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What is epigenetics, and what does it have to do with autism?
This week’s “Got Questions?” answer comes from Alycia Halladay, PhD, Autism Speaks director of research for environmental sciences
If you’ve been following autism research in recent years, you have probably read—many times—that familial, or inherited, risk is seldom the whole picture. A few inherited genes are sufficient by themselves to cause autism. But most so-called “autism genes” only increase the risk that an infant will go on to develop this developmental disorder. As is the case in many complex diseases, it appears that autism often results from a combination of genetic susceptibility and environmental triggers.
This is where epigenetics comes in. Epigenetics is the study of the factors that control gene expression, and this control is mediated by chemicals that surround a gene’s DNA. Environmental epigenetics looks at how outside influences modify these epigenetic chemicals, or “markers,” and so affect genetic activity.
It is important to remember that scientists use the term “environment” to refer to much more than pollutants and other chemical exposures. Researchers use this term to refer to pretty much any influence beyond genetic mutation. Parental age at time of conception, for example, is an environmental influence associated with increased risk of autism, as are birth complications that involve oxygen deprivation to an infant’s brain.
Because epigenetics gives us a way to look at the interaction between genes and environment, it holds great potential for identifying ways to prevent or reduce the risk of autism. It may also help us develop medicines and other interventions that can target disabling symptoms. We have written about epigenetics previously on this blog (here and here). So in this answer, I’d like to focus on the progress reported at a recent meeting hosted by Autism Speaks.
The Environmental Epigenetics of Autism Spectrum Disorders symposium, held in Washington, D.C. on Dec. 8, was the first of its kind. The meeting brought together more than 30 leaders in autism neurobiology, genetics and epidemiology with investigators in the epigenetics of other complex disorders to promote cross-disciplinary collaborations and identify opportunities for future studies.
Rob Waterland, of Baylor College of Medicine in Texas, described epidemiological studies and animal research that suggested how maternal nutrition during pregnancy can affect epigenetic markers in the brain cells of offspring.
Julie Herbstman, of Columbia University, described research that associated epigenetic changes in umbilical cord blood with a mother’s exposure to air pollutants known as polycyclic aromatic hydrocarbons (PAHs). PAHs are already infamous for their association with cancer and heart disease.
Rosanna Weksberg, of the Hospital for Sick Kids in Toronto, discussed findings that suggest how assisted reproductive technology may lead to changes in epigenetically regulated gene expression. This was of particular interest because assisted reproduction has been associated with ASD. Taking this one step further, Michael Skinner, of Washington State University, discussed “transgenerational epigenetic disease” and described research suggesting that exposures during pregnancy produce epigenetic changes that are then inherited through subsequent generations.
Arthur Beaudet, of Baylor College of Medicine, discussed a gene mutation that controls availability of the amino acid carnitine. This genetic mutation has been found to be more prevalent among children with ASD than among non-affected children, suggesting that it might be related to some subtypes of autism. Further study is needed to follow up on the suggestion that dietary supplementation of carnitine might help individuals with ASD who have this mutation. Caution is needed, however. As Laura Schaevitz, of Tufts University in Massachusetts, pointed out, studies with animal models of autism suggest that dietary supplementation may produce only temporary improvements in symptoms of neurodevelopmental disorders.
So what does this all mean for research that aims to help those currently struggling with autism? The meeting participants agreed that the role of epigenetics in ASD holds great promise but remains understudied and insufficiently understood. For clearer answers, they called for more research examining epigenetic changes in brain tissues. This type of research depends on bequeathed postmortem brain tissue, and Autism Speaks Autism Tissue Program is one of the field’s most important repositories. (Find more information on becoming an ATP family here).
The field also needs large epidemiological studies looking at epigenetic markers in blood samples taken over the course of a lifetime. One such study is the Early Autism Risk Longitudinal Investigation (EARLI). More information on participating in EARLI can be found here.
Autism Speaks remains committed to supporting and guiding environmental epigenetics as a highly important area of research. We look forward to reporting further results in the coming year and years.
