genetics

Posted on Autism

Team identify genetic targets for autism spectrum disorder

Chi-Ren Shyu and his team created a new computational method that has connected several target genes to autism. MU College of Engineering

Autism is a spectrum of closely related symptoms involving behavioral, social and cognitive deficits. Early detection of autism in children is key to producing the best outcomes; however, searching for the genetic causes of autism is complicated by various symptoms found within the spectrum. Now, a multi-disciplinary team of researchers at the University of Missouri created a new computational method that has connected several target genes to autism. Recent discoveries could lead to screening tools for young children and could help doctors determine correct interventions when diagnosing autism.

Unlocking the genetic causes of autism requires data-intensive computations. In 2014, the National Science Foundation (NSF) awarded $1 million in two grants to MU to install a supercomputer enabling data-intensive research and education in the fields of bioinformatics and data-driven engineering applications.

In this study we started with more than 2,591 families who had only one child with autism and neither the parents nor the siblings had been diagnosed with autism,” said Chi-Ren Shyu, director of the Informatics Institute and the Paul K. and Dianne Shumaker Endowed Professor in the Department of Electrical Engineering and Computer Science in the MU College of Engineering. “This created a genetically diverse group composed of an estimated 10 million genetic variants. We narrowed it down to the 30,000 most promising variants, then used preset algorithms and the big data capabilities of our high-performance computing equipment at MU to ‘mine’ those genetic variables.”

The genetic samples were obtained from the Simons Foundation Autism Research Initiative. Samples from children with diagnosed cases of autism, and their unaffected parents and siblings were collected leading to more than 11,500 individuals. Using advanced computational techniques, Shyu and his team were able to identify 286 genes that were then collected into 12 subgroups that exhibited commonly seen characteristics of children on the spectrum. Of these genes, 193 potentially new genes not found in previous autism studies were discovered.

“Autism is heterogeneous, meaning that the genetic causes are varied and complex,” said Judith Miles, professor emerita of child health-genetics in the MU Thompson Center for Autism and Neurodevelopmental Disorders. “This complexity makes it tough for geneticists to get at the root of what triggers the development of autism in more conventional ways. The methods developed by Dr. Shyu and the results our team identified are giving geneticists a wealth of targets we’d not considered before–by narrowing down the genetic markers, we may be able to develop clinical programs and methods that can help diagnose and treat the disease. These results are a quantum leap forward in the study of the genetic causes of autism.”

Posted on Autism

Heritability of autism spectrum studied in twins

Heritability of autism spectrum disorder studied in UK twins

Heritability of autism spectrum studied in UK twins

Substantial genetic and moderate environmental influences were associated with risk of autism spectrum disorder (ASD) and broader autism traits in a study of twins in the United Kingdom, according to an article published online by JAMA Psychiatry.

Much of the evidence to date highlights the importance of genetic influences on the risk of autism and related traits. But most of these findings are drawn from samples of individuals which may miss people with more subtle manifestations and may not represent the broader population, according to the study background.

Beata Tick, M.Sc., of King’s College London, and coauthors examined genetic and environmental factors for risk of ASD and related traits from a population-based sample of all the twin pairs born in England and Wales from 1994 through 1996. The twins were assessed using several screening instruments: the Childhood Autism Spectrum Test (6,423 pairs), the Development and Well-being Assessment (359 pairs), the Autism Diagnostic Observation Schedule (203 pairs), the Autism Diagnostic Interview-Revised (205 pairs), and a best-estimate diagnosis (207 pairs). The study included twins with high subclinical levels of autism traits and low-risk twins, as well as those diagnosed with ASD.

The authors found that on all ASD measures, associations among monozygotic (identical) twins were higher than those for dizygotic (fraternal) twins, resulting in heritability estimates of 56 percent to 95 percent. The analyses highlight the importance of genetic factors in the cause of ASD along with moderate nonshared (different experiences among children in the same families) environmental influences, according to the study.

