Single gene might explain dramatic differences among people with schizophrenia

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes. These findings appear in a new imaging-genetics study from the Centre for Addiction and Mental Health (CAMH).

The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work, led by Drs. Aristotle Voineskos and James Kennedy, appears in the latest issue of Molecular Psychiatry.

Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalized for years, while others respond well to treatment.

"What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur," explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. "In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment."

"Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic bases of this condition that affects thousands of Canadians and their families," said Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.

Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.

"We showed that this gene has a bigger effect on age-at-onset than one’s gender has," said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. "This may be a paradigm shift for the field."

The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.

"Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult," said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. "This can have major impact on disease outcome."

In a separate part of the study involving 213 people, the researchers used MRI and diffusion tensor-magnetic resonance brain imaging (DT-MRI). They found that individuals who had the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, and serving as the information highways of the brain.

Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.

"We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have," said Dr. Voineskos. "This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalized treatment options right from the start."

(Image: Akelei van Dam)

Sleep Deprivation May Disrupt Your Genes

Far more than just leaving you yawning, a small amount of sleep deprivation disrupts the activity of genes, potentially affecting metabolism and other functions in the human body, a new study suggests.

It’s not clear how your health may be affected by the genetic disruption if you don’t get enough sleep. Still, the research raises the possibility that the effects of too little sleep could have long-lasting effects on your body.

"If people regularly restrict their sleep, it is possible that the disruption that we see … could have an impact over time that ultimately determines their health outcomes as they age in later life," said study co-author Simon Archer, who studies sleep at the University of Surrey, in England.

The study was published online Feb. 25 in the Proceedings of the National Academy of Sciences.

At issue is how a lack of enough sleep affects the human body. While it’s obvious that people get tired when they don’t sleep, scientists have only recently started to understand how sleep deprivation affects more than the brain, said Dr. Charles Czeisler, chief of the division of sleep medicine at Brigham and Women’s Hospital, in Boston. Research has suggested that sleep is important all the way down to the level of cells, said Czeisler, who was not involved in the new study.

For the study, researchers recruited 26 volunteers who spent a week getting a normal amount of sleep (8.5 hours) and a week getting less than normal (5.7 hours). The participants were still able to enter periods of deep sleep.

The researchers then studied the genes of the participants in blood samples and found that numerous genes, including some related to metabolism, became less active.

So what does that mean for the body? “We have no idea,” Archer said, “but these effects are not minor.” They appear to be similar to those that separate normal from abnormal types of tissue in the body, he said.

Archer said the next step will be to investigate how a lack of sleep affects the body in the long term and to figure out whether some kinds of people are more vulnerable to sleep deprivation’s negative effects on health.

For his part, Czeisler praised the study and said it raises the prospect of a blood test that will tell doctors if a patient’s body is being affected because he or she isn’t getting enough sleep. That’s important because substances such as caffeine can hide the effects of lack of sleep so patients don’t realize there’s a problem, he said.

What about the possibility of a pill that mimics the effects of sleep so people don’t have to bother getting some shut-eye in the first place? There’s no evidence to support the idea of such a pill, Czeisler said, although there’s ongoing research into how to improve the quality of sleep that people do manage to get.

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IQ loss linked to Schizophrenia genes

People at greater genetic risk of schizophrenia could see a fall in IQ as they age, study shows.

Scientists at the University say IQ decline in those at risk could happen even if they do not develop schizophrenia.

The findings could lead to new research into how different genes for schizophrenia affect brain function over time. Schizophrenia - a severe mental disorder characterised by delusions and by hallucinations - is in part caused by genetic factors.

The researchers used the latest genetic analysis techniques to reach their conclusion on how thinking skills change with age.

Retaining our thinking skills as we grow older is important for living well and independently. If nature has loaded a person’s genes towards schizophrenia, then there is a slight but detectable worsening in cognitive functions between childhood and old age. -Professor Ian Deary (Director of the University of Edinburgh’s Centre for Cognitive Ageing and Cognitive Epidemiology)

Historical data

They compared the IQ scores of more than 1,000 people from Edinburgh.

The people were tested for general cognitive functions in 1947, aged 11, and again when they were around 70 years old.