Got more questions? Send them to gotquestions@autismspeaks.org.
Read more autism research news and perspective on the science page.
Thank You for Supporting our Pioneering Research
Guest post by epidemiologist Daniele Fallin, PhD, of Johns Hopkins Bloomberg School of Public Health
My work focuses on autism and understanding how genes and environments interplay to cause this developmental disorder. Much of this work is funded by federal grants, but there can be gaps in what these grants can support, especially in new fields of research. Support from Autism Speaks has been amazing in helping fill these gaps.
In particular, Autism Speaks provided important support for two of my current projects. The funding is allowing us to study families with autism and, so, gain insights into interactions between autism risk genes and environment exposures.
The Early Autism Risk Longitudinal Investigation (EARLI) is a national study of families that have at least one child on the autism spectrum and anticipate having more children. By following these high-risk families we seek to identify causes and risk factors—be they genetic, environmental or a combination of both. Information is regularly collected from mothers enrolled in the study, and their newborns receive free developmental assessments until 3 years of age.
The second study is a genome-wide investigation of DNA methylation, or epigenetics. It will allow us to investigate how various environmental exposures can affect gene expression in ways that increase—or potentially decrease—the risk of autism. This study will place special focus on environmental exposures during crucial periods of prenatal brain development.
Autism Speaks realizes the importance of these new areas of research and has put forth great effort to ensure we can explore and, hopefully, uncover risk factors for autism that, over the long term, may lead to prevention and improved treatments.
We continue to recruit study participants. Specifically we are enrolling mothers who have one or more children with autism and who may become pregnant or who are currently less than 28 weeks pregnant. They must live near an EARLI research site (California, Maryland or Pennsylvania). For more details, please visit www.EARLIstudy.org or our Facebook page.
On behalf of the EARLI research team, I want to extend a special thanks to Autism Speaks supporters for helping make this pioneering research possible.
Explore more of the studies our supporters are funding with our Grant Search Engine. And read more autism research news and perspective on the science page.
Our Science Data-Meister Reflects on the Big Picture
Posted by Dusan Bosnjakovic, director of research information systems for Autism Speaks Autism Genetic Resource Exchange
On a day to day basis, I can get so immersed in the mechanics, data and details of what I do that I sometimes forget to step back and see the bigger picture: The tremendous value of the research information systems that Autism Speaks has created within its Autism Genetic Resource Exchange (AGRE).
I am feeling particularly sensitive to this “big picture” with this week’s announcement of the historic addition of AGRE information to the National Database for Autism Research (NDAR), which is supported and maintained by the National Institutes of Health.
I’m reminded that the goal of all my work is to increase the availability and usefulness of the vital information that we collect—information that can advance the scientific understanding of autism and speed the development of better treatments.
I promise to spare you the technical details. Suffice it to say, our role is to take the anonymous information (de-identified data) we gather from our participating families and put it in an easy-to-use format that autism researchers can use to increase the power and accuracy of their scientific findings and insights.
In joining our data with NDAR’s, we are making more comprehensive data available to the broader scientific community and also linking data collected on participants within AGRE with additional data on the same participants across a variety of other research studies (all anonymous). This is adding significantly to the autism field’s body of scientific knowledge. And this is our obligation to our families: To maximize their contributions and make sure their de-identified data will always be available to qualified scientists who are working to improve the lives of those who struggle with autism. We take pride in providing researchers with the most comprehensive and highest quality of data possible, so that they can do what they do best: science.
Special thanks go to Reinis Berzins, our AGRE data projects coordinator, whose position was made possible by the $1 million National Institutes of Health grant we received to integrate the AGRE and NDAR databases. To learn more about AGRE, please visit its website. To learn more about the AGRE-NDAR federation, please see this week’s related news item.
Read more science news and perspective on the Science Page.
Autism Speaks Science Team Returns from China
Posted by Autism Speaks Chief Science Officer Geri Dawson, Ph.D.
