Autism Genome Project delivers genetic discovery

A new study from investigators with the Autism Genome Project (AGP), the world's largest research project on identifying genes associated with risk for autism, has found that the comprehensive use of copy number variant (CNV) genetic testing offers an important tool in individualized diagnosis and treatment of autism.

Funded primarily by Autism Speaks, the world's leading autism science and advocacy organization, the Autism Genome Project (AGP) involved more than 50 research centers in 11 countries.

The report, published today in the American Journal of Human Genetics, delivers on the 10-year project's objective to provide practical methods for earlier diagnosis and personalized treatment of autism.

Rob Ring

"With the publication of this study, we should step back to recognize and celebrate the pioneering achievements of the AGP and what they have accomplished in helping to launch the field of genomic risk discovery in autism," says Autism Speaks Chief Science Officer Rob Ring.

"The AGP has generated information that holds the potential to guide medical care for certain individuals with autism today."

"They have demonstrated that science can work for families, and Autism Speaks is proud to have been a supporter of the work all along the way."

The study involved CNV testing of 2,446 families affected by autism and 4,768 individuals unaffected by neurologic or psychiatric disorders.

Overall, CNV s were significantly more common in the participating families affected by autism and, the CNV testing uncovered dozens of cases where autism-linked gene changes were associated with additional health risks warranting medical attention.

In nine of the families affected by autism, CNV s involved a gene that indicates elevated risk for seizures and epilepsy.

Stephen Scherer

"This result warrants an immediate referral to a neurologist," explains senior author Stephen Scherer of the Toronto's Hospital for Sick Children and the University of Toronto.

Similarly, CNV  testing indicated a high risk for Duchene muscular dystrophy in several of the autism families and identified syndromes associated with heart problems in others.

CNV s are genetic changes that involve duplication or deletion of entire segments of DNA.

They do not typically show up on standard genetic tests which search for "spelling mistakes" in the DNA letters that compose a gene.

Those standard tests identify a clear genetic autism link in only 15 to 20 percent of the cases.

"This report and its extensive supplements should become a new guidebook for medical geneticists working with families affected by autism," Dr. Scherer says.

In addition, the study added dozens of genes to the growing list of those that contribute to the development of autism.

Surprisingly, the autism genes identified through CNV testing had little overlap with those detected using standard exome gene sequencing, yet researchers say they affect the same brain pathways.

"These gene discoveries will help guide further research on autism subtypes and their treatment," Dr. Scherer says.

In response, the investigators urge medical geneticists to add CNV testing to the standard gene tests for autism and to consult medical recommendations for the many autism-linked syndromes that CNV testing can reveal.

CNV testing is currently available, though it's not typically part of standard genetic testing for autism.

Whole genome sequencing is the next step in genetic testing for Autism but is not yet widely available in ordinary medical settings.

Autism Speaks has taken a world-leadership position in in this direction with its Autism Ten Thousand Genomes (Aut10K) program.

More Information: "Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders" American Journal of Human Genetics: ((2014), doi.org/10.1016/j.ajhg.2014.03.018

Scientist find Gene linked to Asperger Syndrome and empathy

Scientists have confirmed that variations in a particular gene play a key role in the autism spectrum condition known as Asperger Syndrome.

They have also found that variations in the same gene are also linked to differences in empathy levels in the general population.

A study to be published later this month in the journal Molecular Autism confirms previous research that people with Asperger Syndrome (AS) are more likely to carry specific variations in a particular gene.

More strikingly, the study supports existing findings that the same gene is also linked to how much empathy typically shown by individuals in the general population.

The research was carried out by a team of researchers led by Professor Baron-Cohen at the Autism Research Centre at Cambridge University.

Asperger Syndrome is an autism spectrum condition. The researchers looked for sequence variations (called single nucleotide polymorphisms, SNPs) in the gene known as GABRB3 in a total of 530 adults - 118 people diagnosed with AS and 412 people without a diagnosis.

