Over 2,000 Newly Discovered Biological Markers Could Help Explain How Autism Develops

Scientists have discovered a swathe of biochemical regions that look to be deeply involved with the risk factors behind autism spectrum disorder (ASD).

Researchers have identified more than 2,000 of these regulatory regions – markers on top of our DNA that affect how our genetic machinery operates on a functional level – which are involved in learning and strongly associated with ASD.


While we know many cases of ASD are tied to differences in our genetic coding, the findings suggest epigenetic factors affecting non-genetic sequences of DNA could account for the development of the condition in many individuals.

“Our proof-of-concept study demonstrates the feasibility of going after genetic components of autism that are outside of genes and may eventually lead to improvements in the diagnosis and treatment of autism,” says neuroscientist Lucia Peixoto from Washington State University.

Epigenetics is a burgeoning field of science looking at how we inherit traits and changes from environmental or external sources, not just the DNA code that otherwise instructs how our bodies should grow and function.

These kinds of epigenetic mechanisms – which modify how our DNA is expressed at a molecular level – mean experiences in childhood can change our genetic code ever after, with things like babies being biochemically transformed by the amount of cuddles they receive.

Even more amazingly, these changes can persist beyond one lifespan –meaning things your parents did before you were born could have an impact on your own health.

In some cases, epigenetic ‘memories’ can be passed down as far along as 14 generations, so there’s clearly a lot more than just DNA affecting our biological destiny.

In their own study, Peixoto and her team experimented with mice that were placed in a box and given a small shock, which conditioned them to associate the box with an unpleasant experience.

When DNA from the animals’ hippocampus (which processes memory) was later analysed, the researchers found that chromatin – macromolecules that help ‘package’ DNA inside cells – had become more accessible.

With a new bioinformatics tool they developed called DEScan (Differential Enrichment Scan), the team identified 2,365 regions which were epigenetically regulated following the mouse’s conditioning. Interestingly, genes near many of these regions are known risk genes for ASD.

One of the more well-known autism risk genes is called Shank3, which is missing in a small percentage of autism patients. In a previous study, researchers found that by switching this gene on in mice that were engineered without the active Shank3 gene, autism symptoms could be reversed.

In the present research, the team analysed a clinical study involving more than 700 children (some 550 of which had autism), and found that one of the regulatory regions they identified in mice – called rs6010065 – is indeed associated with ASD in humans.

There’s obviously still a huge amount of research to be done here before we know more about how these epigenetic controls might be impacting the development of autism in children, but the researchers are convinced we could have a bright new lead to follow up on.

“One of the major challenges in the genetics of disease is understanding the role of the vast portions of the genome that regulate gene expression,” says one of the researchers, neuroscientist Ted Abel from the University of Iowa.

“[A]ctivity-dependent changes in chromatin accessibility may hold the key to understanding the function of this ‘dark matter’ of the genome and may provide novel insights into the nature of autism and other neurodevelopmental disorders.”

Folic Acid, Multivitamins During Pregnancy May Cut ASD Risk

Israeli researchers caution that ‘the effect of confounding was notable.

Folic acid and multivitamins both before and during pregnancy seemed to reduce the risk of autism spectrum disorder (ASD) in children, a large Israeli study found.

Compared with women with no exposure to folic acid and/or multivitamin supplementation, women who took folic acid and/or these vitamin supplements during pregnancy had a significantly reduced risk of offspring with ASD (adjusted RR 0.27, 95% CI 0.22-0.33, P<0.001), with similar results seen among women who took these supplements before pregnancy (adjusted RR 0.39, 95% CI 0.30-0.50, P<0.001), reported Stephen Z. Levine, PhD, of University of Haifa in Israel, and colleagues.

Similar results were found when the effects of folic acid and multivitamin supplements were examined individually, the authors wrote in JAMA Psychiatry.

But the authors outlined a number of limitations to their findings, namely that “the effect of confounding was notable,” and expressed reservations about residual confounding. They also noted the small size of their study, and pointed out potential misclassification of exposure, or unrecorded use of supplements, such as a mother using over-the-counter supplements. Finally, they pointed out that there was no information about the mothers’ whole-blood folate levels and that the registry could not distinguish between multivitamins with and without folic acid.