The researchers were able to examine people’s genes and calculate each subject’s genetic likelihood of developing schizophrenia, even though none of the group had ever developed the illness.

They then compared the IQ scores of people with a high and low risk of developing schizophrenia.

Scientists found that there was no difference at age 11, but people with a greater genetic risk of schizophrenia had slightly lower IQs at age 70.

Those people who had more genes linked to schizophrenia also had a greater estimated fall in IQ over their lifetime than those at lower risk.

Cognitive impact

With further research into how these genes affect the brain, it could become possible to understand how genes linked to schizophrenia affect people’s cognitive functions as they age. -Professor Andrew McIntosh (Centre for Clinical Brain Sciences)

Schizophrenia affects around 1 per cent of the population, often in the teenage or early adult years, and is associated with problems in mental ability and memory.

The study, which was funded by the BBSRC, Age UK, and the Chief Scientist Office, is published in the journal Biological Psychiatry.

Where does our head come from?

A research group at the Sars Centre in Bergen has shed new light on the evolutionary origin of the head. In a study published in the journal PLoS Biology they show that in a simple, brainless sea anemone, the same genes that control head development in higher animals regulate the development of the front end of the swimming larvae.

In many animals, the brain is located in a specific structure, the head, together with sensory organs and often together with the mouth. However, there are even more distantly related animals, which have a nervous system, but no brain, like sea anemones and corals.
In this study a research group led by Fabian Rentzsch used the sea anemone Nematostella vectensis to find out if one of the ends of the sea anemone corresponds to the head of higher animals. To do this they studied the function of genes that control head development in higher animals during the embryonic development of the starlet sea anemone.

“Despite looking completely different, it has become clear over the last decade, that all animals have a similar repertoire of genes, including those that are required to make the head of higher animals”, says first author and PhD-student Chiara Sinigaglia.

Stands on its head
When the sea anemone is in the larval stage it swims. As adults, the sea anemone stands with one end on the sea floor and uses long tentacles on its upper end to catch small animals which they stuff into the only body opening in the middle of the ring of tentacles.

“Based on the appearance of the adult animals, the lower end of these animals has traditionally been called the foot and the upper end the head”, explains Rentzsch.
What the research group found out was that in the sea anemone the “head gene” function is located at the end that corresponds to the “foot” of the adult animals. The key was to study the larvae of the sea anemones when theystill move around.

“The larvae swims with the “foot” end forward and this end carries their main sense organ, so at this stage it looks more like this might be their head”, says Rentzsch. And indeed, the “head genes” function on this side of the animals.
Sea anemones and all higher animals, including humans, share a common brainless ancestor which lived between 600 and 700 million years ago.

“By revealing the function of “head genes” in Nematostella, we now understand better how and from where the head and brain of higher animals evolved”, Sinigaglia and Rentzsch explain.

Threat bias interacts with combat, gene to boost PTSD risk

Soldiers preoccupied with threat at the time of enlistment or with avoiding it just before deployment were more likely to develop post-traumatic stress disorder (PTSD), in a study of Israeli infantrymen. Such pre-deployment threat vigilance and avoidance, interacting with combat experience and an emotion-related gene, accounted for more than a third of PTSD symptoms that emerged later, say National Institutes of Health scientists, who conducted the study in collaboration with American and Israeli colleagues.

“Since biased attention predicted future risk for PTSD, computerized training that helps modify such attention biases might help protect soldiers from the disorder,” said Daniel Pine, M.D., of the NIH’s National Institute of Mental Health (NIMH).

Pine, Yair Bar-Haim, Ph.D., of Tel Aviv University, and colleagues, report their findings, Feb.  13, 2013, in the journal JAMA Psychiatry.

Autism Speaks Through Gene Expression

Autism spectrum disorders affect nearly 1 in 88 children, with symptoms ranging from mild personality traits to severe intellectual disability and seizures. Understanding the altered genetic pathways is critical for diagnosis and treatment. New work to examine which genes are responsible for autism disorders will be presented at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

“Autism is the most inheritable of neurodevelopmental disorders,” explains Rajini Rao of Johns Hopkins University in Baltimore, Md., “but identifying the underlying genes is difficult since no single gene contributes more than a tiny fraction of autism cases.” Rather, she continues, “mutations in many different genes variably affect a few common pathways.”