The team found that certain SNPs in GABRB3 were significantly more common in people with AS.

They also discovered that additional genetic variations in the same gene were linked to scores on an empathy measure called the Empathy Quotient in the general population.

AS is diagnosed when a person struggles with social relationships and communication, and shows unusually narrow interests and resistance to change, but has good intelligence and language skills.

Most genetic studies of autistic spectrum conditions treat autism as if they are all very similar, whereas in reality there is considerable variation (e.g., in language level and intellectual ability).

Rather than studying people on the autistic condition spectrum, this new study looked only people with AS, as a well-defined subgroup of individuals within this range.

The researchers examined the gene GABRB3 which regulates the functioning of a neurotransmitter called gamma-aminobutyric acid (GABA) and which contains a number of SNPs that vary across the population.

The volunteers were tested for 45 SNPs within this key gene. The team had previously found that SNPs in this gene were more common in adults with AS and also showed a relationship with empathy levels and tactile sensitivity (how sensitive people are to being touched) in the general population.

Testing a new sample of volunteers who had not taken part in previous studies, the researchers found that three of the SNPs were again more common in adults with AS, and two different SNPs in the same gene were again related to empathy levels in the general population, confirming that the gene is involved in autism spectrum conditions.

Professor Baron-Cohen said: "We are excited that this study confirms that variation in GABRB3 is linked not just to AS but to individual differences in empathy in the population.

Many candidate genes do not replicate across studies and across different samples, but this genetic finding seems to be a solid result.

Research now needs to focus on where this gene is expressed in the brain in autism, and how it interacts with other genetic and non-genetic factors that cause AS."

The team was co-led by Dr Bhismadev Chakrabarti from the Department of Psychology at Reading University. He commented: "Genes play an important role in autism and Asperger Syndrome."

"This new study adds to evidence that GABRB3 is a key gene underlying these conditions."

"This gene is involved in the functioning of a neurotransmitter that regulates excitation and inhibition of nerve cell activity so the research gives us vital additional information about how the brain may develop differently in people with Asperger Syndrome."

Varun Warrier, who carried out the study as part of his graduate research at Cambridge University, added: "The most important aspect of this research is that it points to common genetic variants in GABRB3 being involved in both AS and in empathy as a dimensional trait."

"Although GABRB3 is not the only gene to be involved in this condition and in empathy levels, we are confident that we have identified one of the key players."

"We are following this up by testing how much protein GABRB3 produces in the brain in autism, since a genetic finding of this kind becomes more explanatory when we can also measure its function."

More information: "Genetic variation in GABRB3 is associated with Asperger syndrome and multiple endophenotypes relevant to autism." Varun Warrier, Simon Baron-Cohen and Bhismadev Chakrabarti. Molecular Autism 2013, 4:48 DOI: 10.1186/2040-2392-4-48

Genetic discovery could increase understanding of ADHD

Scientists at Trinity College Dublin have discovered that a mutation in a single gene involved in the functioning of the brain's nervous system can lead to hyperactivity symptoms that are characteristic of Attention-Deficit Hyperactivity Disorder (ADHD).

Getting the nervous system wired up properly is a big job. The brain contains billions of different types of nerve cells, which all have to be connected in a very precise fashion.

This circuitry self-assembles as an embryo grows, based on a developmental programme involving the actions of thousands of different genes.

The scientists discovered that a mutation in a single mouse gene, 'Elfn1', can have a big effect.

Their new findings give impetus to discover whether mutations in Elfn1 in humans can give rise to similar symptoms and whether they might play a part in some patients with epilepsy and ADHD.

These two conditions occur together far more often than expected by chance.

In an article just published in the international journal, PLOS ONE, Associate Professor in Genetics at Trinity, Kevin Mitchell, and Research Technical Officer, Dr Jackie Dolan, investigated the importance of the function played by Elfn1 and the protein it produces when expressed.