While they noted that vitamin deficiency has inconsistent links with cognitive functioning, previous epidemiological studies found conflicting results when examining multivitamins or folic acid in pregnancy on the risk of ASD in children.

This case-cohort study examined data from certain healthcare registers in Israel on children born from January 2003 to December 2007. A diagnosis of ASD was performed by a physician after evaluation by a team of experts.

Overall, there were 572 children out of 43,500 in the study (1.3%) with a diagnosis of ASD. The study was comprised of 22,090 girls and 23,210 boys, with a mean age of 10 years at the end of follow-up.

In addition to the effects of folic acid and/or multivitamin supplements, Levine’s group looked at the individual effects of maternal exposure to folic acid and multivitamin supplements compared to unexposed mothers and found similar results:

  • Folic acid during pregnancy: adjusted RR 0.32 (95% CI 0.26-0.41, P<0.001)
  • Folic acid before pregnancy: adjusted RR 0.56 (95% CI 0.42-0.74, P=0.001)
  • Multi-vitamin supplements during pregnancy: adjusted RR 0.35 (95% CI 0.28-0.44, P<0.001)
  • Multi-vitamin supplements before pregnancy: adjusted RR 0.36 (95% CI 0.24-0.52, P<0.001)

Sensitivity analyses that looked at different time periods of exposure or potential additional confounders generally did not lessen these associations, the authors said. They did note that for offspring whose parents had a psychiatric condition, folic acid supplementation did not significantly reduce the risk of ASD.

“This finding may reflect noncompliance, higher rates of vitamin deficiency, or poor diet among persons with psychiatric conditions,” Levine’s group wrote.

Questions and answers about autism spectrum disorders (ASD)

Q: What are autism spectrum disorders?

A: Autism spectrum disorders (ASD) are a group of complex brain development disorders. This umbrella term covers conditions such as autism and Asperger syndrome. These disorders are characterized by difficulties in social interaction and communication and a restricted and repetitive repertoire of interests and activities.

Q: How common are autism spectrum disorders?

A: Reviews estimate that 1 child in 160 has an autism spectrum disorder. This estimate represents an average figure, and reported prevalence varies substantially across studies. Some recent studies have, however, reported rates that are substantially higher.

Q: Do people with an autism spectrum disorder always suffer from intellectual disability?

A: The level of intellectual functioning is extremely variable in persons with an autism spectrum disorder, ranging from profound impairment to superior non-verbal cognitive skills. It is estimated that around 50% of persons with ASD also suffer from an intellectual disability.

Q: How early can an autism spectrum disorder be recognized in children?

A: Identifying an autism spectrum disorder is difficult before the age of about 12 months but diagnosis is generally possible by the age of 2 years. Characteristic features of the onset include delay in the development or temporary regression in language and social skills and repetitive stereotyped patterns of behaviour.

Q: What can parents do to help their child with an autism spectrum disorder?

A: Parents have an essential role in providing support to a child with an autism spectrum disorder. They can help to ensure access to health services and education, and offer nurturing and stimulating environments as their child grows up. Recently, it has been shown that parents can also help deliver psychosocial and behavioural treatments to their own children.

Q: What causes autism spectrum disorders?

A: Scientific evidence suggests that various factors, both genetic and environmental, contribute to the onset of autism spectrum disorders by influencing early brain development.

Q: Are childhood vaccines responsible for autism spectrum disorders?

A: Available epidemiological data show that there is no evidence of a link between measles-mumps-rubella (MMR) vaccine and autism spectrum disorders. Previous studies suggesting a causal link were found to be seriously flawed.

There is also no evidence to suggest that any other childhood vaccine may increase the risk of autism spectrum disorders. In addition, evidence reviews commissioned by WHO concluded that there was no association between the use of vaccine preservatives such as thiomersal and autism spectrum disorders.


