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News Article | May 8, 2017
Site: www.eurekalert.org

La Jolla, Calif., May 8, 2017 - An international collaborative study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP), with major participation from Yokohama School of Medicine, Harvard Medical School, and UC San Diego, has identified the molecular mechanism behind lithium's effectiveness in treating bipolar disorder patients. The study, published in Proceedings of the National Academy of Sciences (PNAS), utilized human induced pluripotent stem cells (hiPS cells) to map lithium's response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. It may also provide the basis to discover new drugs that are safer and more effective than lithium. Bipolar disorder is a mental health condition causing extreme mood swings that include emotional highs (mania or hypomania) and lows (depression) and affects approximately 5.7 million adults in the U.S. Lithium is the first treatment explored after bipolar symptoms, but it has significant limitations. Only approximately one-third of patients respond to lithium treatment, and its effect is only found through a trial-and-error process that takes months--and sometimes years--of prescribing the drug and monitoring for response. Side effects of lithium treatment can be significant, including nausea, muscle tremors, emotional numbing, irregular heartbeat, weight gain, and birth defects, and many patients choose to stop taking the medicine as a result. "Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks," said Evan Snyder, M.D., Ph.D., professor and director of the Center for Stem Cells and Regenerative Medicine at SBP, and senior author of the study. "Importantly, our findings open a clear path to finding safe and effective new drugs. Equally as important, it helped give us insight into what type of mechanisms cause psychiatric problems such as these." "We realized that studying the lithium response could be used as a 'molecular can-opener' to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene--in this case, CRMP2, an intracellular protein that regulates neural networks," added Snyder. In hiPS cells created from lithium-responsive and non-responsive patients, researchers observed a physiological difference in the regulation of CRMP2, which rendered the protein to be in a much more inactive state in responsive patients. However, the research showed that when lithium was administered to these cells, their regulatory mechanisms were corrected, restoring normal activity of CRMP2 and correcting the underlying cause of their disorder. Thus, the study demonstrated that bipolar disorder can be rooted in physiological--not necessarily genetic--mechanisms. The insights derived from the hiPS cells were validated in actual brain specimens from patients with bipolar disorder (on and off lithium), in animal models, and in the actions of living neurons. "This 'molecular can-opener' approach--using a drug known to have a useful action without exactly knowing why--allowed us to examine and understand an underlying pathogenesis of bipolar disorder," said Snyder. "The approach may be extended to additional complex disorders and diseases for which we don't understand the underlying biology but do have drugs that may have some beneficial actions, such as depression, anxiety, schizophrenia and others in need of more effective therapies. One cannot improve a therapy until one knows what molecularly really needs to be fixed." This study was performed in collaboration with Veterans Administration Medical Center in La Jolla, University of California San Diego, Yokohama City University, Massachusetts General Hospital, Harvard Medical School, Mailman Research Center at McLean Hospital, University of Connecticut School of Medicine, University of Pittsburgh Medical Center, National Institute of Mental Health, Vala Sciences, Inc., Broad Institute of MIT and Harvard University, Dalhousie University, Beth-Israel Deaconess Medical Center, Örebro University, Janssen Research & Development Labs, Waseda University, and RIKEN . Funding was provided by the National Institutes of Health (grants RC2MH090011, R21MH093958, R33MH087896 and R01MH095088 and the Library of Integrated Network-based Cellular Signatures Program), the Viterbi Foundation Neuroscience Initiative, the Stanley Medical Research Institute, the Tau Consortium, the California Institute of Regenerative Medicine, the California Bipolar Foundation and the International Bipolar Foundation. Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.


