I want to put an end to the suffering schizophrenia inflicts on the sufferers and their families. A conflict exists between medical opinion and whatever the patient's family has to say, based in their own experiences.
This illness has to be diagnosed before it begins.
http://www.mitomap.org/MITOMAP
Schizophrenia genes
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| Schizophrenia Gene Resource (SZGR) provides a comprehensive online resource for schizophrenia genetics studies. Currently, SZGR collected and integrated genes related to schizophrenia from the following data sources and annotations: association studies, linkage analysis, gene expression, literature search, Gene Ontology annotations, protein-protein interaction networks, KEGG pathways, and microRNAs and their target sites. SZGR also provides an online candidate gene ranking tool to help the user prioritize candidate genes by pre-optimized or custom weight schemes. Click here for a summary table of all gene sets. | ||||||||||||||||||||||||||||||||||||||||||||||||
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Chromosome 22 is the one for schizophrenia Browse by human chromosome | ||||||||||||||||||||||||||||||||||||||||||||||||
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miércoles, 3 de noviembre de 2010
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Delation in chromosome 22
| Chromosome 22 Link to Schizophrenia Strengthened |  | ||
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| 4 November 2005. There is now overwhelming evidence that genetic inheritance plays a major role in susceptibility to schizophrenia. And though no schizophrenia genes have yet been confirmed, there are plenty of candidates. Multiple lines of evidence, for example, suggest that a region in the small arm of chromosome 22 (22q11.2) might confer susceptibility to the disease. Two recent Nature Neuroscience papers bolster that connection. The link between schizophrenia and chromosome 22q11.2 is particularly interesting because that segment of DNA harbors genes for two enzymes that can influence neurotransmission—catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH). COMT, of course, is crucial for dopamine metabolism, so any genetic variance that alters the activity of this enzyme could tip the balance toward too much, or too little, of this neurotransmitter. The PRODH link is less obvious, but again, loss or reduction of PRODH activity could lead to an increase in the level of proline, and it was recently shown that this amino acid accumulates in glutamatergic synapses where it probably modulates glutamate transmission (see, for example, Renick et al., 1999). Now, together, the two papers add weight to the COMT/PRODH link. Allan Reiss and colleagues at Stanford University, California, together with collaborators at Tel Aviv University, Israel; the University of Geneva, Switzerland; and the University of Washington, Seattle, report on a study of adolescents with 22q11.2 deletion syndrome. The disorder is often referred to as velocardiofacial syndrome (VCFS), a term that encompasses some of the most common early childhood manifestations such as cleft palate, heart defects, characteristic facial appearance, minor learning problems, and speech and feeding problems. The constellation of some 30 different identifying features, not all of which appear in any given child, are traceable to the deletion of that region of chromosome 22. About one third of all babies born with these deletions will go on to later develop schizophrenia (see, for example, Murphy et al., 1999). First author Doron Gothelf and colleagues considered whether polymorphisms, or variations, in the undeleted copy of COMT may help to explain why some with the 22q11.2 deletion will develop schizophrenia, while others do not. They followed patients known to have the deletion, correlating the emergence of the disease with a known single nucleotide polymorphism—one that results in a methionine amino acid instead of a valine at position 158 and that ablates about one third of the enzyme’s activity. Gothelf and colleagues tested 24 patients with 22q11.2 deletion syndrome. During childhood, none showed evidence of a psychotic disorder, but in early adulthood, seven did. The authors found that the COMT variant with low enzyme activity (COMTL) correlated with lower verbal IQ and language skills and lower prefrontal cortex volume in these seven adolescents. The results suggest that “extreme deficiency in COMT activity, as present in the COMTL subjects with 22q11.2DS, is an important neurodevelopmental risk factor for decline in PFC [prefrontal cortex] volume and cognition and for the emergence of psychotic symptoms during adolescence,” write the authors. In the second paper, Maria Karayiorgou's group at Rockefeller University, New York, and Joseph Gogos's group at Columbia University, New York, collaborated to model the effect of altering the expression of PRODH. First author Marta Paterlini and colleagues found that in mice, loss of the enzyme leads to increases in neuronal proline and that this, in turn, increases the probability that glutamate will be released into synapses in the hippocampus. In addition, the authors discovered that synaptic plasticity, as defined by the ability of neurons to modulate their activity in response to the activity of other nearby neurons, is compromised. They found, for example, that both paired-pulse facilitation and long-term potentiation, two commonly used measures of plasticity, were inhibited. The authors also found that loss of PRODH and increases in