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What is epigenetics, and what does it have to do with autism?

January 20, 2012 11 comments

This week’sGot 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.


I see more headlines about autism risk and antidepressants in pregnancy. What am I supposed to do?

November 4, 2011 3 comments

This week’s ‘Got Questions?’ answer comes from Rob Ring, PhD, Autism Speaks vice president of Translational Research, and Joe Horrigan, MD, Autism Speaks assistant vice president, head of medical research.

To bring readers up to speed, the above question stems from two reports: In July, a group of California researchers reported a modest increase in the risk that a child would develop autism if his or her mother took selective serotonin uptake inhibitors (SSRIs) during pregnancy. The results were based on a very small sample of children exposed to antidepressants during the time their mothers were pregnant—just 20 children with autism compared to 50 without autism. This past month, another team of scientists reported that rats fed SSRIs as newborn pups exhibited abnormalities in brain development.

Given the great hunger for information about what causes autism, both studies made headlines. Unfortunately, the media stories may have served to alarm without putting these early and inconclusive scientific findings into perspective.

First and foremost, research with animals and investigations looking at a small number of cases are both important for guiding larger, more informative studies. But in and of themselves, these two particular studies don’t come close to reaching the bar at which scientific evidence is reliable enough to warrant a change in behavior. We feel this is particularly true of important medical decisions such as the need to treat depression, which can be a serious and life-threatening illness.

Take, for instance, the small number of children in the California study. This small “sample size” increases the likelihood that the results were due to chance or other unrelated factors. In other words, they may not represent real differences in risk. It is very common in science for such preliminary findings to vanish when researchers repeat the analysis with a larger, more “statistically significant” number of cases.

In addition, among women taking SSRIs, there may be other, hidden factors responsible for raising autism risk among their future children. For example, we know that anxiety is common among persons with an autism spectrum disorder (ASD). In fact, many of those who learn, as adults, that they have an ASD do so when they seek treatment for anxiety and/or related depression. A common type of medicine prescribed in these instances is SSRIs. We also know that ASDs tend to run in families. So it may be that family genetics—not SSRIs—produced the above-mentioned finding of a modest increase in the prevalence of autism among children whose mothers took these antidepressants during pregnancy.

And the rat study? While it’s useful for guiding the focus of further research, we simply can’t extrapolate results from rats to humans.

Finally, we worry about the consequences of women going off antidepressants when they truly need these medications. Certainly if a woman is pregnant or trying to become pregnant, she should discuss all her medicines with her physician—so that with guidance she can weigh the risks and benefits of continuing or discontinuing one or more of them. Certainly, a woman’s untreated depression can itself pose a danger to her pregnancy or newborn child. The bottom line:  If you have concerns regarding your medications during pregnancy, discuss them with your physician, who can help you make the best decision for you and your family.

We hope that we’ve lent some helpful perspective to this issue. Please keep your questions coming (GotQuestions@autismspeaks.org).

What do scientists mean when they talk about ‘environmental factors’ that cause autism?

September 30, 2011 34 comments

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.

‘Meta-analysis’ Clarifies Birth Conditions Associated with Autism

July 11, 2011 50 comments

Posted by Alycia Halladay, PhD, director of research for environmental science, Autism Speaks

For over four decades, autism researchers have been combing through birth records to look for events that might increase the risk that a newborn goes on to develop an autism spectrum disorder (ASD). Many clues have emerged regarding the influence of such factors as prematurity, low birth weight, method of delivery, or even the season in which conception or delivery occurs. But no one study was large enough to provide definitive answers, and inconsistent results between studies have caused confusion among scientists as well as parents trying to follow the science.

Today, the respected journal Pediatrics publishes a study that goes far in cutting through the confusion. Researchers from Harvard and Brown universities reviewed and analyzed the combined results of 40 studies that looked at potential autism risk factors during the birth (perinatal) and newborn (neonatal) period.

Such a “meta-analysis” study is a powerful tool in science, as it allows researchers to combine and compare findings from different sources to get a clearer, more reliable picture of the associations between potential risks and conditions such as autism. Importantly, the study confirmed an association between autism and such conditions as abnormal fetal presentation during delivery (for example, breech), fetal respiratory distress (breathing difficulties), birth injury or trauma, low 5-minute APGAR score (a 1-10 score for assessing newborn health after delivery), newborn seizures, low birth weight, multiple births (twins, triplets, etc.), anemia (low blood iron, and being born in the summer.

Of note, preterm birth was not found to be associated with ASD, of particular interest because there had been considerable differences on this count across earlier studies. Most importantly, perhaps, the researchers concluded that the evidence did not implicate any one perinatal or neonatal factor as causing autism by itself. Rather, the evidence suggests that a combination of these factors—reflecting generally poor conditions during and immediately after birth–may increase the risk that a child with an underlying genetic disposition will develop autism.

One common thread across several of these risk factors is that they result in a lack of adequate blood flow to the brain during the birth process. One hypothesis is that, when combined with a genetic predisposition, oxygen deprivation to the brain worsens abnormal brain development. Studying these and other environmental (versus genetic) risk factors for autism is important to increase our understanding of the biology of ASD and to provide practical guidance for physicians and parents on how to avoid or modify those risk factors that can be changed.

In addition, this meta-analysis strongly suggests that pediatricians and parents should closely monitor the development of babies born in difficult situations so that early intervention can be offered should developmental issues such as autism arise. What this study does not say is that difficult birth means a baby will go on to develop autism. Rather, these conditions and complications may increase the risk of autism among those who have a genetic predisposition for developing it.