News Article | May 5, 2017
Site: www.eurekalert.org

New York, NY, May 5, 2017 - An international group of experts has concluded that, for patients with schizophrenia and related psychotic disorders, antipsychotic medications do not have negative long-term effects on patients' outcomes or the brain. In addition, the benefits of these medications are much greater than their potential side effects. These findings, by Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chairman of Psychiatry at Columbia University College of Physicians and Surgeon and Director of the New York State Psychiatric Institute, and colleagues from institutions in the United States, Germany, The Netherlands, Austria, Japan, and China, were published today in the American Journal of Psychiatry. Nearly seven million Americans take antipsychotic medications for the treatment of schizophrenia and related conditions. The medications are prescribed to alleviate the symptoms of psychosis and longer-term, to prevent relapse. In recent years, however, concerns have been raised that these medications could have toxic effects and negatively impact long-term outcomes. This view, if not justified by data, has the potential mislead some patients (and their families) to refuse or discontinue antipsychotic treatment. For this reason, the researchers undertook a comprehensive examination of clinical and basic research studies that examined the effects of antipsychotic drug treatment on the clinical outcomes of patients and changes in brain structure. "The evidence from randomized clinical trials and neuroimaging studies overwhelmingly suggests that the majority of patients with schizophrenia benefit from antipsychotic treatment, both in the initial presentation of the disease and for longer-term maintenance to prevent relapse," said Dr. Lieberman. Moreover, whatever side effects that these medications might cause are greatly outweighed by their therapeutic benefits. "Anyone who doubts this conclusion should talk with people whose symptoms have been relieved by treatment and literally given back their lives," Lieberman added. The studies also revealed that delaying or withholding treatment has been associated with poorer long-term outcomes. "While a minority of patients who recover from an initial psychotic episode may maintain their remission without antipsychotic treatment, there is currently no clinical biomarker to identify them, and it is a very small number of patients who may fall into this subgroup," said Dr. Lieberman. "Consequently, withholding treatment could be detrimental for most patients with schizophrenia." And while preclinical studies in rodents suggested that antipsychotic medications can sensitize dopamine receptors, there is no evidence that antipsychotic treatment increases the risk of relapse. While antipsychotic medications can increase the risk for metabolic syndrome, which is linked to heart disease, diabetes, and stroke, the study did not include a risk-benefit analysis. "While more research is needed to address these questions, the strong evidence supporting the benefits of antipsychotic medications should be made clear to patients and their families, while at the same time they should be used judiciously" said Dr. Lieberman. The paper is entitled, "The Long-Term Effects of Antipsychotic Medication on Clinical Course in Schizophrenia." The authors are Donald Goff, MD (New York University School of Medicine, New York, NY), Peter Falkai, MD, PhD (Ludwig-Maximilians-University Munich, Germany), Wolfgang Fleischhacker, MD, (Medical University of Innsbruck, Austria), Ragy Girgis, MD (Columbia University Medical Center), Rene M. Kahn, MD, PhD (University Medical Center, Utrecht, The Netherlands;), Hiroyuki Uchida, MD, PhD (Keiyo University, Tokyo, Japan), Jingping Zhao, MD, Ph.D. (Central South University, Chengsha, China), and Jeffrey Lieberman, MD (Columbia University Medical Center and New York State Psychiatric Institute). Dr. Goff has received research support from Avanir Pharmaceuticals, the National Institute of Mental Health, and the Stanley Medical Research Institute. Dr. Fleischhacker has received research support from Boehringer-Ingelheim, Janssen, Lundbeck, and Otsuka; he has received honoraria for serving as a consultant to and/or on advisory boards for Allergan, Dainippon-Sumitomo, GedeonRichter, Janssen, Lundbeck, Otsuka, Takeda, and Teva; and he has received speaker's fees and travel support from AOP Orphan, Dainippon Sumitomo, Gedeon Richter, Janssen, Lundbeck, Pfizer, Otsuka, and Teva. Dr. Girgis receives research support from Allergan, BioAdvantex, Genentech, and Otsuka. Dr. Kahn has received consulting fees from Alkermes, Forrest, Forum, Gedeon-Richter, Janssen-Cilag, Minerva Neurosciences, and Sunovion and speaker's fees from Janssen-Cilag and Lilly. Dr. Uchida has received grants from Astellas Pharmaceutical, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Meiji-Seika Pharmaceutical, Mochida Pharmaceutical, Novartis, Otsuka Pharmaceutical, and Shionogi; speaker's honoraria from Dainippon-Sumitomo Pharma, Eli Lilly, Janssen Pharmaceutical, Meiji-Seika Pharma, MSD, Otsuka Pharmaceutical, Pfizer, Shionogi, and Yoshitomi Yakuhin; and advisory panel payments from Dainippon-Sumitomo Pharma. All other authors report no financial relationships with commercial interests. New York State Psychiatric Institute and Columbia University Department of Psychiatry (NYSPI/Columbia Psychiatry). New York State Psychiatric Institute (founded in 1896) and the Columbia University Department of Psychiatry have been closely affiliated since 1925. Their co-location in a New York State facility on the New York-Presbyterian/Columbia University Medical Center campus provides the setting for a rich and productive collaborative relationship among scientists and physicians in a variety of disciplines. NYSPI/Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders. The Department and Institute are home to distinguished clinicians and researchers noted for their clinical and research advances in the diagnosis and treatment of depression, suicide, schizophrenia, bipolar and anxiety disorders and childhood psychiatric disorders. Their combined expertise provides state of the art clinical care for patients, and training for the next generation of psychiatrists and psychiatric researchers. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.