proline were accompanied by behavioral changes—the mice were generally less active, exploring about 25 percent less than normal mice, and they reacted less frequently in conditioned responses to stimuli such as mild shock. The animals also had a poorer response to psychotomimetic drugs, such as MK801, which increase glutamate release (this could be because the PRODH-deficiency already causes more release of glutamate than normal), but when given amphetamine, locomotor activity increased almost twofold more than in normal animals. “This is reminiscent of the increased susceptibility to the disorganizing effects of D-amphetamine observed in individuals with schizophrenia,” note the authors. Gothelf and colleagues, in their 22q11.2 deletion paper, emphasize that many other genes in the vicinity of COMT and PRODH should be evaluated, and Paterlini and colleagues do just this, using a transcriptional profiling method to evaluate what genes may be turned on or off by the loss of PRODH in their animal model. And one of the genes that interacts most strongly with PRODH was none other than COMT, which was upregulated in the prefrontal cortex of the PRODH-deficient animals. This not only buttresses the argument for COMT and PRODH as key risk factors for schizophrenia, but also suggests that the two genes may interact.—Tom Fagan. References: Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Einstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AI. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23. |
Researchers have made significant strides in teasing apart schizophrenia’s convoluted genetic vulnerabilities, but there’s still a slew of questions. Even with sophisticated technology, researchers are still left scratching their heads about the specifics: what genes are involved, how they incur risk, whether certain mutations link to the different subtypes and so on. Below is a discussion of how genetic research has evolved and what we know today.
Early Research: Family, Twin & Adoption Studies
To determine whether genetics plays any role in schizophrenia, decades ago, researchers began by looking at the prevalence of the disorder in families along with fraternal and identical twins. As many already know, these studies showed that schizophrenia runs in families and has a high heritability rate among identical twins, upward of 80 percent.
What does heritability mean exactly? According to Anna Need, Ph.D, schizophrenia researcher and assistant professor in the Center for Human Genome Variation at Duke University, it tells us that in those particular studies, roughly 80 percent of the variance can be explained by genetics.
Adoption studies are another avenue for answers. This research revealed that kids whose biological parents are schizophrenic (whether the onset was before or after the adoption) were at an elevated risk for psychosis. But kids adopted into families where one of the adoptive parents has schizophrenia were not at an increased risk for developing schizophrenia.
Linkage Studies
Linkage studies explore regions of chromosomes within large families affected by schizophrenia and compare these families to those untouched by the disorder. According to Need, “although some loci have more evidence than others, no chromosomal region has been consistently implicated through linkage studies.” Researchers have either reported different results or others have refuted their findings.
Part of the problem may be that linkage studies typically combine families because families affected by schizophrenia usually don’t have many members. This may confound results, Need said, because it may be that there are “strong [genetic] contributors but they’re different in different families, [so] when you try to combine different studies, they don’t replicate.”
Two fairly recent genome scan meta-analyses did find some significance on several chromosomes. One meta-analysis, which looked at 20 different genome-wide datasets, identified a region on chromosome 2q. The second meta-analysis of 32 studies confirmed a region on chromosome 2q and also on chromosome 5q. These researchers conducted another analysis on 22 studies with samples of European descent and found potential linkage on chromosome 8q. Still, these chromosome regions are very large and have hundreds of genes.
“What we know for sure is there isn’t one or a few causes. That’s all we can say for linkage studies,” Need said.
Candidate Gene Studies
In candidate gene studies, “researchers select individual genes that make sense biologically, or because they are in linkage regions, or both,” Need said. Then they look for differences in the frequency of different variants in people with schizophrenia and without.
However, “these types of studies can be confounded by population differences between cases and controls, small sample size and positive publication bias. Few if any of the hundreds of genes implicated in candidate gene studies are likely to have real effects.”
The Schizophrenia Gene Resource is a database of all the genes implicated in schizophrenia. Currently, the number of genes implicated by candidate gene studies is 281 (here’s the list).
Genome-Wide Association Studies (GWAS)
In genome-wide association studies (GWAS), researchers examine specific gene variants that may be associated with schizophrenia. They compare large groups of people with schizophrenia to healthy controls. In other words, “This is the genetic equivalent of trying to find the person responsible for a crime by fingerprinting everyone in town,” writes one UK neuroscientist on his blog Neuroskeptic.