They did this by experimentally removing it from some mice and comparing the effects against those seen in mice with the normal gene.

Although overall brain anatomy and patterns of connectivity remained normal, there was clear evidence of disturbance in brain function in individuals without Elfn1.

Seizures occurred in some, and these became more common over time and were easily triggered by human interaction.

Secondly, hyperactivity was observed, and this showed an unusual response to the stimulant, amphetamine.

Amphetamine normally causes hyperactivity in animals that have Elfn1 present, as it does in most humans. Here, it reduced the hyperactivity of the mice without the gene.

This is similar to the situation in patients with ADHD, where amphetamine and related drugs have a paradoxical, calming effect.

"These findings clearly show that removal of the Elfn1 gene affects brain circuits with multiple consequences for behaviour," said Dr Dolan.

The seizures likely relate to the function of Elfn1 in dampening the response of the nervous system to strong stimuli in key brain structures called the cortex and hippocampus.

However, the development of ADHD-like hyperactivity focused on a different brain structure, known as the habenula.

This structure is part of a system that integrates information from multiple regions of the brain and regulates the activity of nerve cells that produce mood-regulating chemicals such as dopamine and serotonin.

Professor Mitchell said: "We are at the beginning of this process of figuring out how this gene works and understanding the consequences when it is mutated but, these animals provide a unique model to investigate how subtle changes in brain development can ultimately result in aberrant brain function".

Elfn1 was first discovered by Dr Dolan, Professor Mitchell and colleagues in 2007. The protein it produces when expressed allows communication from one nerve cell to another. In a study published in Science last year, Emily Sylwestrak and Anirvan Ghosh, of the University of California, San Diego, showed that the Elfn1 protein determined what kind of connection was made onto those nerve cells.

More information: dx.plos.org/10.1371/journal.pone.008049

Autism ASD: Researchers discover a potential cause

Topoisomerase inhibitors reduce the expression of long genes in neurons, including a remarkable number of genes implicated in Autism Spectrum Disorders -- 200 kb is four times longer than the average gene. 

Credit: Concept: Mark Zylka. Illustration: Janet Iwasa.

Problems with a key group of enzymes called topoisomerases can have profound effects on the genetic machinery behind brain development and potentially lead to autism spectrum disorder (ASD), according to research announced today in the journal Nature.

Scientists at the University of North Carolina School of Medicine have described a finding that represents a significant advance in the hunt for environmental factors behind autism and lends new insights into the disorder's genetic causes.

"Our study shows the magnitude of what can happen if topoisomerases are impaired," said senior study author Mark Zylka, PhD, associate professor in the Neuroscience Center and the Department of Cell Biology and Physiology at UNC.

"Inhibiting these enzymes has the potential to profoundly affect neurodevelopment—perhaps even more so than having a mutation in any one of the genes that have been linked to autism."

The study could have important implications for ASD detection and prevention.

Mark Zylka

"This could point to an environmental component to autism," said Zylka.

"A temporary exposure to a topoisomerase inhibitor in utero has the potential to have a long-lasting effect on the brain, by affecting critical periods of brain development. "

This study could also explain why some people with mutations in topoisomerases develop autism and other neuro-developmental disorders.

Topiosomerases are enzymes found in all human cells. Their main function is to untangle DNA when it becomes overwound, a common occurrence that can interfere with key biological processes.

Most of the known topoisomerase-inhibiting chemicals are used as chemotherapy drugs. Zylka said his team is searching for other compounds that have similar effects in nerve cells.

"If there are additional compounds like this in the environment, then it becomes important to identify them," said Zylka.

"That's really motivating us to move quickly to identify other drugs or environmental compounds that have similar effects—so that pregnant women can avoid being exposed to these compounds."

Zylka and his colleagues stumbled upon the discovery quite by accident while studying topotecan, a topoisomerase-inhibiting drug that is used in chemotherapy.

