockholm, Sweden

Posting of this summary on this weblog is for the purposes of research into schizophrenia and bipolar disorder.

Photograph of Prof. Paul Lichtenstein courtesy of Karolinska Institutet.

Also see:

The Observed Psychosocial & Psychopharmacological Commonalities Between Schizophrenia & Bipolar Disorder Seem More Than Just A Coincidence: Can We Now Add A Common Genetic Basis?

Large Family Study Links Genetics of Schizophrenia, Bipolar Disorder

Common Causes Of Schizophrenia And Bipolar Disorder

New Clues to Schizophrenia Genetics

An article posted by Virginia Hughes (pictured, right) on her weblog today:

A specific gene in the chromosomal region 22q11 is important for normal brain connectivity and synapse formation, and its absence may lead to schizophrenia, researchers are reporting today in Nature Neuroscience. The same team first linked a deletion in the chromosomal region to the disorder 13 years ago.

This approach of honing in on an individual gene’s effect on the mouse brain, experts predict, will become more common as scientists identify more copy number variations (CNVs) — duplications or deletions of a stretch of DNA — relevant to schizophrenia and autism.

To read the entire article, click here.

Neurons from the 22q11 mouse model (right) have fewer spines than normal mouse (left).

Spontaneous Genetic Mutation Linked to Schizophrenia

From the September 19th edition of Psychiatric News:

By Jun Yan

As the search for genetic causes of schizophrenia intensifies, scientists have yet to find the specific defective genes at fault. The explanation, perhaps, is that variants are individually rare but located all over the genome.

A type of rare and spontaneous mutation that affects specific chromosomes has been linked to a substantial portion of schizophrenia cases and provides clues for the disease pathogenesis, as shown in several recent studies.

Copy-number variations (CNVs) refer to a type of genetic mutation in which chunks of DNA are repeated for a different number of times in a chromosome in different persons. The repeated DNA segments can range in size from thousands to millions of base pairs, may contain a gene or part of a gene, or disrupt a gene located in a chromosome, thus resulting in variations in the number of copies and the function of certain genes.

In two studies published in the July 30 Nature online, two groups of researchers separately found associations between the risk of psychotic disorders and rare CNVs. Deletions of substantial chunks of DNA at certain locations on the chromosomes were more common in individuals with schizophrenia or other psychoses than in healthy controls, the studies showed.

A number of studies have been published within the past few years that began to unravel the complex genetic patterns of mental illness, including but not limited to schizophrenia. Scientists have accumulated much evidence to suggest an important role of genetic predisposition in schizophrenia; however, unlike sickle-cell anemia or Huntington's disease, schizophrenia has a far more complex hereditary pattern and seems to involve a huge number of vulnerable mutations.

To read the entire article, click here.

Hopkins Researchers Piece Together Gene "Network" Linked to Schizophrenia

--Patients Confirmed to Carry Mutations

A September 2nd press release from Johns Hopkins Medicine, Media Relations and Public Affairs:

Reporting this week in the Archives of General Psychiatry, researchers at the Johns Hopkins University School of Medicine have uncovered for the first time molecular circuitry associated with schizophrenia that links three previously known, yet unrelated proteins.

"This is very exciting because until now the many known genetic factors implicated in this condition were not connected in any way," says Akira Sawa, M.D., Ph.D., director of the program in molecular psychiatry and associate professor of psychiatry and neuroscience at Hopkins. "Now, through a cross-disciplinary and cross-departmental collaboration, we not only have figured out how these three proteins interact with each other, we also have found patients who carry mutations. These results give us a really good foundation to dig deeper into such an elusive condition."

Sawa's team previously had characterized the DISC1 gene and protein which are required for proper nervous system development, and when disrupted, significantly contribute to schizophrenia. His team also had shown that DISC1 protein binds to PCM1 protein at the centrosome, which coordinates the structure and movement of cells.

Separately, Hopkins geneticist and associate professor of ophthalmology Nicholas Katsanis, Ph.D., and his team were studying an unrelated family of proteins had discovered that one of them, BBS4, also is found near the centrosome and also binds to PCM1. "But we weren't thinking schizophrenia at the time because BBS4 is involved in Bardet-Biedl Syndrome, which is a wide-ranging condition mainly known for its associated eye and and kidney problems but also does cause behavioral defects in some patients," says Katsanis.

It was Hopkins psychiatrist Nicola Cascella, M.D., co-director of the program in molecular psychiatry and assistant professor of psychiatry who, according to Sawa, "brought it all together" by realizing that the behavioral defects seen in Bardet-Biedl Syndrome patients and the molecular interaction of BBS4 and PCM1 could be related and relevant to schizophrenia.

"Serendipity brought us together from the far corners of campus and allowed us to see the links between these three proteins, centrosomes, and schizophrenia," says Katsanis. So they embarked on a collaboration to see if these coincidental observations would lead to a better understanding of schizophrenia.

