Family studies suggest rare genetic mutations team up to cause schizophrenia

May 28, 2013

Using a novel method of analyzing genetic variations in families, researchers at Johns Hopkins have found that individually harmless genetic variations affecting related biochemical processes may team up to increase the risk of schizophrenia. They say their findings, reported May 28 in Translational Psychiatry, bring some clarity to the murky relationship between genetics and schizophrenia, and may lead to a genetic test that can predict which medications will be effective for individual patients.

"It's long been clear that runs in families, but schizophrenia as a simple inherited disease didn't make sense from an evolutionary point of view because people with the disease tend to have fewer children and the disease-causing genetic variants shouldn't survive," says Dimitri Avramopoulos, M.D., Ph.D., an associate professor of psychiatry in the McKusick-Nathans Institute of . Moreover, he says, studies searching for schizophrenia-linked gene variants have found only weak connections to a few genes—nothing that would explain the persistent prevalence of the disease, which affects about 1 percent of the population.

Most believe that the culprit in so-called complex such as schizophrenia is not just one genetic variant, but more than one acting in concert. It's also likely that individual cases of the disease are caused by different combinations of variants, Avramopoulos says. He and fellow researchers took this hypothesis a step further, theorizing that while our bodies can usually compensate for one that affects a particular system, more than one hit to the same system is likely to tip people toward disease.

The research team devised a technique for analyzing gene-sequencing data that explores whether variants cluster in a subset of cases in a non-random way. After finding support for their hypothesis in previously obtained data on 123 families with at least two schizophrenia-affected members, they decided to sequence genes connected through a biochemical chain reaction that has been linked to the disease in 48 inpatients. Known as the neuregulin signaling pathway, that chain reaction relays signals within the nervous system.

As they had predicted, the researchers found that some of the families had multiple neuregulin signaling-related variants while others had none, a distribution that was highly unlikely to result from chance. Moreover, the schizophrenia patients with neuregulin signaling variants experienced more hallucinations but less impairment than the other schizophrenia patients in the study.

"These results support the idea that there's no single genetic recipe for schizophrenia, but that a buildup of mutations in a pathway related to the disease—like neuregulin signaling—can be the culprit," Avramopoulos says. "The results are also evidence for the current theory that schizophrenia isn't a single disease at all, but a suite of related disorders." Those patients in the study who did not have neuregulin signaling-related variants likely carried variants in a different pathway instead, he notes.

While the results of the study were surprisingly clear-cut given the small number of families in the study, Avramopoulos cautions that larger studies are needed to confirm the results before drawing any firm conclusions. He also plans to study the exact roles of the schizophrenia-linked variants the team identified. Finally, the encouraging results mean it would be worthwhile to apply the new analytic method to other common diseases, such as diabetes and heart disease, which also appear to have complex genetic roots.

Explore further: Genetic risk for schizophrenia is connected to reduced IQ

Related Stories

Genetic risk for schizophrenia is connected to reduced IQ

May 16, 2013
The relationship between the heritable risk for schizophrenia and low intelligence (IQ) has not been clear. Schizophrenia is commonly associated with cognitive impairments that may cause functional disability. There are clues ...

The mysterious GRIN3A and the cause of schizophrenia

March 14, 2013
Since the 1960s, psychiatrists have been hunting for substances made by the body that might accumulate in abnormally high levels to produce the symptoms associated with schizophrenia. In particular, there was a search for ...

Brain cell signal network genes linked to schizophrenia risk in families

April 3, 2013
New genetic factors predisposing to schizophrenia have been uncovered in five families with several affected relatives. The psychiatric disorder can disrupt thinking, feeling, and acting, and blur the border between reality ...

More links found between schizophrenia, cardiovascular disease

January 31, 2013
A new study, to be published in the Feb. 7, 2013 issue of the American Journal of Human Genetics, expands and deepens the biological and genetic links between cardiovascular disease and schizophrenia. Cardiovascular disease ...

Taming suspect gene reverses schizophrenia-like abnormalities in mice

May 22, 2013
Scientists have reversed behavioral and brain abnormalities in adult mice that resemble some features of schizophrenia by restoring normal expression to a suspect gene that is over-expressed in humans with the illness. Targeting ...

Recommended for you

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

Late-breaking mutations may play an important role in autism

July 17, 2017
A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital ...

Newly identified genetic marker may help detect high-risk flu patients

July 17, 2017
Researchers have discovered an inherited genetic variation that may help identify patients at elevated risk for severe, potentially fatal influenza infections. The scientists have also linked the gene variant to a mechanism ...

Newly discovered gene variants link innate immunity and Alzheimer's disease

July 17, 2017
Three new gene variants, found in a genome wide association study of Alzheimer's disease (AD), point to the brain's immune cells in the onset of the disorder. These genes encode three proteins that are found in microglia, ...

3 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Egleton
not rated yet May 28, 2013
How many times was the word "Disease" used in the above article.
Let me lay it out straight out in the open.
Nermal people are hewers of wood and carriers of water. They have No talent.
Back in the days when eugenics had cache it was decided to rid Britain of all madness by preventing families afflicted from breeding.
A list was drawn up and promptly buried. All the talented families were on it.
And here we go again. We are going to genetically cleans the pool.
Madness is the price of genius.
You should be grateful that you harvest the many fruits of insanity, but don't have to pay the price.
Egleton
not rated yet May 28, 2013
In case I was not crystal clear.
Madness is the price others pay for us to be human. Without it we would be apes.
Fabio P_
not rated yet May 31, 2013
@Egleton: That's like saying that fractures are the price we pay for having bones, and that by the same token we should not bother to treat fractures. And for the record, we still are apes. Humans' being apes is not a qualitative judgement, it's a factual statement.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.