News Article | October 27, 2016
Site: www.biosciencetechnology.com

Studying brain tissue from deceased donors, Johns Hopkins scientists have found common groups of genes disrupted among people with schizophrenia, bipolar disorder and major depression. The commonly affected genes sets, identified with RNA sequencing methods, engage in making proteins, controlling brain cell communications and mounting an immune system response, the researchers say. "There are subtle differences in individual genes, and these differences are enriched in sets of genes involved in specific cell processes in the brain tissue of people with a variety of severe mental disorders," says Sarven Sabunciyan, Ph.D., assistant professor of pediatrics and researcher in the Stanley Division of Developmental Neurovirology at the Johns Hopkins University School of Medicine. "It was striking to us that we could identify the broad functional overlaps, knowing there is a lot of variability among individuals with mental disorders." "It is important to show what these seemingly disparate diseases have in common, not only to learn more about them, but because common deficits could suggest similar treatment strategies," says Miranda Darby, Ph.D., a research fellow in Sabunciyan's laboratory and the first author on the study. A report on the work was published online Sept. 13 in Translational Psychiatry. For the study, the researchers took 100 tissue samples from donor brains gathered by the Stanley Medical Research Institute's (SMRI) Array Collection. All samples were from the hippocampus -- the seahorse-shaped part of the brain important for memory and spatial navigation. Thirty-five brains were from people with schizophrenia, 33 were from people with bipolar disorder and 32 were controls without a mental disorder. The research team also used 57 samples from a region of the brain's outer cortex near the eye, the orbitofrontal cortex, all gathered by SMRI's Neuropathy Consortium to verify that the findings in one part of the brain replicated in another part. Thirteen of those brain samples were from people with schizophrenia, 14 with bipolar disorder, 15 with major depression and 15 from controls. Of the total brain samples from both the hippocampus and the orbitofrontal cortex, 57 were from women and 100 were from men. All but seven samples were from Caucasians, and the donors' ages ranged from 19 to 68 at the time of death. The researchers extracted and sequenced the mRNA -- genetic material that function as the blueprints created from DNA and used as guides by cells to build proteins -- from the tissue. The investigators report that each sample from the hippocampus produced on average 154 million sequenced bits of RNA and 140 million sequences for each brain sample from the orbitofrontal cortex. They then aligned the sequences from each sample with a fully sequenced human genome (version 19) and counted the number of times a sequence matched up to each individual gene. In all, 21,861 genes were represented in the hippocampus tissues, and 20,711 were represented in the orbitofrontal cortex region tissues. The researchers identified genes that make either more or less mRNA in individuals with mental disorders than in individuals without a mental disorder. They then compared the list of genes affected in each disorder to lists of genes grouped by their function in the cell, and identified which groups contained a disproportionate number of genes with either increased or decreased mRNA in individuals with schizophrenia, bipolar disorder and major depression. The team reports that out of a total of 1,070 gene sets, 13 of these groups changed in common ways among all three mental disorders. Of these, nine groups containing a total of 338 genes included ribosomal genes, genes responsible for making proteins. A subset of 80 of those protein-making genes was in each of the nine sets, and most of these, the team says, were turned on, or activated, at higher levels compared to controls. For example, in samples from brains of people with bipolar disorder, 78 of these genes were turned on higher in the hippocampus, and 79 were turned on higher in the orbitofrontal cortex than controls. In both regions of the brain, samples from people with major depression had 78 of the genes turned up higher than controls. In people with schizophrenia, 56 genes were turned up in the hippocampus, and 52 were turned up in the orbitofrontal cortex higher than the controls. "Although there isn't a clear reason why the brains of people with these mental disorders would have more of the protein production machinery, we think our findings suggest that it's a fruitful line of investigation to pursue," says Sabunciyan. The remaining four gene groups in common among the brain tissue from all three sets of those with mental illness were "turned down" compared to the controls, the team reported. Two of the gene sets have clear roles in how the brain's neurons send and receive messages to neighboring cells, with one set making up general neuron genes and the other specific to GABA, a neurotransmitter used as the actual messenger between neurons. Another gene group is believed to help operate the ways in which the immune system mounts a response to foreign -- and potentially threatening -- antigens, biological molecules presented by a virus, bacterium or parasite. The researchers say that disruption of the immune system is a hallmark feature long observed in some people with mental illness, particularly in schizophrenia and, to a lesser extent, in bipolar disorder. The fourth gene set included genetic components involved in endocytosis -- the process used to engulf biological molecules outside the cell and bring them inside. When neurons suck up neurotransmitters for recycling after they have been sent or received as a message, they use endocytosis. Endocytosis also plays a role in the immune system's process of engulfing and disposing of germs. Sabunciyan says the research team plans to study these changes in induced pluripotent stem cells derived from patients, which also show an increase in ribosomal gene expression. According to the National Institute of Mental Health, approximately 1 percent of adults develop schizophrenia, about 2.5 percent have bipolar disorder and almost 7 percent of people develop major depression over their lifetimes.