The Autism Speaks science team traveled to Shanghai, China, last week with the goal of enhancing collaboration among Chinese and North American scientists. Despite the challenges of speaking different languages, we learned a lot from each other. Our Chinese colleagues were eager to hear about new research and treatments being developed in North America. The Americans were impressed with the technological prowess of the Chinese.
A prime example of this technological power is the Beijing Genome Institute, the largest genome sequencing institution in the world and a new Autism Speaks partner. In the coming year, the Beijing Genome Institute will be sequencing the DNA of families participating in our Autism Genome Resource Exchange (AGRE) program, allowing us to create the world’s largest whole genome sequence library for autism research. (See our related news item.)
Another example is a recently launched Chinese program that sends text messages to new mothers, alerting them to the early signs of autism. Chinese researchers are studying whether this innovative “eHealth” strategy results in better referral, assessment and intervention rates for children with early symptoms.
Although my conversations and learnings from my Chinese colleagues were enlightening and we planned many future collaborations, the most significant moment for me was talking to 200 Chinese parents of children with autism. I walked into a room filled with mothers and fathers eager to hear new information about autism. Through a translator, I described new research findings and treatments and fielded questions from the audience.
The questions were remarkably similar to those I hear from parents in the United States. One mother told me that her son had frequent tummy aches and constipation; she wondered if this could be related to his autism. Another parent asked what she should do about her daughter’s fear of fireworks, a common part of special events here. Should she keep her at home and miss the family outings? A father showed me a large bag filled with medicines he had purchased through the mail and asked if I thought they would help his child.
We talked about the association between autism and gastrointestinal problems and how treating these physical problems can relieve discomfort and, so, help children gain more from their educational programs. We talked about auditory sensitivities and discussed a range of strategies for helping children cope with loud noises. And we talked about how to evaluate whether a treatment is truly effective and safe for a child.
As our conversation continued, I was struck by the fact that, although China and the United States are very different cultures, autism is a common bond. Parents across the globe are looking for answers to help their children. My hope is that Autism Speaks Global Autism Public Health Initiative will be able to make a difference for these families. By partnering with scientists and clinicians in China, we can translate and adapt many of the tool kits and other resources we have developed here in North America—while also learning from our colleagues and families in China.
Transcript of ‘Genetics of Autism: What It Means for You’ Webchat with Geri Dawson, PhD and Steve Scherer, PhD
On Thursday, October 27 our first “Office Hours” webchat was held with Autism Speaks Chief Science Officer Geri Dawson, PhD, and her guest host: University of Toronto’s Steve Scherer, PhD, a world pioneer in the discovery and understanding of the genes and genetic changes that predispose to autism. Drs. Dawson and Scherer welcomed questions about the emerging understanding of genetic predisposition to autism, related studies supported by Autism Speaks and how this research can lead to new therapies and insights of direct benefit to families and individuals affected by autism.
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Comment From Teresa
Hi :) Thanks for being here for us! My question: with so many children currently being diagnosed with autism – 1 in 110 – is it not equally important to research autism causes not only because of genetics but also caused by environmental issues?
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If environmental factors can lead to autism, why does only one of my twin boys have autism?
This week’s “Got Questions?” response comes from Alycia Halladay, PhD, Autism Speaks’ director of research for environmental science.
Today’s question came in response to my last blog post. In it, I explained that when scientists talk about the “environmental factors” that increase the risk of a disorder, they’re referring to pretty much any influence beyond genetics.
In the case of autism, the clearest evidence of environmental influence seems to surround very early events such as conception, pregnancy and birth. Those with the strongest link include parental age at time of conception (both mom and dad), maternal nutrition or illness during pregnancy, and certain birth complications.
The commenter’s question is a great one that scientists are actively exploring. The short answer is that inherited genes (DNA) and environmental factors seem to interact to influence whether an infant goes on to develop autism. So if the commenter’s twins are fraternal (meaning they share about half their DNA), the difference in their genetic makeup might explain why only one developed autism.
But what if the boys are identical twins–meaning they share exactly the same DNA? In this case, something beyond genes likely accounts for the different outcomes. Comparing the rates of autism among identical and fraternal twins provides clues.