A team of scientists at Johns Hopkins and Tel Aviv University in Israel looked at genetic variations in DNA sequence in the ion transporter NHE9 and found that autism-associated variants in NHE9 result in a profound loss of transporter function. “Altering levels of this transporter at the synapse may modulate critical proteins on the cell surface that bring in nutrients or neurotransmitters such as glutamate,” says Rao. “Elevated glutamate levels are known to trigger seizures, possibly explaining why autistic patients with mutations in these ion transporters also have seizures.”

A unique aspect of the team’s approach was that they exploited decades of basic research done in bacteria and yeast to study a complex human neurological disorder. First, the group at Tel Aviv University, led by Nir Ben-Tal, built structural models of NHE9 using a bacterial relative as a template, allowing the Rao laboratory at Johns Hopkins to use the simple baker’s yeast for screening the mutations. In the future, as genomic information becomes readily available for everyone, such easy, inexpensive, and rapid screening methods will be essential to evaluate rare genetic variants in autism and other disorders.

Rao and her team are optimistic about the potential benefits of their latest findings. “Although the research is still at an early stage, drugs that target the cellular pathways regulated by NHE9 could compensate for its loss of function and lead to potential therapy in the future,” Rao says. “These findings add a new candidate for genetic screening of at-risk patients that may lead to better diagnosis or treatment of autism.”

Discovering the Missing “LINC” to Deafness

Because half of all instances of hearing loss are linked to genetic mutations, advanced gene research is an invaluable tool for uncovering causes of deafness — and one of the biggest hopes for the development of new therapies. Now Prof. Karen Avraham of the Sackler Faculty of Medicine at Tel Aviv University has discovered a significant mutation in a LINC family protein — part of the cells of the inner ear — that could lead to new treatments for hearing disorders.

Her team of researchers, including Dr. Henning Horn and Profs. Colin Stewart and Brian Burke of the Institute of Medical Biology at A*STAR in Singapore, discovered that the mutation causes chaos in a cell’s anatomy. The cell nucleus, which contains our entire DNA, moves to the top of the cell rather than being anchored to the bottom, its normal place. Though this has little impact on the functioning of most of the body’s cells, it’s devastating for the cells responsible for hearing, explains Prof. Avraham. “The position of the nucleus is important for receiving the electrical signals that determine proper hearing,” she explains. “Without the ability to receive these signals correctly, the entire cascade of hearing fails.”

This discovery, recently reported in the Journal of Clinical Investigation, may be a starting point for the development of new therapies. In the meantime, the research could lead towards work on a drug that is able to mimic the mutated protein’s anchoring function, and restore hearing in some cases, she suggests.

Scientists discover how epigenetic information could be inherited

New research reveals a potential way for how parents’ experiences could be passed to their offspring’s genes. The research was published in the journal Science.

Epigenetics is a system that turns our genes on and off. The process works by chemical tags, known as epigenetic marks, attaching to DNA and telling a cell to either use or ignore a particular gene.

The most common epigenetic mark is a methyl group. When these groups fasten to DNA through a process called methylation they block the attachment of proteins which normally turn the genes on. As a result, the gene is turned off.

Scientists have witnessed epigenetic inheritance, the observation that offspring may inherit altered traits due to their parents’ past experiences. For example, historical incidences of famine have resulted in health effects on the children and grandchildren of individuals who had restricted diets, possibly because of inheritance of altered epigenetic marks caused by a restricted diet.

However, it is thought that between each generation the epigenetic marks are erased in cells called primordial gene cells (PGC), the precursors to sperm and eggs. This ‘reprogramming’ allows all genes to be read afresh for each new person – leaving scientists to question how epigenetic inheritance could occur.

The new Cambridge study initially discovered how the DNA methylation marks are erased in PGCs, a question that has been under intense investigation over the past 10 years. The methylation marks are converted to hydroxymethylation which is then progressively diluted out as the cells divide. This process turns out to be remarkably efficient and seems to reset the genes for each new generation. Understanding the mechanism of epigenetic resetting could be exploited to deal with adult diseases linked with an accumulation of aberrant epigenetic marks, such as cancers, or in ‘rejuvenating’ aged cells.