News Article | October 26, 2016
Site: www.eurekalert.org

Studying brain tissue from deceased donors, Johns Hopkins scientists have found common groups of genes disrupted among people with schizophrenia, bipolar disorder and major depression. The commonly affected genes sets, identified with RNA sequencing methods, engage in making proteins, controlling brain cell communications and mounting an immune system response, the researchers say. "There are subtle differences in individual genes, and these differences are enriched in sets of genes involved in specific cell processes in the brain tissue of people with a variety of severe mental disorders," says Sarven Sabunciyan, Ph.D., assistant professor of pediatrics and researcher in the Stanley Division of Developmental Neurovirology at the Johns Hopkins University School of Medicine. "It was striking to us that we could identify the broad functional overlaps, knowing there is a lot of variability among individuals with mental disorders." "It is important to show what these seemingly disparate diseases have in common, not only to learn more about them, but because common deficits could suggest similar treatment strategies," says Miranda Darby, Ph.D., a research fellow in Sabunciyan's laboratory and the first author on the study. A report on the work was published online Sept. 13 in Translational Psychiatry. For the study, the researchers took 100 tissue samples from donor brains gathered by the Stanley Medical Research Institute's (SMRI) Array Collection. All samples were from the hippocampus -- the seahorse-shaped part of the brain important for memory and spatial navigation. Thirty-five brains were from people with schizophrenia, 33 were from people with bipolar disorder and 32 were controls without a mental disorder. The research team also used 57 samples from a region of the brain's outer cortex near the eye, the orbitofrontal cortex, all gathered by SMRI's Neuropathy Consortium to verify that the findings in one part of the brain replicated in another part. Thirteen of those brain samples were from people with schizophrenia, 14 with bipolar disorder, 15 with major depression and 15 from controls. Of the total brain samples from both the hippocampus and the orbitofrontal cortex, 57 were from women and 100 were from men. All but seven samples were from Caucasians, and the donors' ages ranged from 19 to 68 at the time of death. The researchers extracted and sequenced the mRNA -- genetic material that function as the blueprints created from DNA and used as guides by cells to build proteins -- from the tissue. The investigators report that each sample from the hippocampus produced on average 154 million sequenced bits of RNA and 140 million sequences for each brain sample from the orbitofrontal cortex. They then aligned the sequences from each sample with a fully sequenced human genome (version 19) and counted the number of times a sequence matched up to each individual gene. In all, 21,861 genes were represented in the hippocampus tissues, and 20,711 were represented in the orbitofrontal cortex region tissues. The researchers identified genes that make either more or less mRNA in individuals with mental disorders than in individuals without a mental disorder. They then compared the list of genes affected in each disorder to lists of genes grouped by their function in the cell, and identified which groups contained a disproportionate number of genes with either increased or decreased mRNA in individuals with schizophrenia, bipolar disorder and major depression. The team reports that out of a total of 1,070 gene sets, 13 of these groups changed in common ways among all three mental disorders. Of these, nine groups containing a total of 338 genes included ribosomal genes, genes responsible for making proteins. A subset of 80 of those protein-making genes was in each of the nine sets, and most of these, the team says, were turned on, or activated, at higher levels compared to controls. For example, in samples from brains of people with bipolar disorder, 78 of these genes were turned on higher in the hippocampus, and 79 were turned on higher in the orbitofrontal cortex than controls. In both regions of the brain, samples from people with major depression had 78 of the genes turned up higher than controls. In people with schizophrenia, 56 genes were turned up in the hippocampus, and 52 were turned up in the orbitofrontal cortex higher than the controls. "Although there isn't a clear reason why the brains of people with these mental disorders would have more of the protein production machinery, we think our findings suggest that it's a fruitful line of investigation to pursue," says Sabunciyan. The remaining four gene groups in common among the brain tissue from all three sets of those with mental illness were "turned down" compared to the controls, the team reported. Two of the gene sets have clear roles in how the brain's neurons send and receive messages to neighboring cells, with one set making up general neuron genes and the other specific to GABA, a neurotransmitter used as the actual messenger between neurons. Another gene group is believed to help operate the ways in which the immune system mounts a response to foreign -- and potentially threatening -- antigens, biological molecules presented by a virus, bacterium or parasite. The researchers say that disruption of the immune system is a hallmark feature long observed in some people with mental illness, particularly in schizophrenia and, to a lesser extent, in bipolar disorder. The fourth gene set included genetic components involved in endocytosis -- the process used to engulf biological molecules outside the cell and bring them inside. When neurons suck up neurotransmitters for recycling after they have been sent or received as a message, they use endocytosis. Endocytosis also plays a role in the immune system's process of engulfing and disposing of germs. Sabunciyan says the research team plans to study these changes in induced pluripotent stem cells derived from patients, which also show an increase in ribosomal gene expression. According to the National Institute of Mental Health, approximately 1 percent of adults develop schizophrenia, about 2.5 percent have bipolar disorder and almost 7 percent of people develop major depression over their lifetimes. Robert Yolken, M.D., the Theodore and Vada Stanley Distinguished Professor of Neurovirology in Pediatrics at Johns Hopkins, is an additional author on the study. This study was funded by the nonprofit Stanley Medical Research Institute.