Biologically-Inspired Biomarkers for Mental Disorders

In a study published in Nature in February 2017, investigators from the Infant Brain Imaging Study (IBIS) described promising findings in screening children for autism spectrum disorders (ASDs). Using brain magnetic resonance imaging (MRI) to assess cortical development and brain volume, investigators were able to predict in infants as young as 6-12 months of age at risk for ASD—that is, with an ASD-affected sibling—which children would develop ASD by 24 months of age. While this study requires further validation in a larger cohort—15 of 106 high-risk subjects ultimately developed ASD—it speaks to the vast unmet medical need of biomarkers for neurodevelopmental and psychiatric disorders. This need is especially striking given evidence that early intervention may be critical for correcting an array of mental illnesses. For instance, with particular regard to ASDs, a long-term follow-up of the parent-mediated social communication therapy for young children with autism (PACT) controlled trial, published in The Lancet in November 2016 showed that autistic children receiving therapy between 2-4 years of age showed clinical improvement up to six years after the therapy had ended.

The global burden of mental illness is staggering, with recent data published in The Lancet in February 2016 suggesting that psychiatric disorders are the leading cause of years lost to disability. These data are simply estimates, though, largely confounded by how mental illnesses are classified and diagnosed. At present, the approved diagnoses of all psychiatric disorders—from schizophrenia and major depressive disorder (MDD) to obsessive-compulsive disorder and ASDs—are arrived at through reporting of mental and behavioral symptoms by patients or caregivers to mental health professionals. Many disorders catalogued in the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases describe a spectrum of symptoms. For example, for a diagnosis of MDD, a patient must display at least five of nine symptoms in the DSM. It is therefore feasible that two patients, both with MDD, share only one common symptom. Cultural and social norms and stigmas can further complicate patient and caregiver reporting of symptoms or how these symptoms are interpreted by mental health professionals. Co-morbidities with other psychiatric disorders are also not uncommon and contribute to a dizzying heterogeneity in possible diagnoses. Clinical biomarkers could help transcend these limitations.

Unlike many other diseases, there are no approved clinical tests for psychiatric disorders beyond mental and behavioral evaluation. There are no presymptomatic risk prediction tests, like the PLAC test to measure lipoprotein phospholipase A2 for risk of cardiovascular events. There are no diagnostic or monitoring tests, like blood hemoglobin A1c for diabetes management. There are no prognostic tests, like the gene array MammaPrint in breast cancer for risk of tumor recurrence. Despite considerable maturation of fundamental neuroscience in the last decades, owing largely to technological advances allowing sophisticated interrogation of the brains of model organisms and humans, our understanding of the biological underpinnings of psychiatric disease is still in its infancy.

There is considerable optimism, though, that we are nearing a turning point in psychiatric disease research, which could pave the way not only for much-needed new therapies, but also for the critical risk assessment, diagnostic, and prognostic clinical tests required to identify and monitor disease. Initially proposed in 2008, the National Institutes of Mental Health at the US NIH proposed a new way of categorizing mental illness—bridging genetics, neuroscience (looking at molecules, cells, neural circuits, and physiology of the brain), and behavioral science. These Research Domain Criteria (RDoC) aspire to classify illness based on observable behavioral and neurobiological measures.

In keeping with the RDoC ethos, a number of independent researchers and large consortia aim to address mental disorders from a quantifiable biological perspective. Among many others, several consortia include: the Psychiatric Genomics Consortium (PGC), looking for genetic relationships to disease; brain banking repositories from the Stanley Medical Research Institute and Pritzker Neuropsychiatric Disorders Research Consortium, looking for molecular, cellular, and anatomical markers of illness; repositories of resting state and functional MRI or positron emission tomography (PET) imaging data, including the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) group, Functional Imaging Biomedical Research Network, and the Autism Brain Imaging Data Exchange. Further strategies include looking for blood-based biomarkers of disease using proteomics and metabolomics, along with profiling the gut microbiota of patients, as the latter has recently been associated with various mental disorders. Along with approved diagnostic criteria, many clinical trials are now investigating some or all of genetic, imaging, electrophysiological, and blood-based profiling as secondary readouts of therapeutic interventions. Perhaps the largest problem in translating ever-expanding datasets into clinically-relevant outputs will be in integrating the gathered information. However, consortia such as PGC and ENIGMA also aim to bring together data scientists to share algorithms for mining data and turning it into a framework for so-called computational psychiatry.