“We conclude that liability to ASD and a more broadly defined high-level autism trait phenotype in U.K. twins 8 years or older derives from substantial genetic and moderate nonshared environmental influences,” the study concludes.

Posted on Autism

Studies provide insights into inherited causes of autism

DNA and weight loss

DNA and weight loss

The most consistent finding of autism research lies in the revelation that the disorders are incredibly complex. Two new studies in the January 23 issue of the Cell Press journal Neuronthat add to the growing appreciation of this complexity focus on identifying inherited genetic mutations linked with autism spectrum disorders. The mutations–which are distinct from the spontaneous mutations that have been the focus of previous studies–may provide valuable insights into the causes of autism.

“It’s long been known that autism is a heritable condition and that some cases appear to run in families. Our studies are among the first to begin to address this heritable component,” says Dr. Christopher Walsh of Boston Children’s Hospital, who is the senior author of one of the papers.

Both groups sequenced the portion of the genome that codes for proteins, also known as the exome, in individuals with autism, their relatives, and controls. In one study, investigators focused on rare mutations that completely abolish the function of particular genes–and therefore the expression of a protein. “We utilized new genome-sequencing technologies to discover a component of autism that can be traced to recessive inheritance–

that is, when a child inherits two broken copies of the same gene, one from each parent who is a carrier,” explains senior author Dr. Mark Daly of Massachusetts General Hospital and the Broad Institute. “There were twice as many autism cases as control individuals that were apparently missing an important protein somewhere in the genome,” he adds. Their findings suggest that 5% of autism risk is linked to inherited mutations that completely disrupt the functions of genes.

Like Dr. Daly and his colleagues, Dr. Walsh and his team identified and characterized cases of autism due to the inheritance of two gene mutations, one from each parent. In this work, though, the researchers found that the partial loss of a gene’s function–not only complete absence of function–is linked to autism spectrum disorders. They identified several genes–such as those involved in neurometabolic pathways–that were not previously associated with autism risk, and they revealed a striking variability of autism severity despite inheritance of similar genetic mutations.

“These two studies firmly establish that recessive mutations contribute importantly to autism, not just in specialized populations but in the population at large,” says first author Dr. Timothy Yu, of Boston Children’s Hospital.

With follow-up work, identifying the various genes that are silent or partially disabled in autism cases can provide key clues to understanding the underlying biology of autism spectrum disorders and potentially help generate new therapies.

Posted on Autism

Saliva-based RNA panel distinguishes children on autism spectrum from non-autistic peers

DNA and weight loss

DNA and weight loss

Results from multi-institutional research collaboration published in Frontiers in Genetics journal

Newly published research shows that a saliva-based biomarker panel and associated algorithm could improve the ability to accurately identify children with autism spectrum disorder (ASD) in its earliest stages, announced Quadrant Biosciences Inc. In a study of more than 450 children ages 18 months to 6 years, researchers demonstrated that a panel of 32 small RNAs could differentiate children with autism from children exhibiting typical development or non-ASD developmental delay with 85% accuracy. This test accuracy was achieved both during the model development and during validation of the test in a separate set of children.

The publication, entitled “Validation of a salivary RNA test for childhood autism spectrum disorder,” was published online in Frontiers in Genetics by researchers Steven Hicks, M.D., Ph.D., of the Pennsylvania State College of Medicine and Frank Middleton, Ph.D., of SUNY Upstate Medical University in collaboration with scientists from Quadrant Biosciences.

Following a pilot study demonstrating that many of these RNA elements could be detected in the saliva of children with ASD, the researchers determined that saliva-based testing could provide the means to broadly interrogate genomic, physiologic, microbiome, and environmental factors implicated in ASD in a single, non-invasive, high-throughput analysis.