Torrey E.F.,Stanley Medical Research Institute | Yolken R.H.,Johns Hopkins University
Trends in Parasitology | Year: 2013

Waterborne outbreaks of Toxoplasma gondii have focused attention on the importance of oocysts shed in the feces of infected cats. Cat feces deposited annually into the environment in the United States total approximately 1.2 million metric tons. The annual oocyst burden measured in community surveys is 3 to 434 oocysts per square foot and is greater in areas where cats selectively defecate. Because a single oocyst can possibly cause infection, this oocyst burden represents a major potential public health problem. The proper disposal of cat litter, keeping cats indoors, reducing the feral cat population, and protecting the play areas of children might potentially reduce the oocyst burden. © 2013 Elsevier Ltd.


Torrey E.F.,Stanley Medical Research Institute | Bartko J.J.,Stanley Medical Research Institute | Yolken R.H.,Johns Hopkins University
Schizophrenia Bulletin | Year: 2012

The failure to find genes of major effect in schizophrenia has refocused attention on nongenetic, including infectious factors. In a previous study, antibodies to Toxoplasma gondii were found to be elevated in 23 studies of schizophrenia (OR 2.73; 95% CI 2.10-3.60). The current study replicates this finding with 15 additional studies (OR 2.71; 95% CI 1.93-3.80) and compares this with other identified schizophrenia risk factors. The highest risk factors are having an affected mother (relative risks [RR] 9.31; 95% CI 7.24-11.96), father (RR 7.20; 95% CI 5.10-10.16), or sibling (RR 6.99; 95% CI 5.38-9.08) or being the offspring of immigrants from selected countries (RR 4.5; 95% CI 1.5-13.1). Intermediate risk factors, in addition to infection with T. gondii, include being an immigrant from and to selected countries (RR 2.7; 95% CI 2.3-3.2), being born in (RR 2.24; 95% CI 1.92-2.61) or raised in (RR 2.75; 95% CI 2.31-3.28) an urban area, cannabis use (OR 2.10-2.93; 95% CI 1.08-6.13), having minor physical anomalies (OR 2.23; 95% CI 1.42-3.58), or having a father 55 or older (OR 2.21-5.92; 95% CI 1.46-17.02). Low-risk factors include a history of traumatic brain injury (OR 1.65; 95% CI 1.17-2.32), sex abuse in childhood (OR 1.46; 95% CI 0.84-2.52), obstetrical complications (OR 1.29-1.38; 95% CI 1.00-1.84), having a father 45 or older (OR 1.21-1.66; 95% CI 1.09-2.01), specific genetic polymorphisms (OR 1.09-1.24; 95% CI 1.06-1.45), birth seasonality (OR 1.07-1.95; 95% CI 1.05-2.91), maternal exposure to influenza (RR 1.05; 95% CI 0.98-1.12), or prenatal stress (RR 0.98-1.00; 95% CI 0.85-1.16). © 2010 The Author.


Kim S.,Stanley Medical Research Institute | Webster M.J.,Stanley Medical Research Institute
Molecular Psychiatry | Year: 2011