Recent genomics and transcriptomics studies have already begun to bear fruit, discovering genetic loci and transcriptional profiles associated with increased risk for schizophrenia, ASDs, MDD, and other mental illnesses. A number of these findings suggest many psychiatric disorders are genetically complex, without a single causative variation. Defining polygenic signatures of disease remains an obstacle to overcome. Another obstacle regards brain imaging data. Because of the infrastructure required to perform these studies, they are often too underpowered to confidently assign hallmarks of disease. It is hoped that a multi-center consortium approach will allow researchers not only to image the healthy brain to arrive at a “gold standard”—another factor sorely lacking when compared to, say, a normal range of hemoglobin A1c levels in healthy and diabetic patients—but will also identify clinically-relevant image-based biomarkers for psychiatric illness. Perhaps the closest to clinical utility for psychiatric biomarkers will be in patient stratification and pharmacogenomics-based drug responses. For instance, recent studies have identified biomarkers for prediction of treatment response to antipsychotics in schizophrenia or to lithium in bipolar disorder. Identifying the most efficacious treatment regimen as early as possible could have longstanding benefits for patients, as exemplified by the PACT trial.

In the current issue of EBioMedicine, Chattopadhyay et al. highlight the above themes of early intervention and biomarker discovery in psychiatric disorders. Imaging adolescents with MDD, the authors found high resting state connectivity in brain regions involved in emotional processing, unlike adult MDD patients. Importantly, this connectivity dysfunction could be normalized when subjects were assigned to a cognitive behavioral therapy intervention. Indeed, finding reliable biological signatures of mental illness can not only inform diagnosis of patients, but also allow physicians to monitor patient responses to therapies, critical issues in psychiatric disorders where subjects may—thus far, unpredictably—experience waxing and waning bouts of illness and remission. With the emergent technologies in the neuroscience toolkit to probe the brain, broad multi-center collaboration to allow sufficiently-powered experiments, large data-mining efforts, and increasing social acceptance of psychiatric disorders to encourage participation of subjects in research studies, we look forward to what we believe is a new dawn for biologically-inspired classification of mental disorders.


New Study Shows Probiotics May Prevent ADHD And Autism Spectrum Disorders

New Study Shows Probiotics May Prevent ADHD And Autism Spectrum Disorders

By now, we are well aware of the gut-brain connection.  Can supplementing with probiotics reduce the risk for brain disorders in children, including ADHD and autism spectrum disorders?


There is a growing amount of medical research indicating that alterations in the type of bacteria that live in our gastrointestinal (GI) tract can influence brain function, mood and overall mental health. A new study from Finland is the first to show that probiotic supplementation early in life may be an effective way to reduce the rising tide of brain disorders in children, such as attention deficit hyperactivity disorder and autism spectrum disorders.

Background Data:

Gastrointestinal (GI) disturbances are very common in children with brain disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) including Asperger’s syndrome (AS). A number of mechanisms have been suggested linking these brain disorders as well as some of the common digestive disturbances these kids experience to alterations in the gut bacteria.

One novel theory is that lower levels of beneficial gut bacteria such as Lactobacillus and Bifidobacteria in children with ASD and ADD leads to an increase in toxin-producing bacteria such as Clostridium species. One study that supports this link that a gut microbial imbalance, such as the presence of toxin-producing Clostridium species, could contribute to ASD behavioral symptoms involved 11 children with ASD who were treated for 8 weeks with vancomycin. This antibiotic is often used in the treatment of chronic diarrhea due to Clostridium difficile. In this small study, scores for behavior and communication improved significantly during the treatment period; however, these gains only lasted while the children were given the antibiotic. This study raises the possibility that using probiotics, rather than antibiotics, may be helpful in at least some cases of ASD and, perhaps, ADHD as well.

In addition to the possibility that children with ASD and/or ADHD may be influenced by the absorption of gut-derived bacterial toxins, an altered gut flora also leads to increased gut permeability. Several studies have shown that the integrity of the intestinal lining is compromised in both ADHD and ASD. Increased gut permeability could lead to the absorption of microbial byproducts as well as partially digested food-derived compounds that may affect brain cell function directly or lead to immune responses that could also affect brain cells. Since probiotics can also improve the gut barrier, they may provide additional benefits in ADHD and ASD through this mechanism as well. Furthermore, since approximately 80% of the immune system resides in and around the intestinal lining, probiotics may also favorably affect the immune system to reduce the GI inflammation often observed in children with ADHD and ASD.