In 2009, three of the biggest GWAS studies were published in Nature. One study from the International Schizophrenia Consortium compared 3,322 Europeans with schizophrenia with 3,587 people without the condition. They found the strongest association on chromosome 22 on the gene that codes for the protein myosin. They also found an association on chromosome 6p at the major histocompatibility complex (MHC).
A second study used the Molecular Genetics of Schizophrenia sample, consisting of 2,681 people of European descent with schizophrenia and 2,653 without, along with 1,286 African American people with schizophrenia and 973 without. They also found an association between chromosome 6p and schizophrenia.
In the last study, researchers part of the SGENE-plus consortium analyzed a sample of 2,663 people with schizophrenia and 13,498 healthy controls. Like the others, they implicated the MHC region on chromosome 6p. When they increased their sample by adding subjects from the latter studies, they also found two other gene variants on the MHC region and two variants on other chromosomes not found in the other studies.
These studies caused quite the stir, but for different reasons — depending on who you asked. UK’s The Independent, for instance, declared that researchers had “unlocked the secrets of schizophrenia.” Press releases referred to the studies as “landmark” and “breakthroughs.” Many science writers, however, were unimpressed, slamming such overly enthusiastic interpretations.
As Nicholas Wade of The New York Times wrote:
Schizophrenia too seems to be not a single disease, but the end point of 10,000 different disruptions to the delicate architecture of the human brain.
Yes, that discovery is a landmark. The kind that says you have 10,000 miles yet to go.
The march of science is not direct but two steps forward, one step back. This was the step back. But it was a completely necessary one…
(This is another critique from the Neuroskeptic blog.)
Need acknowledged that the “increased risk [conveyed by any one of these associated variants] is minuscule.” One of the papers also reported that the combined effects of thousands of gene variants with very tiny effects could account for up to 30 percent of the risk for schizophrenia.
Still, while these findings don’t bring us closer to predicting schizophrenia, they do pinpoint molecular pathways that may be involved, she said. Take the implication of the major histocompatibility complex (MHC). Researchers have been studying MHC’s role in schizophrenia since the 1970s. While the MHC region has a variety of functions, most are involved in immune function, such as recognizing foreign substances in the body. This region has been linked to about 100 different diseases, including type 1 diabetes and multiple sclerosis.
Many researchers have theorized that exposure to infections may contribute to schizophrenia. A 2006 study of Danish people with schizophrenia and their parents found that nine autoimmune diseases were more common in the schizophrenia sample than in controls. Twelve were more common in parents with affected kids than in controls. Also, a history of any autoimmune disease was associated with a 45 percent increased risk for schizophrenia. However, Kári Stefánsson, CEO of deCode Genetics in Iceland who also led one of the Nature studies, told the Associated Press: “It’s guilt by association; it’s not really a link.”
Rare Gene Variants
Rare variations in genes may explain why researchers have struggled to find specific genes that cause schizophrenia. GWAS only examine common variants, but the same technology can allow the detection of large rare variations, called copy number variations (CNVs). These are regions of the chromosome that are either deleted or duplicated.
(For instance, if a normal sequence is W, X, Y, Z, a deletion might look like: W, Y, Z; a duplication might look like: W, W, X, Y, Z.)
There were two noteworthy studies published in Nature in 2008 that found the same deletions in schizophrenia patients. One study found three deletions on chromosomes 1 and 15: 1q21.1, 15q11.2 and 15q13.3. The International Schizophrenia Consortium also found deletions on chromosomes 15q13.3 and 1q21.1. Also, according to the authors, “As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients.”
These deletions are so rare that they only occurred in less than 1 percent of the schizophrenia sample. But, according to the researchers’ calculations, these deletions increased schizophrenia risk 12- and 15-fold.
“Several regions, and even one single gene (NRXN1) have now been associated with schizophrenia through CNV studies,” Need said. Curiously, every variant associated with schizophrenia also has been linked to other seemingly very different brain conditions including mental retardation, autism and even epilepsy, she added.