Cytoarchitectural abnormalities have been described in the prefrontal cortex (PFC) of subjects with psychiatric disorders. We explored the possible genetic causalities that may underlie the cytoarchitectural abnormalities of calbindin-containing γ-aminobutyric acid (GABA)ergic neurons and perineuronal oligodendrocytes in the PFC of subjects with psychiatric disorders by converging results from genome-wide single-nucleotide polymorphism (SNP) scans for the traits and expression SNP (eSNP) associations. In the initial genome-wide scans, we identified several development- and apoptosis-related genes associated with the cytoarchitectural traits. Moreover, the susceptibility gene for bipolar disorder, PPP2R2C, was found to be associated with the number of perineuronal oligodendrocytes. Further eSNP analyses indicated that two novel candidate genes, RAB2A and SLC38A1, were associated with the density of calbindin-positive neurons and the number of perineuronal oligodendrocytes, respectively. Our findings may provide novel insights into the genetic causalities associated with cytoarchitectural abnormalities in the PFC of subjects with major psychiatric disorders as well as into the etiology of such disorders. © 2011 Macmillan Publishers Limited All rights reserved.


An integrative database, Stanley Neuropathology Consortium Integrative Database (SNCID) (http://sncid.stanleyresearch.org), has been developed to facilitate psychiatric research. The SNCID includes 1749 neuropathological markers measured in 12 different brain regions in 60 human subjects (15 each schizophrenia, bipolar disorder, depression, and unaffected controls). Genome-wide expression microarray datasets from three independent studies are also included. Statistical analysis tools such as variance analysis, correlation analysis, and functional annotation tools have been integrated into the database. In this report, we first replicate an earlier correlation analysis between genome-wide expression profiles and an abnormal cytoarchitectural marker using the SNCID. We then show the potential for identifying neuropathological markers that are abnormal in subjects with psychiatric disorders. We also identify biological pathways associated with several abnormal neuropathological markers, including those in the dopamine, glutamate, Reelin, and γ-aminobutyric acid (GABA)ergic systems. Data exploration using the SNCID may provide insights into the biological pathways associated with the neurotransmitter abnormalities identified in subjects with major psychiatric disorders. © 2010 Nature Publishing Group All rights reserved.


Torrey E.F.,Stanley Medical Research Institute
Schizophrenia Bulletin | Year: 2011

Stigma against mentally ill persons is a major problem and has increased in incidence. Multiple studies have suggested that the perception of violent behavior by seriously mentally ill individuals is an important cause of stigma. It is also known that treating seriously mentally ill people decreases violent behavior. Therefore, the most effective way to decrease stigma is to make sure that patients receive adequate treatment. © 2011 The Author.


Kim S.,Stanley Medical Research Institute | Webster M.J.,Stanley Medical Research Institute
Molecular Psychiatry | Year: 2010

Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n = 14; bipolar disorder, n = 13; depression, n = 12 and controls n = 15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders. © 2010 Nature Publishing Group All rights reserved.

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