“Growing evidence suggests that autism arises from interactions between a child’s genes and the environment. This study measured factors that may control interactions between genes and the environment, especially the microbiome,” said Dr. Hicks. “Though children with autism have diverse genetic backgrounds, we found that a set of 32 RNA factors in their saliva could accurately distinguish them from peers without autism. Given this array of ASD risk factors, we believe a ‘poly-omics’ RNA-based approach that integrates genetic, epigenetic, and metagenomics methods would be well suited to the development of an objective biomarker-based test.”

The Study

The multi-center study included 456 children recruited during the past three years. The authors compared saliva samples from 238 children with ASD to 218 children without ASD (including 84 children with developmental delay and 134 with typical development). Levels of human and bacterial RNAs were measured in the saliva samples using comprehensive next-generation sequencing. The top RNAs were identified using robust machine-learning algorithms from the first 372 children and then validated in the remaining 84 samples that were not used in the machine learning. Notably, this validation set also included samples collected from children at the University of California, Irvine, to verify that the RNA algorithm performed accurately in samples from different geographic regions.

Need for Earlier Autism Diagnosis

Screening for autism typically relies on a parent-based questionnaire called the Modified Checklist for Autism in Toddlers Revised (MCHAT-R). Children with a positive MCHAT-R score are generally referred for diagnostic evaluation. However, due to the high number of false-positive results on the MCHAT-R, wait times for autism evaluation often exceed one year. While diagnosis is possible in children as young as 24 months, the average age of ASD diagnosis in the United States today is greater than 4 years. Early diagnosis is important because intensive behavioral therapy has been shown to improve the symptoms of autism, and children benefit more from such intervention the earlier it is started.

Daniel Coury, M.D., Professor of Clinical Pediatrics and Psychiatry at The Ohio State University College of Medicine and a member of the Section of Developmental & Behavioral Pediatrics at Nationwide Children’s Hospital, sees the benefit of this RNA biomarker-based test in a clinical setting. “Often autism-specific interventions are delayed while awaiting a diagnosis. It frequently takes months to obtain an autism evaluation due to the large number of referrals, many of whom will not receive a diagnosis of autism,” he explained. “A test which can separate children who have screened M-CHAT-positive into high likelihood of autism or low likelihood of autism could help streamline waitlists and permit earlier diagnosis and enrollment in autism treatment.”

Dr. Middleton from SUNY Upstate Medical University agreed. “The ability to accurately discriminate between children with autism and their peers with non-ASD developmental delay is of paramount importance in the field. While the algorithm is not designed as a screening tool, it can provide valuable information in children with a positive MCHAT-R screen, over 80% of whom will not have ASD. In this way, it can be used to prioritize specialist referral or to provide an objective aid to an autism diagnosis.”

Leave a comment Posted on Genetics, Pain Management

‘Gene for chronic pain identified’ Do you have it?

 

'Gene for chronic pain identified' Do you have it?

‘Gene for chronic pain identified’ Do you have it?

A “gene responsible for chronic pain has been identified”, reports the BBC. It said that this could lead to drugs for treating long-lasting back pain.

This story is based on research carried out in mice. Researchers found that deleting a gene called HCN2 from the pain-sensing nerves in mice stopped them from having the chronic hypersensitivity to pain caused by nerve damage. However, their ability to sense short-term (acute) pain, for example from heat or pressure, was not affected.

This research has highlighted a potential role for HCN2 in one type of chronic pain, called neuropathic pain, produced by damage to nerves themselves. However, it’s important to note that this study was in mice and looked at the effect of removing the HCN2 gene rather than using chemicals to block its function. Therefore, it cannot tell us whether this strategy will be successful in treating human forms of chronic pain. This knowledge may help scientists to develop drugs to target this kind of pain in the future, but much more research will be needed to determine whether this will be the case.

Where did the story come from?

The study was carried out by researchers from the University of Cambridge and the University of Cadiz. Funding was provided by the UK Biotechnology and Biological Sciences Research Council, the European Union, Organon Inc. and a Cambridge Gates Foundation studentship. The study was published in the peer-reviewed journal Science .

The BBC provides a good description of this study, clearly stating that it was carried out in mice.

What kind of research was this?