However, the researchers, who were funded by the Wellcome Trust, also found that some rare methylation can ‘escape’ the reprogramming process and can thus be passed on to offspring – revealing how epigenetic inheritance could occur. This is important because aberrant methylation could accumulate at genes during a lifetime in response to environmental factors, such as chemical exposure or nutrition, and can cause abnormal use of genes, leading to disease. If these marks are then inherited by offspring, their genes could also be affected.

Scientists Work To Unravel Mystery Behind Woman Who Doesn’t Grow

Twenty year old Brooke Greenberg hasn’t grown since age five. For the last 15 years mystified doctors have been unable to explain the cause for Brooke’s disorder that has kept her aging in check. At age twenty, she maintains the physical and mental appearance of a toddler.

Eric Shadt wants to solve this most bizarre of medical mysteries. Director of the Icahn Institute for Genomics and Multiscale Biology at the Mount Sinai Medical Center in New York, Shadt is leading research to uncover the genetic cause for Brooke’s condition.

Because hormones control many of the maturation processes, one of the first things the research team looked at was to see if Brooke’s own hormone levels might be abnormal. In a piece he wrote on Katie Couric’s website on whose show he and the Greenberg family recently appeared, Shadt explained that Brooke “has no apparent abnormalities in her endocrine system, no gross chromosomal abnormalities, or any of the other disruptions known to occur in humans that can cause developmental issues.”

The researchers are now painstakingly analyzing Brooke’s entire genome in search of unique mutations. Needless to say, it is a formidable undertaking. “Cracking the code on Brooke’s condition,” Shadt wrote, “is the proverbial searching for a needle in a haystack, since likely there is one or a small number of letters changed in Brooke’s genome that has caused her condition.”

New Discovery in Autism-Related Disorder Reveals Key Mechanism in Brain Development and Disease

A new finding in neuroscience for the first time points to a developmental mechanism linking the disease-causing mutation in an autism-related disorder, Timothy syndrome, and observed defects in brain wiring, according to a study led by scientist Ricardo Dolmetsch and published online yesterday in Nature Neuroscience. These findings may be at the heart of the mechanisms underlying intellectual disability and many other brain disorders.

The present study reveals that a mutation of the disease-causing gene throws a key process of neurodevelopment into reverse. That is, the mutation underlying Timothy syndrome causes shrinkage, rather than growth, of the wiring needed for the development of neural circuits that underlie cognition.

“In addition to the implications for autism, what’s really exciting is that we now have a way to get at the core mechanisms tying genes and environmental influences to development and disease processes in the brain,” said Dolmetsch, Senior Director of Molecular Networks at the Allen Institute for Brain Science.

“Imagine what we can learn if we do this hundreds and hundreds of times for many different human genetic variations in a large-scale, systematic way. That’s what we are doing now at the Allen Institute,” Dolmetsch continued.

In normal brain development, brain activity causes branches emanating from neural cells to stretch or expand. In cells with the mutation, these branched extensions, called dendrites, instead retract in response to neural activity, according to this study. This results in abnormal brain circuitry favoring connections with nearby neurons rather than farther-reaching connections. Further, the study identified a previously unknown mode of signaling to uncover the chemical pathway that causes the dendritic retraction.

This finding may have wide-reaching implications in neuroscience, as impaired dendrite formation is a common feature of many neurodevelopmental disorders. Further, the same gene has been implicated in other disorders including bipolar disorder and schizophrenia.

Under Dolmetsch’s leadership, the Molecular Networks program at the Allen Institute, one of three major new initiatives announced by the Institute last March, is using similar methods on a grand scale. The Institute is probing a large number of human genetic variations and many pathways in the brain to untangle the cellular mechanisms of neurodevelopment and disease. In addition to identifying the molecular and environmental rules that shape how the brain is built, the program will create new research tools and data sets that it will share publicly with the global research community.

Timothy syndrome is a neurodevelopmental disorder associated with autism spectrum disorders and caused by a mutation in a single gene. In addition to autism, it is also characterized by cardiac arrhythmias, webbed fingers and toes, and hypoglycemia, and often leads to death in early childhood.

(Image: iStock)