There has never, so far, been a convincing genetic link for schizophrenia, until now. People who have the human genetic disorder 22q11.2 deletion syndrome. The syndrome occurs when part of chromosome 22, near the middle, is deleted and individuals are left with one rather than the usual two copies of about 25 genes.
Here is some more from the NIH "Genetics Home Reference":
22q11.2 deletion syndrome has many possible signs and symptoms that can affect almost any part of the body. The features of this syndrome vary widely, even among affected members of the same family. Common signs and symptoms include heart abnormalities that are often present from birth, an opening in the roof of the mouth (a cleft palate), and distinctive facial features. People with 22q11.2 deletion syndrome often experience recurrent infections caused by problems with the immune system, and some develop autoimmune disorders such as rheumatoid arthritis and Graves disease in which the immune system attacks the body's own tissues and organs. Affected individuals may also have breathing problems, kidney abnormalities, low levels of calcium in the blood (which can result in seizures), a decrease in blood platelets (thrombocytopenia), significant feeding difficulties, gastrointestinal problems, and hearing loss. Skeletal differences are possible, including mild short stature and, less frequently, abnormalities of the spinal bones.An estimated 1 in 4,000 people have 22q11.2 deletion syndrome. About 30 percent of individuals with the deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disorder
Many children with 22q11.2 deletion syndrome have developmental delays, including delayed growth and speech development, and learning disabilities. Later in life, they are at an increased risk of developing mental illnesses such as schizophrenia, depression, anxiety, and bipolar disorder. Additionally, affected children are more likely than children without 22q11.2 deletion syndrome to have attention deficit hyperactivity disorder (ADHD) and developmental conditions such as autism spectrum disorders that affect communication and social interaction.
Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. Doctors named these conditions DiGeorge syndrome, velocardiofacial syndrome (also called Shprintzen syndrome), and conotruncal anomaly face syndrome. In addition, some children with the 22q11.2 deletion were diagnosed with the autosomal dominant form of Opitz G/BBB syndrome and Cayler cardiofacial syndrome. Once the genetic basis for these disorders was identified, doctors determined that they were all part of a single syndrome with many possible signs and symptoms. To avoid confusion, this condition is usually called 22q11.2 deletion syndrome, a description based on its underlying genetic cause.
For the sake of reference, about 1 in 100 people will develop schizophrenia, 1.1%, while the rate the deletion syndrome is .00025%. Clearly, there are a LOT of people presenting with schizophrenia who do not have the deletion syndrome.
This syndrome apparently can cause increased expression of Drd2 in the thalamus, and Drd2 is associated with D2 dopamine receptors. The researchers identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in mouse models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an unusual elevation of Drd2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics.
The downside of this research is that there will be new drugs developed to target the voices heard by those with schizophrenia, despite mounting evidence that befriending the voices is better long-term solution than psychopharmacological interventions.
Date: June 5, 2014Here is the abstract from Science - the article itself is behind the usual pay wall.
Source: St. Jude Children's Research Hospital
Summary: Scientists have identified problems in a connection between brain structures that may predispose individuals to hearing the 'voices' that are a common symptom of schizophrenia. Researchers linked the problem to a gene deletion. This leads to changes in brain chemistry that reduce the flow of information between two brain structures involved in processing auditory information.
Conceptual illustration (stock image). Scientists have identified problems in a connection between brain structures that may predispose individuals to hearing the "voices" that are a common symptom of schizophrenia. Credit: © yalayama / Fotolia
St. Jude Children's Research Hospital scientists have identified problems in a connection between brain structures that may predispose individuals to hearing the "voices" that are a common symptom of schizophrenia. The work appears in the June 6 issue of the journal Science.
Researchers linked the problem to a gene deletion. This leads to changes in brain chemistry that reduce the flow of information between two brain structures involved in processing auditory information.
The research marks the first time that a specific circuit in the brain has been linked to the auditory hallucinations, delusions and other psychotic symptoms of schizophrenia. The disease is a chronic, devastating brain disorder that affects about 1 percent of Americans and causes them to struggle with a variety of problems, including thinking, learning and memory.
The disrupted circuit identified in this study solves the mystery of how current antipsychotic drugs ease symptoms and provides a new focus for efforts to develop medications that quiet "voices" but cause fewer side effects.
"We think that reducing the flow of information between these two brain structures that play a central role in processing auditory information sets the stage for stress or other factors to come along and trigger the 'voices' that are the most common psychotic symptom of schizophrenia," said the study's corresponding author Stanislav Zakharenko, M.D., Ph.D., an associate member of the St. Jude Department of Developmental Neurobiology. "These findings also integrate several competing models regarding changes in the brain that lead to this complex disorder."