The next natural step for researchers, Need said, is to begin sequencing the entire genome to locate smaller rare variations. She and her colleagues at Duke have already sequenced 60 to 70 genomes, and 150 exomes (just the coding parts of the genome). Interestingly, just a year ago, it would’ve taken six weeks to sequence one genome and a hefty amount of $40,000. (The first-ever genome cost $3 billion and took more than a decade.) Now it takes about two weeks and costs around $5,000 (an amount that’s steadily decreasing).
A Dearth of Definitive Answers
With an amazing array of advanced tools, you may be wondering why researchers haven’t already discovered the driving forces behind schizophrenia. In a few words, “There aren’t any [easy answers],” Need said.
Schizophrenia is a highly heterogeneous disease. And with each investigation into its causes, we realize just how colossal its complexities are.
It would be great to be able to put schizophrenia into a neat box with several clear-cut causes, but that’s not the reality. Need believes that there may be anywhere between 100 and 10,000 genes with mind-damaging mutations. But how they function depends on a person’s other genes and their environment. A lot of factors may “modify these strong effects and differ between families,” she said.
The goal, according to Need, isn’t “to understand why every single patient gets schizophrenia” but to be able to find other paths to target medication. Right now, drugs used to treat schizophrenia affect the dopamine system, but they aren’t effective for everyone and have difficult side effects. In other words, researchers want “to have enough clues to zoom in on specific molecular pathways to target for treatment.”
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A Schizophrenia Gene Locus on Chromosome 17q21 in a New Set of Families of Mexican and Central American Ancestry: Evidence From the NIMH Genetics of Schizophrenia in Latino Populations Study
Michael Escamilla, M.D., Elizabeth Hare, Ph.D., Albana M. Dassori, M.D., M.P.H., Juan Manuel Peralta, M.S., Alfonso Ontiveros, M.D., Humberto Nicolini, M.D., Henriette Raventós, M.D., M.Sc., Rolando Medina, M.D., M.P.H., Ricardo Mendoza, M.D., Alvaro Jerez, M.D., Rodrigo Muñoz, M.D., M.P.H., and Laura Almasy, Ph.D.Abstract |
OBJECTIVE: The present study investigated a new set of families of Latin American ancestry in order to detect the location of genes predisposing to schizophrenia and related psychotic disorders. METHOD: A genome-wide scan was performed for 175 newly recruited families with at least two siblings suffering from a psychotic disorder. Best-estimate consensus procedures were used to arrive at diagnoses, and nonparametric allele-sharing statistics were calculated to detect linkage. RESULTS: Genome-wide significant evidence for linkage for the phenotype of DSM-IV schizophrenia or schizoaffective disorder was found in a region on chromosome 17q21 (lod score, 3.33). A region on chromosome 15q22-23 showed suggestive evidence of linkage with this same phenotype (lod score, 2.11). Analyses using a broader model (any psychosis) yielded evidence of suggestive linkage for the 17q21 region only, and no region achieved genome-wide significance of linkage. CONCLUSIONS: The new set of 175 families of Mexican and Central American ancestry delineates two new loci likely to harbor predisposition genes for schizophrenia and schizoaffective disorder. The region with the strongest support for linkage in this sample, 17q21, has been implicated in meta-analyses of schizophrenia genome screens, but the authors found no previous reports of it as a locus for schizophrenia in specific population- or family-based studies, and it may represent the location of a schizophrenia predisposition gene (or genes) of special relevance in Mexican and Central American populations.
Introduction |
Genome-wide linkage scans of families with multiple cases of schizophrenia have been a valuable tool in identifying genes that contribute to this disorder in the general population (1–5). Beginning in the mid-1990s, genome-wide linkage screens of multiplex schizophrenia families have resulted in identification of several chromosomal regions that displayed significant linkage results in distinct populations (4, 6–8). Although replication of results has been difficult, as is to be expected in the study of illnesses that are genetically complex, initial localization of schizophrenia predisposition genes to chromosomes 1, 6, 8, and 13 has led to eventual determination of specific genes that are associated with schizophrenia (9). Previously, we reported the results of phase 1 of the National Institute of Mental Health (NIMH) Genetics of Schizophrenia in Latino Populations Study, which revealed the main loci for psychosis genes in 99 families of Mexican and Central American origin (8). Here we report the results of phase 2 of this study, in which 175 new multiplex families of Mexican and Central American origin were analyzed in a genome-wide screen. This new set of families was recruited from the southwestern United States, Mexico, and Central America. In this new sample, we report evidence of genome-wide significant linkage for the phenotype of schizophrenia to chromosome 17. This is a chromosomal location that has not been significantly linked to schizophrenia in any previous population study of which we are aware, although it has been suggested as a potential locus for schizophrenia in meta-analyses.