Lastly, a recent study in healthy women showed that supplementation with a mixture of probiotic bacteria had significant effects on brain regions that control central processing of emotion and sensation indicating that the probiotic bacteria themselves may be capable of exerting beneficial effects directly on brain function and mood.

New Data:

To test the hypothesis that probiotic supplementation may protect against the development of ADHD and AS, researchers in Finland looked closer at a study that was originally designed to test the effect of early supplementation with a probiotic in infancy on the later development of eczema. The mothers of 159 children were recruited in the and randomized in double-blind, placebo-controlled manner to receive 10 billion colony-forming units of Lactobacillus rhamnosus or placebo daily for 4 weeks before expected delivery. After delivery, the capsule contents were given either to the children, or continuously to the mothers, if breast-feeding, for 6 months.

To evaluate for a possible link between probiotic supplementation and ADHD or AS, 75 of these children were evaluated by an experienced child psychiatrist or neurologist not involved in the study or follow-up and the children were randomized and blinded so as not to produce any study bias. Results showed that ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (0/40). The probability value of this occurring was 0.008 indicating that it was not due to chance, but rather to a clear effect.

Because fecal samples were stored, the researchers were able to analyze the children for gut bacteria during their first six months of life. What the researchers found was that the numbers ofBifidobacterium species bacteria in feces during the first 6 months of life was lower in children with ADHD and AS compared to the healthy children.

The researchers concluded “Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.”


When I read this study, my immediate response was WOW. Not because the results were unexpected, but rather my surprise that someone actually studied the possibility that probiotic supplementation may offer significant protection against the development of AS and ADHD.

What are the takeaways from this study? Alterations in gut bacteria and/or GI function/integrity may be a major factor in the development of childhood behavioral disorders. I strongly encourage all expecting mothers to supplement their diets with a high quality probiotic supplement, continue with that supplement while breastfeeding, and give their infants a probiotic supplement when they are no longer being breastfed.

My specific product recommendations are for women to use the Ultimate Probiotic Women’s Formula from Natural Factors at a dosage of one capsule per day for general support that will provide 12 billion live bacteria. For infants and children, I recommend the Ultimate Probiotic Children Formula from Natural Factors. For children 0-5 years old: 1/2 teaspoon, 1 to 3 times per day. For children 6-12 years old: 1 teaspoon, 1 to 3 times a day. Both of these formulas contain a good dosage of Lactobacillus rhamnosus along with compatible other probiotic bacteria.

Induced Labor Not Linked to ASD

No relationship between labor induction and an increased risk for autism spectrum disorders (ASD) is seen when family variables are taken into account, a new study suggests. These findings run counter to previous studies, in which an association between induction and ASD was reported.

The difference lies in the use of a family comparison design involving discordant pairs of siblings or first cousins; that is, comparing one child born after induction of labor with a relative born after no induction of labor, lead author Anna Sara Oberg, PhD, and colleagues write in an article published online July 25 in JAMA Pediatrics. This allowed the authors to “control for all shared maternal factors (present across all pregnancies) that are unmeasured in registries but appear to confound the association between labor induction and neurodevelopmental disorders in the offspring.”

The findings suggest that concerns about ASD “should not factor into the clinical decision about whether to induce labor,” they write.

Dr Oberg, from the Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, and coauthors studied all live births in Sweden between 1992 and 2005. Using several nationwide registries that include all Swedish residents, they calculated induced births, ASD diagnoses, and maternal lifestyle and socioeconomic information such as reproductive history, use of tobacco, health history, and cohabitation status. The authors followed all the children born during the study period through the end of 2013 or until they were diagnosed with ASD, died, or emigrated from Sweden.

The baseline analysis accounted for birth year, parity, and maternal age, in addition to induction of labor. The researchers then added other covariates, including stable ones such as maternal educational level, as well as those specific to each pregnancy, such as maternal smoking, multiple gestations, preeclampsia, and urogenital infection, among others. The final model included a “fixed-effect” adjustment to allow for comparison between maternal siblings or maternal first cousins, while continuing to account for the covariates that were unique to each birth.

There were 1,362,950 members of the cohort, including 22,077 who were diagnosed with ASD during follow-up. Labor induction was used in 11% of live births during the study. Of the maternal sibling pairs in the sample, 15.2% were discordant for labor induction, as were 18.2% of the maternal cousin pairs. Primiparity, older maternal age, and higher maternal body mass index all were risk factors for induction, along with pregnancy complications such as gestational diabetes, gestational hypertension, and preeclampsia. By the time the cohort members were 20 years of age, ASD had been diagnosed in 3.5% of the offspring in the induced sample and 2.5% of the offspring in the noninduced sample.