The work was done in a mouse model of the human genetic disorder 22q11 deletion syndrome. The syndrome occurs when part of chromosome 22 is deleted and individuals are left with one rather than the usual two copies of about 25 genes. About 30 percent of individuals with the deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disorder. DNA is the blueprint for life. Human DNA is organized into 23 pairs of chromosomes that are found in nearly every cell.
Earlier work from Zakharenko's laboratory linked one of the lost genes, Dgcr8, to brain changes in mice with the deletion syndrome that affect a structure important for learning and memory. They found evidence that the same mechanism was at work in patients with schizophrenia. Dgcr8 carries instructions for making small molecules called microRNAs that help regulate production of different proteins.
For this study, researchers used state-of-the-art tools to link the loss of Dgcr8 to changes that affect a different brain structure, the auditory thalamus. For decades antipsychotic drugs have been known to work by binding to a protein named the D2 dopamine receptor (Drd2). The binding blocks activity of the chemical messenger dopamine. Until now, however, how that quieted the "voices" of schizophrenia was unclear.
Working in mice with and without the 22q11 deletion, researchers showed that the strength of the nerve impulse from neurons in the auditory thalamus was reduced in mice with the deletion compared to normal mice. Electrical activity in other brain regions was not different.
Investigators showed that Drd2 levels were elevated in the auditory thalamus of mice with the deletion, but not in other brain regions. When researchers checked Drd2 levels in tissue from the same structure collected from 26 individuals with and without schizophrenia, scientists reported that protein levels were higher in patients with the disease.
As further evidence of Drd2's role in disrupting signals from the auditory thalamus, researchers tested neurons in the laboratory from different brain regions of mutant and normal mice by adding antipsychotic drugs haloperidol and clozapine. Those drugs work by targeting Drd2. Originally nerve impulses in the mutant neurons were reduced compared to normal mice. But the nerve impulses were almost universally enhanced by antipsychotics in neurons from mutant mice, but only in neurons from the auditory thalamus.
When researchers looked more closely at the missing 22q11 genes, they found that mice that lacked the Dgcr8 responded to a loud noise in a similar manner as schizophrenia patients. Treatment with haloperidol restored the normal startle response in the mice, just as the drug does in patients.
Studying schizophrenia and other brain disorders advances understanding of normal brain development and the missteps that lead to various catastrophic diseases, including pediatric brain tumors and other problems.
The study's first author is Sungkun Chun, Ph.D., a postdoctoral fellow in Zakharenko's laboratory. The other authors are Joby Westmoreland, Ildar Bayazitov, Donnie Eddins, Amar Pani, Richard Smeyne, Jing Yu and Jay Blundon, all of St. Jude.
The research was funded in part by grants (MH097742, MH095810, DC012833) from the National Institutes of Health and ALSAC.
The above story is based on materials provided by St. Jude Children's Research Hospital. Note: Materials may be edited for content and length.
S. Chun, J. J. Westmoreland, I. T. Bayazitov, D. Eddins, A. K. Pani, R. J. Smeyne, J. Yu, J. A. Blundon, S. S. Zakharenko. (2014). Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models. Science; 344(6188): 1178-1182. DOI: 10.1126/science.1253895
Sungkun Chun, Joby J. Westmoreland, Ildar T. Bayazitov, Donnie Eddins, Amar K. Pani, Richard J. Smeyne, Jing Yu, Jay A. Blundon, Stanislav S. Zakharenko
Auditory hallucinations in schizophrenia are alleviated by antipsychotic agents that inhibit D2 dopamine receptors (Drd2s). The defective neural circuits and mechanisms of their sensitivity to antipsychotics are unknown. We identified a specific disruption of synaptic transmission at thalamocortical glutamatergic projections in the auditory cortex in murine models of schizophrenia-associated 22q11 deletion syndrome (22q11DS). This deficit is caused by an aberrant elevation of Drd2 in the thalamus, which renders 22q11DS thalamocortical projections sensitive to antipsychotics and causes a deficient acoustic startle response similar to that observed in schizophrenic patients. Haploinsufficiency of the microRNA-processing gene Dgcr8 is responsible for the Drd2 elevation and hypersensitivity of auditory thalamocortical projections to antipsychotics. This suggests that Dgcr8-microRNA-Drd2–dependent thalamocortical disruption is a pathogenic event underlying schizophrenia-associated psychosis.
Editor's SummaryGenes, synapses, and hallucinations
In a schizophrenia mouse model, Chun et al. found that an abnormal increase of dopamine D2 receptors in the brain's thalamic nuclei caused thalamocortical synapse deficits owing to reduced glutamate release. Antipsychotic agents or a dopamine receptor antagonist reversed this down-regulation. The defect was associated with the loss of a component of the microRNA processing machinery encoded by the dgcr8 gene.