In July, researchers used our Autism Genetic Resource Exchange (AGRE) to complete the largest autism twin study to date. They found a 70 percent overlap in autism among identical twins and a 35 percent overlap among fraternal twins. That overlap between fraternal twins is much higher than the estimated 19 percent overlap between different-age siblings.
These numbers tell us that it’s not always genes alone that determine whether a child develops autism. If it were, two identical twins would always share the same outcome, and the rate of a shared autism among fraternal twins would look more like that for different-age siblings. So we conclude that shared environmental influences are also at play.
Although twins share very similar pregnancy and birth environments, those environments aren’t exactly the same. For example, twins can have different positions in the womb or different placentas, and this can affect such environmental influences as blood and oxygen flow. Indeed, twins often have different birth weights, a known risk factor for autism.
It’s important to remember that “environmental” influences such as these don’t cause autism by themselves. Rather, if a child has a genetic predisposition for developing autism, these influences may further increase the risk.
Autism Speaks continues to fund and otherwise support research on both genetic and nongenetic risk factors for autism. EARLI is a network of researchers who follow mothers of children with autism beginning at the start of another pregnancy. IBIS is a study of early brain development in the younger siblings of children with autism. These studies depend on the participation and support of the autism community. Please visit our Participate in Research page to learn more.
Importantly, these studies provide insights into the underlying biology of different types of autism. This in turn becomes a basis for developing ways to treat and possibly prevent autism. As always, the goal of the research we support is to improve the lives of all on the autism spectrum.
And thanks for the question. Please keep them coming.
What do scientists mean when they talk about ‘environmental factors’ that cause autism?
This week’s “Got Questions?” response comes from Alycia Halladay, PhD, Autism Speaks’ director of research for environmental science.
Research has taught us that there’s no simple explanation for what causes autism. We know that genes play a role, but they aren’t the whole picture. Environment also matters.
However “environment” can be a tricky term, as pediatrician Perri Klass recently noted in her New York Times column. In autism research, we use the word to refer to pretty much any influence beyond inherited genes—not just exposure to pollutants or other toxic chemicals.
In fact, the environmental factors that research most strongly links to autism are influences such as maternal infection during pregnancy (especially rubella), birth complications (especially those involving oxygen deprivation), and parental age at time of conception (dad as well as mom). Parents who wait less than one year between pregnancies may be at a slightly higher risk for having a child with autism. (Conversely, there is strong evidence that mothers who take prenatal vitamins before conceiving reduce the odds that their children will develop autism.)
Clearly, countless fetuses and babies are exposed to “environmental risk factors” such as these without ever developing autism. But if a child is genetically predisposed to autism, it appears that these influences further increase the risk. For this reason, we say that environmental factors increase the risk of autism rather than cause it.
Research has suggested that many other environmental, or nongenetic, factors may increase the risk for autism. But scientists can’t yet say whether these involve direct (versus coincidental) links. Such factors include a pregnant woman’s exposure to certain chemicals such as pesticides and phthalates (commonly found in plastics) or certain drugs such as terbutaline (used to stop premature labor), valproic acid (to control seizures), and some antipsychotics and mood stabilizers. Of course, in the case of medications, any possible increased risk of autism must be balanced against a woman’s medical needs—which can likewise affect the health of her pregnancy and children.
In addition, most environmental factors associated with autism appear to increase risk only slightly and only in combination with other factors such as genetic predisposition. So it is difficult, in most cases, to pinpoint any one environmental influence. For these reasons, Autism Speaks continues to fund research on a wide range of environmental risk factors. Importantly, the more we learn about how these influences affect brain development, the better we can help the children, adults and families who are affected by autism.
Want to learn more about the research Autism Speaks is funding? On our Science Grant Search page, you can browse studies by topic and location. Finally, if you or your child is affected by autism, please consider participating in one of our clinical studies. Thanks, and please keep sending us your questions.
Autism in the Family – More Common Than We Thought
This is a guest blog post from Autism Speaks Science Board member John Elder Robison, author of Look Me in the Eye: My Life with Asperger’s and Be Different: Adventures of a Free-Range Aspergian.