Method |
Subjects
Families were recruited from sites throughout the southwestern United States, Mexico, and Central America. Each family had at least two siblings who had been previously diagnosed with either schizophrenia or schizoaffective disorder (according to inpatient or outpatient records). Assessment of affected subjects was conducted as described previously (8). In brief, clinical material was collected for each affected individual, including a direct interview by means of the Diagnostic Interview for Genetic Studies (version 2.0) (10), an interview with a close relative using the Family Interview for Genetic Studies (11), and any available hospitalization or treatment records. Assessments with the Diagnostic Interview for Genetic Studies were all conducted in the subject’s preferred language, by a psychiatrist who had participated in reliability training exercises with the research consortium. Final DSM-IV lifetime diagnoses were assigned by a consensus best-estimate team, as previously described (8). This team also provided consensus information on lifetime history of psychosis, as defined by any of criteria A 1–4 of the DSM-IV criteria for schizophrenia. Table 1 lists the total number of families included in this current analysis, as well as the number of affected relative pairs under the broad and narrow models, and the diagnoses of the subjects studied. No families from the previous sample (8) were included in this current analysis. After consensus diagnoses were completed, the number of affected sibling pairs was 247 for the broad analysis (plus 71 other types of affected relative pairs) and 231 for the narrow analysis (plus 35 additional types of affected relative pairs). This group of genotyped affected sibling pairs is more than twice the size of our previously studied set of 99 families, which had 81 and 70 fully genotyped affected sib pairs, respectively, for the broad and narrow models.
gene
From Medscape Medical News > Psychiatry
Schizophrenia Gene Mutation Discovered
Findings Renew Hope for the Development of New, More Effective Drugs
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February 3, 2011 — Scientists have discovered a gene mutation that is strongly linked to schizophrenia and a signalling pathway that may be treatable with existing drugs.
"This discovery is the latest in a series of studies by our group and by others that have changed the tables in terms of genetic studies in schizophrenia," Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at the University of California (UC), San Diego, who led the team that made the discovery, told Medscape Medical News.
"Mutations in the VIPR2 gene, which can be found in about 1 in 300 patients, are responsible for some amount of schizophrenia, but the fact that this mutation is rare does not necessarily diminish its importance because this is a drug-able gene," he said.
The findings were published online February 3 in Nature.
Important Piece of the Puzzle
Uncovering such a gene affords important insight into the biology of schizophrenia, he said.
"Just because only 1 in 300 patients has this mutation doesn't mean that only 1 in 300 patients has a problem with this signaling pathway. There may actually be a broader segment of schizophrenia patients who have something that is related to this, so uncovering this particular piece of the puzzle is actually quite important."
Schizophrenia is thought to be caused by environmental and genetic factors and occurs in 1% of the population or 10% of those with a first-degree relative, such as a parent or sibling, who has the disorder.
In previous research, Dr. Sebat, together with renowned geneticist Mary-Claire King, PhD, a professor of medical genetics at the University of Washington, Seattle, discovered that rare mutations at many locations in the human genome resulted in a significantly higher risk for schizophrenia.
These mutations consisted of copy number variants (CNVs) — a type of genetic variation in which the number of copies of a gene differs between individuals.
"This work showed that mutations that cause schizophrenia in individuals can be quite rare and that the primary cause of the disease in one patient is different than the cause of the disease in another patient," said Dr. Sebat, who is also chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases and a member of the Institute for Genomic Medicine at UC San Diego.
However, the work did not identify the specific genes involved.
Turning Down the Volume
In this research, Dr. Sebat and his team scanned for CNVs in the genomes of 8290 patients diagnosed as having schizophrenia and 7431 healthy controls.
"We found very strong links to multiple sites in the genome. Some had been picked up in our earlier work, but we uncovered an important new finding — duplications at the tip of chromosome 7q were detected in individuals with schizophrenia at a rate that was 14 times higher than in healthy controls. These CNVs impact the VIPR2 gene, which is important for brain development."
Vasoactive intestinal peptide receptor 2 (VIPR2) is expressed in the nervous system, in blood vessels and the gastrointestinal tract, in addition to the brain.