Investigating the drug's effects in mouse and human-derived nerve cells, they noticed that the drug tended to interfere with the proper functioning of genes that were exceptionally long—composed of many DNA base pairs.

The group then made the serendipitous connection that many autism-linked genes are extremely long.

"That's when we had the 'Eureka moment,'" said Zylka. "We realized that a lot of the genes that were suppressed were incredibly long autism genes."

Of the more than 300 genes that are linked to autism, nearly 50 were suppressed by topotecan. Suppressing that many genes across the board—even to a small extent—means a person who is exposed to a topoisomerase inhibitor during brain development could experience neurological effects equivalent to those seen in a person who gets ASD because of a single faulty gene.

The study's findings could also help lead to a unified theory of how autism-linked genes work. About 20 percent of such genes are connected to synapses—the connections between brain cells.

Another 20 percent are related to gene transcription—the process of translating genetic information into biological functions.

Zylka said this study bridges those two groups, because it shows that having problems transcribing long synapse genes could impair a person's ability to construct synapses.

"Our discovery has the potential to unite these two classes of genes—synaptic genes and transcriptional regulators," said Zylka.

"It could ultimately explain the biological mechanisms behind a large number of autism cases."

More information: Nature paper dx.doi.org/10.1038/nature12504

Anxiety Control: A Portion of hippocampus found to play a major role

Columbia University Medical Center (CUMC) researchers have found the first evidence that selective activation of the dentate gyrus, a portion of the hippocampus, can reduce anxiety without affecting learning. 

The findings suggest that therapies that target this brain region could be used to treat certain anxiety disorders, such as panic disorder and post-traumatic stress syndrome (PTSD), with minimal cognitive side effects.

The study, conducted in mice, was published today in the online edition of the journal Neuron. The dentate gyrus is known to play a key role in learning.

Rene Hen

Some evidence suggests that the structure also contributes to anxiety. "But until now no one has been able to figure out how the hippocampus could be involved in both processes," said senior author Rene Hen, PhD, professor of neuroscience and pharmacology (in psychiatry) at CUMC.

"It turns out that different parts of the dentate gyrus have somewhat different functions, with the dorsal portion largely dedicated to learning and the ventral portion dedicated to anxiety," said lead author Mazen A. Kheirbek, PhD, a postdoctoral fellow in neuroscience at CUMC.

To examine the role of the dentate gyrus in learning and anxiety, the investigators used a state-of-the-art technique called optogenetics, in which light-sensitive proteins, or opsins, are genetically inserted into neurons in the brains of mice.

Neurons with these genes can then be selectively activated or silenced through the application of light (via a fiber-optic strand), allowing researchers to study the function of the cells in real time.

Previously, the only way to study the dentate gyrus was to silence portions of it using such long-term manipulations as drugs or lesions, techniques that yielded conflicting results.

In the current study, opsins were inserted into dentate gyrus granule cells (the principal cells of the dentate gyrus).

The researchers then activated or silenced the ventral or dorsal portions of the dentate gyrus for three minutes at a time, while the mice were subjected to two well-validated anxiety tests (the elevated plus maze and the open field test).

"Our main findings were that elevating cell activity in the dorsal dentate gyrus increased the animals' desire to explore their environment. But this also disrupted their ability to learn. Elevating activity in the ventral dentate gyrus lowered their anxiety, but had no effect on learning," said Dr. Kheirbek.

The effects were completely reversible—that is, when the stimulation was turned off, the animals returned to their previous anxiety levels.

"The therapeutic implication is that it may be possible to relieve anxiety in people with anxiety disorders by targeting the ventral dentate gyrus, perhaps with medications or deep-brain stimulation, without affecting learning," said Dr. Hen.

Dr Hen is also a director of the Division of Integrative Neuroscience, The New York State Psychiatric Institute, and a member of The Kavli Institute for Brain Science.

"Given the immediate behavioral impact of such manipulations, these strategies are likely to work faster than current treatments, such as serotonin reuptake inhibitors."