This morning I read a striking a new study which addressed the question of autism in siblings – how common is it? The findings will be of vital interest to many; most especially young families with an autistic infant.California Autism Twin Study Suggests Prenatal Risk Factors
Posted by Clara Lajonchere, PhD, vice president of clinical programs, Autism Speaks
As head of clinical programs at Autism Speaks, I oversee a number of vital resources for researchers studying the causes and treatment of autism. Today brought the publication of a new and revealing study made possible by Autism Speaks’ Autism Genetic Resource Exchange (AGRE).
Autism researchers have been studying twins for years for insights into the genetic and nongenetic factors that influence the development of autism. One of the most powerful ways to do so is to study twins (both identical and non-identical) where at least one of the pair has autism. This approach allows us to look at how often both twins receive a diagnosis of autism. Study of identical twins, who share 100 percent of their genes, then helps us determine the degree to which autism is inherited, or genetic; and comparison to fraternal twins, who share around 50 percent of their DNA, allows us to understand how environmental influences add to the risk of autism spectrum disorder (ASD).
But until now we’ve had only three, small twin studies, which together looked at just 66 twin pairs–a number too small to produce reliable conclusions. Still, these studies were the best we had, and theysuggested that when one identical twin develops an ASD, the chance of the other twin developing the disorder is as high as 90 percent. These same studies showed little to no overlap among fraternal twins – leading to the conclusion that inherited genes alone produced the risk.
Now comes the game changer. The California Autism Twins Study (CATS) is the largest ever study of twins with ASD, with scientifically reliable information on 192 twin pairs, both identical and fraternal. It was conducted by a group of renowned researchers in collaboration with the AGRE team. AGRE clinical staff collected DNA and helped perform the home-based diagnostic and cognitive testing on many of the participants, using scientifically validated research measures for diagnosing ASD.
So what were its dramatic findings?
It found that when one identical twin develops autism, the chance of the other twin developing the disorder is 70 percent. More surprisingly, it documented a whopping 35 percent overlap among fraternal twins. This is strong evidence that environmental influences are at play. Moreover, the 35 percent “both twins affected” rate is higher than the 3 percent to 14 percent overlap between different age siblings. (i.e. If one child in a family has autism, there is a 3 percent to 14 percent chance that a younger sibling will develop it.) This suggests that there are environmental influences uniquely shared by twins–for instance, in the womb and perhaps during birth.
In other words, we now have strong evidence that, on top of genetic heritability, a shared prenatal environment may have a greater than previously realized role in the development of autism in twins
This has important implications for future research. For instance, is there a particular time period during the pregnancy when a child’s brain development is particularly vulnerable to environmental influences? And what might these influences be? Already we have evidence implicating such factors as advanced parental age, maternal nutrition, maternal infections (especially flu) during pregnancy, and premature and/or underweight birth. Indeed, multiple-birth pregnancies are themselves associated with increased risk of developmental disorders such as cerebral palsy and autism.
Only by further studying these issues can we begin to provide parents and parents-to-be with the reliable guidance they seek and need. Autism Speaks is currently investing in several studies that are exploring how environmental factors increase the risk for ASD. As we go forward in these endeavors, we greatly value your input. So please write and share your comments on our blog and website. For more on the study, read The Womb as Environment.
On July 5th, NBC Nightly News came to Andy Shih, Autism Speaks’ vice president of scientific affairs, for perspective on the game-changing California Autism Twins study. To view the clip please visit here.
More national television media coverage of the ground-breaking results of the California Autism Twin study–research made possible by the Autism Speaks Autism Genetic Resource Exchange (AGRE) and Autism Speaks’ supporters such as you.
Shank synaptic genes in autism: Human genetics to mouse models and therapeutics
This is a guest post by by Mehreen Kouser, a Dennis Weatherstone Fellow, and Ph.D. Candidate working with Dr. Craig Powell at the UT Southwestern.