When the scientists measured the expression of the VIPR2 gene in blood cells from the patients with schizophrenia, they found that individuals with mutations had greater expression of VIPR2 and greater activity of the receptor.
"We concluded that the effect of the causal mutations is to raise the volume on the VIP signaling pathway," Dr. Sebat said.
"VIP is already in clinical trials because of its known roles in regulating vasodilation. It regulates the nervous system, and the cardiovascular system, and the gut. In the case of patients with schizophrenia, you wouldn't want to use VIP because their problem is that the volume is already turned up too high on VIP signaling, so in this case you'd want to use an antagonist that would turn the volume down," he said.
New Diagnostics
In addition to the opportunity to develop new drugs, there is also the opportunity to develop new diagnostics, Dr. Sebat added.
A genetic test for mutations in VIPR2 could help to identify people who are at risk for schizophrenia and could also help to identify those who would most likely benefit from treatment.
"A genetic test for mutations in VIPR2 could help to identify people who are at risk for schizophrenia and could also help to identify those who would most likely benefit from treatment."
It has been known for decades that genetics plays an important role in schizophrenia, and yet genetics has not been used at all in the diagnosis of the disorder. Dr. Sebat called this a paradox.
"This is a segment of the population that is completely underserved in terms of molecular diagnostics. So you would want to apply a genetic test like this for VIPR2 in mental illness. It may only identify a small group of patients, but it would still provide very valuable information."
Psychiatry is in serious need of new, more effective drugs, and in the absence of any strong genetic findings uncovering a clear drug target, there really haven't been any leads or any real avenues for the rational development of new therapies.
Discovery of this gene means that there is hope for the development of new drugs for schizophrenia, he said.
"The first antipsychotics were developed in the 1950s and little has changed since then. Psychiatry is in serious need of new, more effective drugs, and in the absence of any strong genetic findings uncovering a clear drug target, there really haven't been any leads or any real avenues for the rational development of new therapies," he said.
"The fact that large-scale genetic studies can uncover something like this is very encouraging, and we are hopeful that this and other findings that are likely to emerge from this type of research will kick start the development of new drugs," Dr. Sebat added.
Dr. Sebat has disclosed no relevant financial relationships.
Schizophrenia genes
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| News Releases Issued: March 19, 2002 runews@rockefeller.edu Contact: Joseph Bonner (212) 327-7900 | ||
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Schizophrenia Predisposition Linked to Two Genes on Chromosome 22 In a systematic study of 13 genes on human chromosome 22 in an area of the chromosome previously linked to schizophrenia, a team of scientists in the United States and South Africa identified two genes from this group that contribute to susceptibility to this psychiatric disorder. The report, published in the March 12 Early Edition of Proceedings of the National Academy of Sciences, examined about half of the genes in a region of chromosome 22 called 22q11. The scientists, led by Rockefeller University researcher Maria Karayiorgou, M.D., have recently completed analysis of all the genes in this region and plan to publish a report on the remainder at a later date. Previous studies by Karayiorgou and others revealed that 25 to 30 percent of people with microdeletions (genetic flaws that remove chunks of human chromosomes) in 22q11 develop schizophrenia, a common severe mental illness that affects 1 percent of the population and is characterized by disordered thinking as well as deficits in emotional and social behavior. The role of 22q11 microdeletions in schizophrenia were strengthened by additional studies by Karayiorgou and others showing that these microdeletions occur in up to 2 percent of adult schizophrenic patients and up to 6 percent of patients with childhood onset schizophrenia, a particularly aggressive form of the disease that causes symptoms in children by age 13. In the general population, about 1 in 4000 people (0.025 percent) have 22q11 microdeletions. The scientists hypothesized that while deletions of genes from chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population, other types of more subtle genetic flaws such as common variants of individual genes from the 22q11 region may make a larger contribution in non-deleted schizophrenic patients in the wider population. In the research reported in PNAS, scientists examined 22q11 in 242 non-deleted people affected by schizophrenia and their parents, as well as people not diagnosed with schizophrenia, focusing on variations in 13 genes in that region. The 242 affected individuals were taken from three independent patient populations: 107 adult schizophrenics from North America, 26 children diagnosed with childhood onset schizophrenia and 109 schizophrenic patients of South African