Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations that account for at least 10 percent of the non-familial cases of the disease. Researchers describe specific genetic mutations present in individuals who have schizophrenia, but not present in their biological parents who do not have the disease. These individuals were eight times more likely to have these mutations than unaffected individuals. This new data, reported in the May 30 on-line issue of Nature Genetics, will help researchers account for the persistence of schizophrenia in the population despite low birth rates among people with the disease.Researchers at Columbia University Medical Center scanned the genome of 1,077 people which included 152 individuals with schizophrenia, 159 individuals without schizophrenia, and both of their biological parents for copy number mutations. They found mutations, either a gain or loss of genes, in 15 individuals diagnosed with schizophrenia that were not present in the chromosomes of either biological unaffected parent. Only two of such mutations were found in those without schizophrenia. Study subjects were from the European-origin Afrikaner population in South Africa, a genetically homogenous population that is ideal for genetic evaluation.

“We now know the cause of around 10 percent of the cases of sporadic schizophrenia,” said Maria Karayiorgou, M.D., professor of psychiatry, Columbia University Medical Center, the senior author on the study. “Schizophrenia is not as much of a ‘big black box’ as it used to be. The identification of these genes lets us know what brain development pathways are involved in disease onset, so that in the future we can look at better ways of treating this devastating disease.”

Schizophrenia affects approximately 1 percent of the population worldwide. About 40 percent of the disease is thought to be inherited, with the other 60 percent sporadically showing up in people whose family history does not include the disease.

One of the new or de novo mutations researchers found in more than one affected individual in this study was a deletion of a region of chromosome 22. Dr. Karayiorgou had previously provided evidence that loss of genes in this region, 22q11.2, was responsible for introducing “new” or sporadic cases of schizophrenia in the population. This confirms 22q11.2 as the only known recurrent such mutation linked to schizophrenia.

“We have already demonstrated 22q11.2 to be involved in sporadic schizophrenia and we have made considerable progress in understanding the underlying biological mechanisms,” said Dr. Gogos. “Now, we have a new set of mutations that we can investigate. The more information we have about the biological basis for this disease, the more information we can provide to those who suffer from it and their families.”

“Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism,” explains National Institute of Mental Health Director Thomas R. Insel, M.D. “Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may stem from both hereditary and non-hereditary processes. This line of research holds promise for improved treatments – and perhaps someday even prevention – of developmental brain disorders.”

Karayiorgou and co-senior author Joseph A. Gogos, M.D., Ph.D., associate professor of physiology and neuroscience at Columbia University Medical Center, agree that the goal is for psychiatrists to be able to inform patients that they have a mutation that is causing their disease and ultimately to be able to tailor treatments to individual patients based on their specific mutation. This tailored treatment is a ways off, according to Dr. Karayiorgou, but she says patients and their families are relieved to know that there is a biological cause of their illness.

The researchers plan to extend their screen for additional de novo mutations by using increased resolution scans to study additional families. They also plan to scrutinize further genes affected by the identified mutations through human genetics and animal model approaches.

Blocking a common immune system response cleared up plaques associated with Alzheimer’s Disease and enabled treated mice to recover some lost memory, Yale University researchers report Friday in the journal Nature Medicine.Researchers hope the new approach may one day overcome one of the biggest obstacles to development of new dementia medications – the difficulty in finding drugs that can safely cross the blood-brain barrier.

The results of the research surprised the scientists working in the lab of Richard Flavell, senior author of the paper, chairman of the Department of Immunobiology at Yale and investigator with the Howard Hughes Medical Institute. Flavell’s team originally thought that blocking the immune system molecule TGF-β(or transforming growth factor), might actually increase the buildup of amyloid plaques associated with Alzheimer’s Disease

Earlier studies had shown that Alzheimer’s patients tend to have elevated amounts of TGF-β, which plays a key role in activating immune system response to injury. Some had thought the presence of the molecule was simply an attempt to quiet the inflammatory response caused by a buildup of plaque.

Instead, the team found that as much as 90 percent of the plaques were eliminated from the brains of mice genetically engineered to block TGF-β in the peripheral immune cells.

It was like a vacuum cleaner had removed the plaques,” Flavell said.

When the TGF-β pathway was interrupted in mice engineered to have Alzheimer’s, the mice showed an improved ability to perform some tests, including navigating mazes when compared to mice without TGF-β blocked. Scientists also found lower levels of other biological markers associated with the dementia.

When TGF-β was blocked, the immune system seemed to unleash immune cells known as peripheral macrophages. The macrophages passed through the blood-brain barrier and surrounded the neurons and plaques in the brains of mice. “If results from our study in mice engineered to develop Alzheimer’s-like dementia are supported by studies in humans, we may be able to develop a drug that could be introduced into the bloodstream to cause peripheral immune cells to target the amyloid plaques,” said Terrence Town, lead author of the study.

People with schizophrenia from families with no history of the illness were found to harbor eight times more spontaneous mutations – most in pathways affecting brain development – than healthy controls, in a study supported in part by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH). By contrast, no spontaneous mutations were found in people with schizophrenia who had family histories of the illness.

“Our findings strongly suggest that rare, spontaneous mutations likely contribute to vulnerability in cases of schizophrenia from previously unaffected families,” said Maria Karayiorgou, M.D., of Columbia University, who led the research team. “This may also shed light on why the illness has frustrated efforts to implicate gene variants with major effects, and seems to defy natural selection by persisting in the population even though relatively few of those affected have children.”

Karayiorgou and her colleagues report on their whole genome study online in Nature Genetics, May 30, 2008.

“Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism,” explained NIMH Director Thomas R. Insel, M.D. “Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may not be inherited from parents, at least in the sense that these vulnerabilities were not present in the parental genome. This line of research holds promise for improved treatments – and perhaps someday even prevention – of developmental brain disorders.”

Although it’s known that genetics plays a major role in the transmission of both autism and schizophrenia, most cases are sporadic rather than familial.

Echoing findings of another recent study, Karayiorgou and her colleagues determined that most of the suspect mutations were not random, but found in genes and pathways involved in brain development. However, whether a mutation was spontaneous or inherited was not determined for most of the subjects included in the earlier study.

To pinpoint the sources of the glitches, the researchers in the new study compared genetic data from 369 subjects with data from their biological parents – in a total sample of 1,077 individuals drawn from the European ancestry Afrikaner population in South Africa. Including parental genes makes it possible to definitively determine what’s inherited.

Scans of each person’s genome detected the spontaneous mutations in 15 of 152 individuals (10 percent) with non-familial schizophrenia, and only in two of 159 people (1 percent) without the illness – the eight-fold difference. Such sporadic cases were only 1.5 times more likely than controls to harbor inherited mutations.

The researchers also found three deletions of genetic material at a site on chromosome 22 previously implicated in schizophrenia, confirming it as the only known recurrent such mutation linked to schizophrenia.