The initial analyses appeared to confirm the findings of earlier studies: Labor induction was associated with a significantly higher risk for ASD (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.27 – 1.38) in the baseline model. This did not change substantially after adjustment for stable maternal characteristics (HR, 1.31; 95% CI, 1.26 – 1.37). Additional adjustment for pregnancy-specific factors resulted in a slight reduction in association (HR, 1.19; 95% CI, 1.13 – 1.24), but the association was still significant. However, the association disappeared (HR, 0.99; 95% CI, 0.88 – 1.10) when the authors applied fixed-effects models, “comparing discordant siblings to each other to account for all the factors they share.”

These findings suggest there is some other, still-unknown factor responsible for confounding the relationship between labor induction and ASD seen in earlier studies, Dr Oberg and colleagues write. Genes that govern cellular calcium homeostasis might be one culprit. An environmental factor might be delivery at a higher-intensity medical system, where clinicians might induce labor more readily and diagnose neurodevelopmental disorders more frequently.

Several prenatal and perinatal factors have been studied as possible candidates for ASD risk, but often the result is simply more questions, Daniel L. Coury, MD, writes in an editorial accompanying the article. For example, some evidence implicates maternal use of selective serotonin reuptake inhibitors in the incidence of ASD. “Should pregnant women take these medications, or should physicians advise against?” he asks. Similarly, one study showed a higher risk for intellectual disability among children conceived through assisted reproductive technology, but a later study, which followed a different cohort of children only through 36 months of age, failed to support this finding. “Which study is correct? How should clinicians counsel families regarding the risk?”

To help parents make better decisions, Dr Coury, from the Section of Developmental-Behavioral Pediatrics, Department of Pediatrics, Nationwide Children’s Hospital/The Ohio State University, Columbus, suggests more extensive discussion of research findings in lay terms and weighing the benefits against the risks. “The suicides prevented by [selective serotonin reuptake inhibitor] medications outweigh most concerns of adverse effects. The potential that each child brings to the world outweighs any risk associated with [assisted reproductive technology]. The benefits of labor induction, when performed in accordance with clinical guidelines, include the delivery of a healthy neonate and a healthier outcome for the mother.”

Study limitations include a lack of information on the type of labor induction used and the inability to identify the factors responsible for raising the risk for ASD in this population, the authors write. Still, they conclude, “the findings of this study provide no support for a causal association between induction of labor and offspring development of ASD.”

We all carry the genes for autism, study finds

The autism spectrum is a continuum, scientists say, and we’re all on it.

A large international study of the genes that predispose people to autism spectrum disorders (ASD) suggests that the same gene variants are also present in the wider population, where they can contribute to a range of behavioural and developmental traits with lesser severity than clinical ASD.

According to the researchers, there’s no real cut-off point on the autism spectrum – rather, it’s a continuum of complex genetic factors that can affect our behaviour. But for a small percentage of the community who have more of certain gene variants than others, this gives them a greater likelihood of demonstrating the social and behavioural traits recognised as clinical ASD.

“This is the first study that specifically shows that [genetic] factors that we have unambiguously associated with autism are also very clearly associated with social communication differences in the general population,” geneticist Elise Robinson from Harvard University told Nicola Davis at The Guardian.

“The primary implication is that the line at which we say people are affected or unaffected is arbitrary,” she added. “There is no clear objective point either in terms of genetic risk or in terms of behavioural traits, where you can say quite simply or categorically that you’re affected or unaffected. It’s like trying to pick a point where you say someone is tall or not.”

Autism spectrum disorders – which include autism, Asperger syndrome and unspecified pervasive developmental disorders – affect about 1 in 100 children. Symptoms include social interaction difficulties, communication impairments, and stereotyped or repetitive behaviour.

But while only 1 in 100 children may be clinically diagnosed with ASD, the implications of the study – published in Nature Genetics – are that these children represent just the “severe tail” of a range of behavioural and developmental traits also found in the broader population.