This year IMFAR hosted a Scientific Panel titled “Shank synaptic genes in autism: Human genetics to mouse models and therapeutics” organized and chaired by Dr. Craig Powell. This panel consisted of four presentations starting with the unequivocal role of Shank3 in autism and ending with potential treatment strategies in genetically mutated mouse models of Shank3.
Over the past few years , Shank3 has emerged as the new “it” gene for autism. Current estimates suggest that Shank3 errors account for 0.5-2 % of autism diagnoses making it a major genetic cause of autism. Several recent human studies have implicated mutations/deletions/duplications in the Shank family of proteins, especially Shank3, to be involved in ASD and 22q13 Deletion Syndrome. Shank3 is a scaffolding protein that is involved in synapse architecture. Mutations in Shank3 are known to affect synaptic connections between neurons in similar ways to other autism-relevant genes such as neuroligin and neurexin. Thus understanding the role of Shank3 in autism is critical.
The first presenter at this panel was Dr. Catalina Betancur from INSERM in France. Dr. Betancur was a major player in the discovery of Shank3’s relevance to autism. She carefully detailed all known human mutations, deletions, and duplications published since the first paper on Shank3 mutations in idiopathic autism was published in 2007.She also outlined the case for Shank3 as a major causative gene in the symptoms of the 22q13 chromosomal deletion syndrome known as Phelan-McDermid Syndrome. In addition, Dr. Betancur detailed the work of her laboratory and others implicating Shank2, another member of the Shank gene family, in autism.
Dr. Joseph Buxbaum from Mount Sinai School of Medicine in New York was the next presenter. His laboratory was the first to publish a genetic mouse model of Shank3 successfully Shank3. Their Shank3 mutant mouse closely mimics autism-associated mutations in this area of the Shank3 gene. His work focused on the heterozygous mutation of Shank3 gene as this is the state of autism patients with Shank3 mutations. Characterization of this mouse model, clearly suggests that Shank3 plays an important role in synapse architecture, function, and plasticity. Among the most intriguing findings in his presentation was his ability to reverse the manifestations of Shank3 mutation in brain slices treated with Insulin-like Growth Factor-1 (IGF-1). This gives us the much needed hope that Shank3 mutation models of autism will lead to identification of novel therapeutic targets that can be validated in these models.
Next, Dr. Yong-hui Jiang from Duke University in North Carolina presented his work on a genetic mouse model very similar to that of Dr. Buxbaum’s group, but his focus was the homozygous mutation of Shank3 mutating both copies of the gene. He noted that the Shank3 gene is more complex than originally thought, with potentially having as many as six variants or isoforms. His careful analysis of this mutant model clarified that only a portion of Shank3 isoforms are affected by this genetic strategy. He identified abnormalities in synaptic connection morphology in his model. Moreover, his lab characterized this mouse model extensively on autism related behaviors and found them to be impaired in the social behaviors, repetitive behaviors, communication, motor coordination and learning and memory. These results demonstrate that human diseases can be successfully modeled in mice. The hope is that if we can reverse them in mice, treatments for humans are not far away.
Dr. Joao Peca from Guoping Feng’s lab at MIT in Massachusetts concluded the session by presenting a completely different Shank3 mutation in mice. He began his presentation by telling us about another synaptic gene called SAPAP3 and showing us its involvement in a repetitive grooming behavior in mice. He showed that SAPAP3 knockout mice continuously groom themselves and that this behavior can be reversed by putting this gene back into the striatum of mice later in life. He also showed that Shank3 is a strong binding partner of SAPAP3 and their Shank3 mutant mice have the same increase in repetitive grooming behaviors. Like the other Shank3 mutations, this mutant does not affect all forms of Shank3, but may mimic a different human mutation.
This panel set the stage for future advances in the area of Shank3 and autism. Only 4 years after the initial study implicating Shank3 in autism, we now have at least 3 different animal models and 4 publications on these models. Although, we may face grave challenges in sorting through the heterogeneity of mutations, deletions, and duplications and their different consequences, these presenters clearly demonstrate that this strategy will lead to identification of potential therapeutic targets that can be readily tested in animal models.