According to Dr. Hen, such an intervention would probably work best in people with panic disorder or PTSD.

"There is evidence that people with these anxiety disorders tend to have a problem with pattern separation—the ability to distinguish between similar experiences," he said.

"In other words, they overgeneralize, perceiving minor threats to be the same as major ones, leading to a heightened state of anxiety. Such patients could conceivably benefit from therapies that fine-tune hippocampal activity."

Dr. Hen and his team are currently exploring strategies aimed at modulating the activity of the ventral dentate gyrus by stimulating neurogenesis in the ventral dentate gyrus.

"Indeed the dentate gyrus is one of the few areas in the adult brain where neurons are continuously produced, a phenomenon termed adult hippocampal neurogenesis," added Dr. Hen.

More information: The title of the paper is "Differential control of learning and anxiety along the dorso-ventral axis of the dentate gyrus."  

Diabetes: New Compund Prevents Retina Damage

A compound that prevents damage to the retina caused by diabetic retinopathy has been developed by scientists. University of Michigan Kellogg Eye Center scientists have developed a compound that targets two mechanisms: inflammation and the weakening of the blood barrier that protects the retina that is the root cause of the disease. Diabetic retinopathy is the most common diabetic eye disease. It is caused by changes in the blood vessels in the retina, and can cause blindness in adults. In some people with diabetic retinopathy, blood vessels may swell and leak fluid. In others, abnormal new blood vessels grow on the surface of the retina. The retina is the light-sensitive tissue at the back of the eye. A healthy retina is necessary for good vision.

Crystal structure of Vammin, a VEGF-F from a snake venom

Until now, scientists believed that retina damage was caused by the activity of vascular endothelial growth factor (VEGF), a protein that weakens the protective blood-retinal barrier. Drugs, created to treat diabetic retinopathy, have been desigend to block the protein but now, researchers have found that inflammation could also contribute to the disease. "In diabetic retinopathy and a host of other retinal diseases, increases in VEGF and inflammatory factors - some of the same factors that contribute to the response to an infection - cause blood vessels in the eye to leak which, in turn, results in a buildup of fluid in the neural tissue of the retina," said David A Antonetti, a Kellogg Eye Center researcher, in a statement. "This insidious form of modified inflammation can eventually lead to blindness."

Scientists created the new compound while studying kinase C (aPKC), a protein that was common to both mechanisms as an important target in regulating the disease process. They claim that the new compound blocks the kinase C (aPKC) protein, which in turn blocks the VEGF protein and reduces inflammation. "This is a great leap forward. We've identified an important target in regulating blood vessel leakage in the eye and we have a therapy that works in animal models. Our research is in the early stages of development. We still have a long way to go to demonstrate effectiveness of this compound in humans to create a new therapy but the results are very promising," Antonetti said.

Parenting: When does Discipline Begin?

To read more of this article click on the link to the Newsletter here

Spare the rod and develop the child

Children in a school that uses corporal punishment performed significantly worse in tasks involving “executive functioning” – psychological processes such as planning, abstract thinking, and delaying gratification – than those in a school relying on milder disciplinary measures such as time-outs, according to a new study involving two private schools in a West African country.

The findings, published by the journal Social Development, suggest that a harshly punitive environment may have long-term detrimental effects on children’s verbal intelligence and their executive-functioning ability. As a result, children exposed to a harshly punitive environment may be at risk for behavioral problems related to deficits in executive-functioning, the study indicates.

The study – by Prof. Victoria Talwar of McGill University, Prof. Stephanie M. Carlson of the University of Minnesota, and Prof. Kang Lee of the University of Toronto, involved 63 children in kindergarten or first grade at two West African private schools. Their families lived in the same urban neighborhood. The parents were largely civil servants, professionals and merchants.

In one school, discipline in the form of beating with a stick, slapping of the head, and pinching was administered publicly and routinely for offenses ranging from forgetting a pencil to being disruptive in class. In the other school, children were disciplined for similar offenses with the use of time-outs and verbal reprimands.