This was animal research looking at whether an ion channel protein called HCN2 might play a role in the sensing of pain. Ion channels are protein “pores” in the cell membrane that control the flow of electrically charged atoms into or out of the cell. In nerves this flow of ions is essential for allowing them to transmit signals.

The researchers say that the frequency with which the nerves involved in sensing pain send signals to the brain (called their rate of firing) affects how intense a pain is felt to be. This rate could be influenced by ion channels, including the HCN ion channel family.

The HCN1 and HCN2 members of the HCN ion channel family are present at high levels in nerves involved in sensations such as pain and touch. Previous experiments have suggested that HCN1 does not play a large role in sensing pain, so the researchers wanted to investigate whether HCN2 might be important in sensing pain.

Animal and laboratory research is often the best way to investigate the role of individual proteins in biological processes, as researchers can remove individual genes and see what effect this has. This type of research could not be carried out in humans.

What did the research involve?

The researchers looked at the role of the HCN2 ion channel in mice by genetically engineering them to lack the gene that produces this protein in their pain-sensing nerves. They then looked at what effect this had on the ability of the pain-sensing nerves to send signals, and on how the mice sensed pain.

The researchers initially tried genetically engineering mice to lack the HCN2 gene throughout their bodies, but this led to the mice having serious movement problems and dying before they reached six weeks of age. They then decided to remove the HCN2 gene in the pain-sensing nerves only, so that these widespread adverse effects would not occur.

The researchers tested the mice’s responses to pain using standard tests. For example, they tested how quickly they withdrew their feet in response to touching a hot or cold surface or to the application of pressure (called painful ‘stimuli’). They also tested these responses after injecting the mice with chemicals that cause inflammation and make normal mice hypersensitive to these painful stimuli.

Finally, they looked at the effect of exposing these mice to long-lasting pain caused by damage to their nerves. This type of pain is called neuropathic pain. They used a standard way of replicating this type of pain, by placing pressure on the mice’s sciatic nerve. This usually makes mice more sensitive to painful stimuli.

What were the basic results?

The researchers found that mice that were genetically engineered to lack the gene for HCN2 in their pain-sensing nerves had disruptions to the normal electrical processes that led to firing of these nerves.

The HCN2-lacking mice did not show any change to their pain threshold on short-term exposure to heat or pressure. However, when injected with chemicals that cause inflammation and make normal mice hypersensitive to heat- and pressure-induced pain, the HCN2-lacking mice did not show hypersensitivity to heat-induced pain.

The HCN2-lacking mice also displayed the usual hypersensitivity to pressure-induced pain after the injection also seen in normal mice.

If the genetically engineered mice received a nerve injury, they did not show the increase in sensitivity to heat, cold or pressure that normal mice with this injury showed.

How did the researchers interpret the results?

The researchers concluded that the presence of HCN2 is necessary for the sensing of pain caused by nerve injury, called neuropathic pain. They say that HCN2 also appears to have a role in sensing inflammation-associated pain. They say that chemicals that can selectively block HCN2 may be useful as pain medication to block the effects of neuropathic and inflammatory pain.

Conclusion

This research has highlighted a potential role for HCN2 in one type of chronic pain, called neuropathic pain. This knowledge may help scientists to develop drugs to target this kind of pain.

Neuropathic pain is pain that arises from damage to or disorders of the nervous system. For example, the pain associated with spinal cord injury, shingles or from tumours pressing on nerves is neuropathic. This type of pain is reportedly difficult to treat with drugs.

Scientists will now be interested in finding chemicals that can block the action of HCN2, and testing the effect that such chemicals have on pain-sensing in animals. As removing HCN2 completely in mice had serious adverse effects, scientists would have to ensure that they could block the protein in such a way that reduced pain but did not have these adverse effects. Any chemicals that show promise and appear to be safe would then need to be tested in humans.

It is important to point out that this process of drug development takes a long time and is not always successful, with some chemicals that seem to have an effect in animals not working in humans.