How do the scientists know this? By comparing data on some 38,000 individuals sourced from a number of studies on cohorts of both ASD-affected and unaffected individuals. By studying polygenic risk factors (small effects of thousands of genetic differences, distributed across the genome) and de novo risk factors (rare genetic variants of large effect), in these data sets, the continuum of ASD-related traits became clear.

“There has been a lot of strong but indirect evidence that has suggested these findings,” said researcher Mark Daly, co-director of the Broad Institute’s Medical and Population Genetics (MPG) program. “Once we had measurable genetic signals in hand – both polygenic risk and specific de novo mutations known to contribute to ASD – we were able to make an incontrovertible case that the genetic risk contributing to autism is genetic risk that exists in all of us, and influences our behaviour and social communication.”
However, just because everybody carries some degree of genetic risk when it comes to ASD gene variants, doesn’t mean we all would find social interactions difficult to some extent, nor that people’s genetic makeup is the only reason they might develop ASD.

“This research suggests that studies of the autistic population can gain from integrating studies of the general population, and so adds to the evidence that autism involves many complex and interacting factors including genetics, the environment and the development of the brain,” Carol Povey, director of the National Autistic Society Centre for Autism, who was not involved with the research, told The Guardian. “While this research refers to ‘autism-related’ traits in the general population, people should not take away the message that ‘we’re all a little bit autistic’.”

Rather, what the study gives us, according to its authors, is a broader framework in which to examine how ASD comes to be. “A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology,” they write in Nature Genetics.

“We can use behavioural and cognitive data in the general population to untangle the mechanisms through which different types of genetic risk are operating, ” said Robinson. “We now have a better path forward in terms of expecting what types of disorders and traits are going to be associated with certain types of genetic risk.”




Autism spectrum disorders (ASD) affect 1 to 2 percent of children in the United States. Hundreds of genetic and environmental factors have been shown to increase the risk of ASD. Researchers at UC San Diego School of Medicine previously reported that a drug used for almost a century to treat trypanosomiasis, or sleeping sickness, reversed environmental autism-like symptoms in mice.

Now, a new study published in this week’s online issue of Molecular Autism, suggests that a genetic form of autism-like symptoms in mice are also corrected with the drug, even when treatment was started in young adult mice.

The underlying mechanism, according to Robert K. Naviaux, MD, PhD, the new study’s principal investigator and professor of medicine at UC San Diego, is a phenomenon he calls the cellular danger response (CDR). When cells are exposed to danger in the form of a virus, infection, toxin, or even certain genetic mutations, they react defensively, shutting down ordinary activities and erecting barriers against the perceived threat. One consequence is that communication between cells is reduced, which the scientists say may interfere with brain development and function, leading to ASD.

Researchers treated a Fragile X genetic mouse model, one of the most commonly studied mouse models of ASD, with suramin, a drug long used for sleeping sickness. The approach, called antipurinergic therapy or APT, blocked the CDR signal, allowing cells to restore normal communication and reversing ASD symptoms.

“Our data show that the efficacy of APT cuts across disease models in ASD. Both the environmental and genetic mouse models responded with a complete, or near complete, reversal of ASD symptoms,” Naviaux said. “APT seems to be a common denominator in improving social behavior and brain synaptic abnormalities in these ASD models.”

Weekly treatment with suramin in the Fragile X genetic mouse model was started at nine weeks of age, roughly equivalent to 18 years in humans. Metabolite analysis identified 20 biochemical pathways associated with symptom improvements, 17 of which have been reported in human ASD. The findings of the six-month study also support the hypothesis that disturbances in purinergic signaling – a regulator of cellular functions, and mitochondria (prime regulators of the CDR) – play a significant role in ASD.

Naviaux noted that suramin is not a drug that can be used for more than a few months without a risk of toxicity in humans. However, he said it is the first of its kind in a new class of drugs that may not need to be given chronically to produce beneficial effects. New antipurinergic medicines, he said, might be given once or intermittently to unblock metabolism, restore more normal neural network function, improve resilience and permit improved development in response to conventional, interdisciplinary therapies and natural play.

“Correcting abnormalities in a mouse is a long way from a cure in humans,” cautioned Naviaux, who is also co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, “but our study adds momentum to discoveries at the crossroads of genetics, metabolism, innate immunity, and the environment for several childhood chronic disorders. These crossroads represent new leads in our efforts to understand the origins of autism and to develop treatments for children and adults with ASD.”