While overall performance on the executive-functioning tasks was similar in the younger children from both schools, the Grade 1 children in the non-punitive school scored significantly higher than those in the punitive school. These results are consistent with research findings that punitive discipline may make children immediately compliant – but may reduce the likelihood that they will internalize rules and standards. That, in turn, may result in lower self-control as children get older.

“This study demonstrates that corporal punishment does not teach children how to behave or improve their learning,” Prof. Talwar said. “In the short term, it may not have any negative effects; but if relied upon over time it does not support children’s problem-solving skills, or their abilities to inhibit inappropriate behaviour or to learn.”

Despite the age-old debate over the effects of corporal punishment, few studies have examined the effects on executive-functioning ability. This new study uses a quasi-experimental design to derive data from a naturally occurring situation in which children were exposed to two different disciplinary environments. The parents of children in both schools endorsed physical punishment equally, suggesting that the school environment can account for the differences found.

There are many further questions that remain unanswered. “We are now examining whether being in a punitive environment day in and day out will have other negative impacts on children such as lying or other covert antisocial behaviors. Also, we are pursuing the long term consequences of experiencing corporal punishment. For example, what would children’s cognitive and social development be 5 or 10 years down the road?,” said Prof. Kang Lee.

Addendum: My Latin teacher was a very aggressive man and believed in corporal punishment for the slightest thing. He also insisted on complete silence whilst translating Latin text into English. It was during one such exercise that the teacher slumped over his desk and died of a major heartattack. But, because we were in fear of this man, even in death, it was fully 10 minutes before anyone plucked up courage to seek assistance. At the age of 12 years I learned a very salutory lesson on how to behave, or how not to behave, when in a position of authority.

How the Brain Detects Silence: Research Discovery

A team of University of Oregon researchers have isolated an independent processing channel of synapses inside the brain's auditory cortex that deals specifically with shutting off sound processing at appropriate times. Such regulation is vital for hearing and for understanding speech.

The discovery, detailed in the Feb. 11 issue of the journal Neuron, goes against a long-held assumption that the signaling of a sound's appearance and its subsequent disappearance are both handled by the same pathway.

The new finding, which supports an emerging theory that a separate set of synapses is responsible, could lead to new, distinctly targeted therapies such as improved hearing devices, said Michael Wehr, a professor of psychology and member of the UO Institute of Neuroscience.

"It looks like there is a whole separate channel that goes all the way from the ear up to the brain that is specialized to process sound offsets," Wehr said. The two channels finally come together in a brain region called the auditory cortex, situated in the temporal lobe.

To do the research, Wehr and two UO undergraduate students - lead author Ben Scholl, now a graduate student at the Oregon Health and Science University in Portland, and Xiang Gao - monitored the activity of neurons and their connecting synapses as rats were exposed to millisecond bursts of tones, looking at the responses to both the start and end of a sound. They tested varying lengths and frequencies of sounds in a series of experiments.

It became clear, the researchers found, that one set of synapses responded "very strongly at the onset of sounds," but a different set of synapses responded to the sudden disappearance of sounds. There was no overlap of the two responding sets, the researchers noted. The end of one sound did not affect the response to a new sound, thus reinforcing the idea of separate processing channels.

The UO team also noted that responses to the end of a sound involved different frequency tuning, duration and amplitude than those involved in processing the start of a sound, findings that agree with a trend cited in at least three other studies in the last decade.

"Being able to perceive when sound stops is very important for speech processing," Wehr said. "One of the really hard problems in speech is finding the boundaries between the different parts of words. It is really not well understood how the brain does that."

As an example, he noted the difficulty some people have when they are at a noisy cocktail party and are trying to follow one conversation amid competing background noises. "We think that we've discovered brain mechanisms that are important in finding the necessary boundaries between words that help to allow for successful speech recognition and hearing," he said.