Afrikaner origin. The researchers found variants in two genes, PRODH2 and DGCR6, enriched in patients with schizophrenia as compared to unaffected individuals who served as "normal controls" for the study. Two additional lines of evidence showed that of the two genes, PRODH2 may play a more important role. First, experiments on a PRODH2-deficient mouse conducted by Karayiorgou's lab in 1999 revealed deficits in sensorimotor gating, which is the ability to filter sensory inputs such as sounds. Sensorimotor gating is also affected in people with schizophrenia. Second, Karayiorgou and her colleagues, by analyzing the publicly available sequence of chromosome 22, discovered a linked "pseudogene" of PRODH2. The pseudogene, which is 97 percent similar to the true gene in its DNA sequence, does not produce a functional protein. The researchers discovered that the PRODH2 pseudogene serves to introduce missense mutations—mutations leading to amino acid substitutions that produce a nonfunctioning protein—in the gene that confer susceptibility through a process called gene conversion. "Pseudogene-like variations of PRODH2 may prevent synthesis of a fully functional enzyme and seem important for increasing susceptibility to schizophrenia because they are present either exclusively or in higher frequencies in people with schizophrenia as compared to controls," says Karayiorgou, associate professor and head of the Laboratory of Human Neurogenetics at Rockefeller. "We also suspect that these variations modulate the onset age of schizophrenia." The sequencing of the human genome has revealed thousands of pseudogenes. An implication of this work is that it points to pseudogenes as a possible constant and renewable source of variation that can be effectively transferred to linked susceptibility genes via gene conversion. PRODH2 encodes for a brain enzyme called proline dehydrogenase, which is involved in neuron signal transmission as well as cell death. "The particular pathway in which PRODH2 is involved is largely undescribed, and is a novel pathway that will open up several different avenues for new drug development," she says. Karayiorgou's co-authors are Hui Liu, Christina Sobin, Brandi L. Galke and Maude L. Blundell at Rockefeller; Simon C. Heath at Memorial Sloan-Kettering Cancer Center; J. Louw Roos at the University of Pretoria, Republic of South Africa; Marge Lenane and Judith L. Rapoport at the National Institute of Mental Health; Brian Robertson at the University of Capetown, Republic of South Africa; Ellen M. Wijsman at the University of Washington; and Joseph A. Gogos at Columbia University College of Physicians and Surgeons. This work was supported by grants from the New York Academy of Medicine, the EJLB Foundation, the Essel Foundation and the Norman and Rosita Winston Foundation. Clinical work at The Rockefeller University Hospital General Clinical Research Center was supported in part by a grant from the National Institutes of Health |
Cold sores and schizophrenia
Cold sore virus may contribute to cognitive and brain abnormalities in schizophrenia
May 28, 2010Exposure to the common virus that causes cold sores may be partially responsible for shrinking regions of the brain and the loss of concentration skills, memory, coordinated movement and dexterity widely seen in patients with schizophrenia, according to research led by Johns Hopkins scientists.
"We're finding that some portion of cognitive impairment usually blamed solely on the disease of schizophrenia might actually be a combination of schizophrenia and prior exposure to herpes simplex virus 1 infection, which reproduces in the brain," says study leader David J. Schretlen, Ph.D., an associate professor in the Department of Psychiatry at Johns Hopkins University School of Medicine.
The research, described in the May Schizophrenia Research, could lead to new ways to treat or prevent the cognitive impairment that typically accompanies this mental illness, including with antiviral drugs, the scientists say.
Doctors have long known that cognitive impairment, including problems with psychomotor speed, concentration, learning, and memory, are prevalent features of schizophrenia, which affects an estimated one percent of the U.S. population. Cognitive deficits often surface months to years before symptoms that are traditionally used to diagnose this disease, such as delusions or hallucinations.
Some previous studies have shown that schizophrenic patients with antibodies to herpes simplex virus 1 (HSV-1), the virus that causes cold sores, often have more severe cognitive deficits than patients without these antibodies. Other studies have shown that patients with HSV-1 antibodies have decreased brain volumes compared to patients without the antibodies. However, it has been unclear whether the cognitive deficits are directly related to the decreased brain volume.
To investigate, Schretlen and his colleagues recruited 40 schizophrenic patients from outpatient clinics at the Johns Hopkins and Sheppard Enoch Pratt hospitals in Baltimore, Md. Blood tests showed that 25 of the patients had antibodies for HSV-1 and 15 didn't. The researchers gave all of the patients tests to measure speed of coordination, organizational skills and verbal memory. The patients then underwent MRI brain scans to measure the volume of particular regions of their brains.