Molecular network identified underlying autism spectrum disorders

Researchers in the United States have identified a molecular network that comprises many of the genes previously shown to contribute to autism spectrum disorders. The findings provide a map of some of the crucial protein interactions that contribute to autism and will help uncover novel candidate genes for the disease. The results are published in Molecular Systems Biology.

“The study of disorders is extremely challenging due to the large number of clinical mutations that occur in hundreds of different human genes associated with autism,” says Michael Snyder, Professor at the Stanford Center for Genomics and Personalized Medicine and the lead author of the study. “We therefore wanted to see to what extent shared molecular pathways are perturbed by the diverse set of mutations linked to autism in the hope of distilling tractable information that would benefit future studies.”

The researchers generated their interactome – the whole set of interactions within a cell – using the BioGrid database of protein and genetic interactions. “We have identified a specific module within this interactome that comprises 119 proteins and which shows a very strong enrichment for autism genes,” remarks Snyder.

Gene expression data and were used to identify the module with members strongly enriched for known autism genes. The sequencing of the genomes of 25 patients confirmed the involvement of the module in autism; the candidate genes for autism present in the module were also found in a larger group of more than 500 patients that were analyzed by exome sequencing. The expression of genes in the module was examined using the Allen Human Brain Atlas. The researchers revealed the role of the corpus callosum and oligodendrocyte cells in the brain as important contributors to using genome sequencing, RNA sequencing, antibody staining and functional genomic evidence.

“Much of today’s research on autism is focused on the study of neurons and now our study has also revealed that oligodendrocytes are also implicated in this disease,” says Jingjing Li, Postdoctoral Fellow at the Stanford Center for Genomics and Personalized Medicine who helped to spearhead the work. “In the future, we need to study how the interplay between different types of brain cells or different regions of the brain contribute to this disease.”

“The module we identified which is enriched in autism genes had two distinct components,” says Snyder. “One of these components was expressed throughout different regions of the brain. The second component had enhanced molecular expression in the corpus callosum. Both components of the network interacted extensively with each other.”

The working hypothesis of the scientists, which is consistent with other recent findings, is that disruptions in parts of the interfere with the circuitry that connects the two hemispheres of the brain. This likely gives rise to the different phenotypes of autism that result due to impairment of signaling between the two halves of the brain.

“Our study highlights the importance of building integrative models to study complex human diseases,” says Snyder. “The use of biological networks allowed us to superimpose clinical mutations for autism onto specific disease-related pathways. This helps finding the needles in the haystack worthy of further investigation and provides a framework to uncover functional models for other diseases.”

Salience network is linked to brain disorders

How does the brain determine what matters? According to a new scientific article, a brain structure called the insula is essential for selecting things out of the environment that are “salient” for an individual, and dysfunction of this system is linked to brain disorders such as autism, psychosis and dementia.

In psychology and neuroscience, the term “salient” is used to describe a thing, person, place or event that stands out, or that is set apart from others. The current article, published online by Nature Reviews Neuroscience evaluates recent studies on salience processing.

The findings show that the is a complex and multi-purpose structure that can be separated into, at least, three separate regions with distinct functions. Specific subdivisions of the insular cortex, along with other cortical and subcortical regions, form a “salience network.” Compromises to the integrity of this network can contribute to deficits in attention and affect, as well as social and cognitive processes.

“We are constantly bombarded with stimuli from the environment that place demands on our attention,” said Lucina Q. Uddin, assistant professor of Psychology in the College of Arts and Sciences at the University of Miami and author of the article. “The function of one of the insular cortex subdivisions is crucial for orchestrating activity in other brain regions that are important for guiding attention,” Uddin said.

The article implies that mapping the structure and function of the insular cortex may help provide more targeted drugs and behavioral treatments for certain developmental and degenerative disorders of the brain.

“Understanding of the functions of each insular region and how they operate as a network will be valuable in understanding other disorders that are associated with insular dysfunction including anxiety, depression and chronic pain,” Uddin said.

The opinion piece is titled “Salience Processing and Insular Cortical Function and Dysfunction.” Uddin is now working on characterizing insula dysfunction as it relates to autism spectrum disorders.