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.
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Read more autism research news and perspective on the science page.
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.
The Mount Sinai Children’s Environmental Health Center, in partnership with Autism Speaks, is holding a one day workshop, Exploring the Environmental Causes of Autism and Learning Disabilities, at the New York Academy of Medicine on Wednesday, December 8, 2010. The goal of the workshop will be to develop new strategies for discovery of environmental risk factors for autism, autism spectrum disorder (ASD) and other neurodevelopmental disorders in children.
The workshop will help identify opportunities to study gene/environment interactions in autism, and help guide research priorities for the newly formed Autism and Learning Disabilities Discovery and Prevention Program at Mount Sinai. Scientists from National Institute of Environmental Health Sciences, Centers for Disease Control and Prevention, National Institute of Child Health and Human Development and leading academic institutions from around the world will present recent research and engage in discussions to identify gaps and opportunities, especially in the area of environmental causation by toxic chemicals.
On Saturday, April 17, CBS’ Evening News featured a segment entitled “Where America Stands on Autism.” The segment focuses on a wide range of autism research being supported in part, by Autism Speaks. Dr. Geri Dawson, Autism Speaks’ chief science officer, is interviewed as well as Joe Piven at UNC and the Henderson family, who are study participants. The story also featured a groundbreaking discovery by the Autism Genome Project, led by Dr. Hakon Hakonarson. To participate in the imaging study featured in the story please visit http://www.ibis-network.org/.Read a guest post by one of the EARLI Study’s Outreach Coordinators and watch the segment below.
This is a guest post by Alycia Halladay, Ph.D. and Leanne Chukoskie, Ph.D. Dr. Halladay is Autism Speaks’ Director, Research for Enivronmental Services. Leanne earned her Ph.D. at NYU’s Center for Neural Science studying the neural mechanisms that mediate vision during eye movements. During her postdoctoral training at the Salk Institute she studied search behavior in both humans and animals. A family connection as well as the curious manner in which people with autism tend to scan a visual scene led her to work for Autism Speaks as the Assistant Director of Science Communication and Special Projects. Leanne also continues her research as a Project Scientist at UCSD.
This is a guest post by Alycia Halladay, Ph.D. Dr. Halladay is Autism Speaks’ Director, Research for Enivronmental Services.
Instead of focusing on just genetics or just environmental factors, autism researchers have been studying gene-environment interactions as possible risk factors of the disorder. A next series of posts will begin to try and explain why this is an important concept, and how it is changing the way scientists think about causes.
Why is this concept important?
First, in the context of risk factors, if only the separate contributions of genetics and environmental influences is calculated without considering the interaction, the proportion of the disorder that is attributable to both is underestimated. For example, environmental factors may play an important role in the development of some diseases. However, in others, the effect is only seen in susceptible individuals. Studies that examine gene-environment interactions can do the following (taken from Hunter, 2005)
- Obtain a better estimate of the risk associated with genetic and environmental risk factors
- Strengthen the association between environmental risk factors and disease
- Help researchers understand the biological mechanism of disease
- Determine which environmental factors produce risk
- Lead to new prevention and therapeutic strategies
What does it mean?
As most people know, genetics typically refers to the stable sequence of nucleotides on DNA strands in every cell of the human body. The nucleotides are translated to amino acids, which in turn create proteins. The amino acid sequence determines how proteins are configured, which may affect their function. Put in an oversimplistic fashion, these proteins are what affect cell function. Some of the genetic code is inherited from both parents, and will be conferred to their children; another, more recently studied type of genetics, called epigenetics, refers to a change in protein synthesis that is not due to alterations in the DNA code. In other words, the DNA code stays the same but the way it is expressed changes. These concepts will also be discussed in a later chapter. With regards to the term “environment”, this is a term that can refer to many “non-genetic” influences on biology and behavior. Typically when they hear “environment” people think of one of the hundreds of thousands of potential chemicals and toxins that are present in food, air and water. However, environment can also include some demographic characteristics like socioeconomic status, nutritional status and education, as well as medical procedures and illnesses, and exposure to vitamins, pharmaceuticals and/or alternative medicines. It can even refer to exposures that we may not be thinking about every day, like UV sunlight, cosmetics, food additives, and ventilation in the home. While most people think of gene-environment interactions as an environmental risk factor producing more profound effects in a susceptible individuals, some genes may offer protection against deleterious environmental effects. Other genes may promote healthy development and their effects stifled, or even enhanced, in different environments. These concepts will be explored further in a different chapter.
How are these interactions determined and studied?
The best way to determine whether an interaction exists in a human population is an epidemiologic study. One of the biggest challenges is the need for large samples, or many individuals to enroll and participate. Typically, self-report measures are obtained from all participants and family members, and DNA and other biologicals are included to study DNA/RNA and level of exposure. If other measures are available such as medical records, these are also collected throughout the study. Genetic and environmental factors, and their interaction, can be studied retrospectively (after the disease has developed) or prospectively (prior to when the disease appears). Each design has strengths and weaknesses, and in many cases both approaches are taken to identify and then replicate findings. Other study designs include case-control vs. case-case. Case-control refers to studying both individuals with and without the disease. Case-case refers to studying cases (in this case individuals with autism only) both with and without different exposure levels and/or genotypes.
In the 25 days leading up to Autism Speaks’ fifth anniversary, we summarized significant advances in autism science and updates since these advances occurred. This is a time for celebration and reflection, as well as focusing on next steps. On the eve of the fifth anniversary, this opinion piece, written by Nicholas Kristof, appeared in the New York Times and has generated considerable interest.
At Autism Speaks, we are investigating environmental links to autism as well as gene-environment interactions through our various grants and initiatives. In our environmental portfolio, we are currently supporting grants that examine the effects of environmental agents in animals, in which we look for some of the hallmarks of autism. Researchers in this area are studying animals with different genetic mutations and environmental exposures to the response of the immune system, the effectiveness of the body’s systems at clearing toxins and in changes in the expression of certain genes that occur as a result of the early environment. In addition we are also funding an expansion of epidemiology and brain development projects, including the Early Autism Risk Longitudinal Investigation (EARLI) and the Infant Brain Imaging Study (IBIS) to learn about gene-environment interactions that may affect the developing fetus. In the next weeks, we’ll be posting several pieces about gene-environment interactions to educate our community on these important interactions and inform you of the latest autism research in this area.