As in previous studies, results showed that patients with antibodies to HSV-1 performed significantly worse on the cognitive tests than patients without the antibodies. But expanding on those earlier studies, analysis of the brain scans showed that the same patients who performed poorly on the tests also had reduced brain volume in the anterior cingulate, which controls processing speed and the ability to switch tasks. There was also shrinkage in the cerebellum, which controls motor function.
These results suggest that HSV-1 might be directly causing the cognitive deficits by attacking these brain regions, Schretlen says.
Though the researchers aren't sure why schizophrenia might make brains more vulnerable to a viral assault, Schretlen says the results already suggest new ways of treating the disorder. Data from other studies has shown that antiviral medications can reduce psychiatric symptoms in some patients with schizophrenia. "If we can identify schizophrenic patients with HSV-1 antibodies early on, it might be possible to reduce the risk or the extent of cognitive deficits," he adds.
Provided by Johns Hopkins Medical Institutions
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BookmarkAge-Associated Defects in Schizophrenia: Gene Network-Based Analysis Reveals Unexpected Results
ScienceDaily (Mar. 2, 2010) — The underlying causes of the debilitating psychiatric disorder schizophrenia remain poorly understood. In a new study published online March 2, 2010 in Genome Research, 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.
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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 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.
Schizophrenia 3
Common Virus May Lead to Cognitive Problems in Schizophrenia
Reviewed by John M. Grohol, Psy.D. on June 4, 2010
John Hopkins scientists discovered shrinking regions of the brain and the loss of concentration skills, memory, coordinated movement and dexterity widely seen in patients with schizophrenia may result from exposure to herpes simplex.
“We’re finding that some portion of cognitive impairment usually blamed solely on the disease of schizophrenia might actually be a combination of schizophrenia and prior exposure to herpes simplex virus 1 infection, which reproduces in the brain,” says study leader David J. Schretlen, Ph.D., an associate professor in the department of psychiatry at Johns Hopkins University School of Medicine.
The research, described in the May Schizophrenia Research, could lead to new ways to treat or prevent the cognitive impairment that typically accompanies this mental illness, including with antiviral drugs, the scientists say.
Doctors have long known that cognitive impairment, including problems with psychomotor speed, concentration, learning, and memory, are prevalent features of schizophrenia, which affects an estimated one percent of the U.S. population.
Cognitive deficits often surface months to years before symptoms that are traditionally used to diagnose this disease, such as delusions or hallucinations.
Some previous studies have shown that schizophrenic patients with antibodies to herpes simplex virus 1 (HSV-1), the virus that causes cold sores, often have more severe cognitive deficits than patients without these antibodies.
Other studies have shown that patients with HSV-1 antibodies have decreased brain volumes compared to patients without the antibodies. However, it has been unclear whether the cognitive deficits are directly related to the decreased brain volume.
To investigate, Schretlen and his colleagues recruited 40 schizophrenic patients from outpatient clinics at the Johns Hopkins and Sheppard Enoch Pratt hospitals in Baltimore, Md. Blood tests showed that 25 of the patients had antibodies for HSV-1 and 15 didn’t.
The researchers gave all of the patients tests to measure speed of coordination, organizational skills and verbal memory. The patients then underwent MRI brain scans to measure the volume of particular regions of their brains.
As in previous studies, results showed that patients with antibodies to HSV-1 performed significantly worse on the cognitive tests than patients without the antibodies. But expanding on those earlier studies, analysis of the brain scans showed that the same patients who performed poorly on the tests also had reduced brain volume in the anterior cingulate, which controls processing speed and the ability to switch tasks.
There was also shrinkage in the cerebellum, which controls motor function.
These results suggest that HSV-1 might be directly causing the cognitive deficits by attacking these brain regions, Schretlen says.
Though the researchers aren’t sure why schizophrenia might make brains more vulnerable to a viral assault, Schretlen says the results already suggest new ways of treating the disorder. Data from other studies has shown that antiviral medications can reduce psychiatric symptoms in some patients with schizophrenia.
“If we can identify schizophrenic patients with HSV-1 antibodies early on, it might be possible to reduce the risk or the extent of cognitive deficits,” he adds.
Source: John Hopkins Medical Institutions