First, to show that the three proteins do in fact physically interact with each other in a cell, the research teams attached different tags to each protein and followed the proteins in cells grown in the lab. They found that all three proteins do end up together, at the centrosome. When the researchers removed either DISC1 or BBS4 from cells, PCM1 would not make it to the centrosome, leading the researchers to conclude that DISC1 and BBS4 act together to recruit PCM1.

The researchers then asked if the failure of PCM1 recruitment to the centrosome in mice lacking either DISC1 or BBS4 affects brain development. To do this they reduced the amount of each of the three factors in the brains of developing mice. As a result, nerve cells in the cerebral cortex-the part of the brain responsible for memory and thought-failed to grow properly, suggesting that these three proteins act together synergistically during normal brain development.

The teams' next question was whether PCM1 could contribute to schizophrenia. By examining DNA from families with schizophrenia, the researchers discovered a mutation in PCM1 in one family, but only carried by family members who had been diagnosed with schizophrenia.

"This connection is exactly the sort of daisy chain from gene to disease that psychiatrists pray for," says Cascella. "This is a molecular pathway that we can potentially target for drug therapy."

"We are beginning to sub-stratify psychiatric illness into discrete molecular causes," adds Katsanis. "Now that we know that that a subset of schizophrenia is related to centrosomes and these associated proteins, we can start looking at broader questions of how people get psychiatric illness. We have a hook, now we can start fishing."

The research was funded by the National Institutes of Mental Health Silvio O. Conte Center grant, U.S. Public Health Service, as well as foundation grants from Stanley, NARSAD, and S-R. It was also funded by the Japanese ministry and foundations of JSPS, Japan Brain, Tokyo Biochemical Research and Brain Science

Authors on the paper are Atushi Kamiya, Perciliz Tan, Caitlin Englehard, Koko Ishizuka, Pulver, Cascella, Katsanis, and Sawa, all of Hopkins; Ken-ichiro Kubo and Kazunori Nakajima of Keio University in Tokyo, Japan; and Akiharu Kubo and Sachiko Tsukita of Kyoto University in Kyoto, Japan.

Also see:

Recruitment of PCM1 to the Centrosome by the Cooperative Action of DISC1 and BBS4: A Candidate for Psychiatric Illnesses (PDF)

New schizophrenia pathway discovered by chance

Gene-Hunters Find Hope and Hurdles in Schizophrenia Studies

From the July 31st edition of The New York Times:

By Nicholas Wade

Two groups of researchers hunting for schizophrenia genes on a larger scale than ever before have found new genetic variants that point toward a different understanding of the disease.

The variants discovered by the two groups, one led by Dr. Kari Stefansson of Decode Genetics in Iceland and the other by Dr. Pamela Sklar of Massachusetts General Hospital, are rare. They substantially increase the risk of schizophrenia but account for a tiny fraction of the total number of cases.

This finding, coupled with the general lack of success so far in finding common variants for schizophrenia, raises the possibility that the genetic component of the disease is due to a large number of variants, each of which is very rare, rather than to a handful of common variants.

“What is beginning to emerge is that a lot of the risk of brain diseases is conferred by rare deletions,” Dr. Stefansson said. The three variants discovered by his group and Dr. Sklar’s involve the deletion of large sections of DNA from specific sites in a patient’s genome.

To read the entire article, click here.

Also see:

Gene flaws link to schizophrenia

Genetic hot spots tied to schizophrenia

Insel: 'Different Kind of Science' Poised to Transform Psychiatry

From the July 4th edition of Psychiatric News:

By Mark Moran

Understanding genomic variation and how it affects normal or abnormal development of brain circuits in different ways at different points in time will help push psychiatric diagnosis and treatment into the 21st century.

Psychiatry is still awaiting the "disruptive innovations" in scientific research that have helped to reconceptualize disease in other areas of medicine, said Thomas Insel, M.D., director of the National Institute of Mental Health (NIMH), at APA's 2008 annual meeting in Washington, D.C., in May.

The study of genomic variation and its role in leading to changes in complex brain circuitry, recognition of the longitudinal and developmental nature of disorders, and the discovery of biomarkers linked to a more precise understanding of the pathophysiology of disease are the tools of a 21st-century science promising to transform the treatment of mental illness.

Insel said those same tools have been applied in other areas of medicine to reconceptualize the nature of disease and to reduce mortality dramatically for people with such disorders as cardiovascular disease and cancer.

In contrast, the diagnosis and treatment of mental illness, he said, have been stuck in a 20th-century model.

To read the entire article, click here.

NIMH Director Thomas Insel, M.D.: "Genes code for proteins that play out in particular brain areas at particular times to change the way brain circuitry develops. It's all about variation and how it plays out at each of these levels."

Photo credit: Mark Moran