As in my last post, I want to invite readers to explore the many environmental risk studies that Autism Speaks is supporting with donor dollars, scientific resources, and the participation of autism families in clinical studies. Please see our Grants Search and Participate gateways at www.autismspeaks.org. Thanks for being a vital part of our mission to improve the lives of all who struggle with autism. For more on the Pediatrics meta-analysis study, also see Autism Speaks news.

Epidemiology sheds new light on risk factors for ASD

May 19, 2011 11 comments

by Alycia Halladay, Ph.D, Director of Environmental Science 

Research using identical and fraternal twins is typically used to identify genetic influences on the development of ASD.  This year, researchers studied a large group of twins and examined the concordance of different types of symptoms (1).  Using this approach, the researchers found that the concordance of severe autism between identical twins and fraternal twins was about the same, indicating a strong environmental component to ASD severity.  But what are those environmental factors?   Epidemiological studies are providing clues.

At this year’s IMFAR, new data was presented that focused on studying groups of people and their exposures to a number of environmental factors.   Each used different designs with their own unique advantages.  For example, at UC Davis, the CHARGE study (www.beincharge.ucdavis.edu) examined the risk of developing autism following exposure to a number of factors that were identified through self report or medical records.  Those that showed an association were antidepressant SSRI use (2) and metabolic disorders including hypertension and diabetes (3).  On the other hand, a previously identified factor, maternal infection, was not associated (4).  Why not?  The researchers suggested that fever, not infection per se, may be a factor.  Using self-report and medical records obtained prior to study entry may not accurately capture all relevant information, and an infection or fever may be missed in some reports.  However, other types of information, such as method of birth, is easier to gather accurately.  An analysis revealed that non-emergency or elective c-section deliveries did not show a significant association with autism, addressing a concern that many public and community stakeholders have expressed (5).

As an alternative to retrospective reports, the Early Markers of Autism Study in California is obtaining samples of blood from pregnant women by obtaining extra blood taken during the alpha-fetal protein screen that is banked.  Not all states bank these samples for research, so this is a unique resource.  By examining the levels of mercury in blood taken during pregnancy together with newborn blood spots, the researchers can get a more comprehensive picture of the prenatal environment.  They reported no difference in mercury levels compared to those of non-affected children during gestation, and also reported no difference in thyroid hormone levels (6,7).  Examination of subgroups of autism with regression did not change the results.  While these data are incredibly novel and valuable, these studies were not designed to capture information throughout the entire pregnancy nor capture factors after birth

Another way to study exposures during pregnancy is through birth certificate data.  In some states, the birth certificate contains information such as the place of birth and the occupation of the mother and the father.  Using this information, scientists found that occupational exposures in mothers to certain chemicals resulted in an increased risk of ASD in offspring (8).

While each approach brings unique strengths, all researchers agree that the most comprehensive way to capture all information accurately, is a prospective design.  This means identifying children as soon as possible and following them from that point on to gather every piece of relevant information from medical reports to blood samples.  Autism Speaks is proud to co-sponsor such a study:  the Early Autism Risk Longitudinal Investigation (EARLI).   This groundbreaking project will provide even more answers to what causes autism, and needs the help of the community to do so.

So how can researchers blend or expand their research if they are using only one type of design? Autism Speaks and the National Institutes for Environmental Health Sciences are sponsoring a network of projects called the Environmental Epidemiology of Autism Research Network (EEARN). The goal of this network is to improve communication among researchers in this field, identify opportunities for collaborative projects and improve research tools for both existing, and new projects. Over 20 studies from 8 countries are represented in the network. We will keep you updated on the activity of the network, and we hope you will keep checking in for updates.

1.     Understanding Clinical Variability In Autism: Results From a California Twin Study. W. Froehlich*1, S.

Cleveland1, A. Torres1, J. M. Phillips1, B. Cohen2, A. Fedele3, T. Torigoe2, J. Collins4, K. S. Smith5, L. Lotspeich1, L. A.  Croen4, S. Ozonoff6, C. Lajonchere7, J. K. Grether5, N. Risch8 and J. Hallmayer1, (1)Stanford University, Stanford, CA, (2)Autism Genetic ResourceExchange, Los Angeles, CA, (3)Autism Speaks, Westmont, NJ,

United States, (4)Kaiser Permanente, Division of Research, Oakland, CA, (5)California Department of Public Health, Richmond , CA, (6)UC Davis MIND Institute, Sacramento, CA, (7)Autism Speaks, Los Angeles, CA, United States, (8)University of California San Francisco, San Francisco, CA

2.     SSRI Use During Pregnancy and Risk of ASD or Developmental Delay In Children. R. A. Harrington*1,L. C. Lee1, C. K. Walker2, R. L. Hansen3, S. Ozonoff3 and I. Hertz-Picciotto4, (1)Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, (2)Department of Public Health Sciences, University of California at Davis, Davis, CA, (3)MIND Institute, University of California at Davis, Sacramento, CA, (4)Department of Public Health Sciences, University of California Davis, Davis, CA

3.     The Role of Maternal Diabetes and Related Conditions In Autism and Other Developmental Delays. P. Krakowiak*1,2, A. A. Bremer3, A. S. Baker1, C. K. Walker1,4, R. L. Hansen2,3 and I. Hertz-Picciotto1,2, (1)Public Health Sciences, University of California, Davis, Davis, CA, (2)M.I.N.D. Institute, Sacramento, CA, (3)Pediatrics, University of California, Davis, Sacramento, CA, (4)Obstetrics & Gynecology, University of California, Davis, Sacramento, CA

4.     Prenatal Influenza or Fever and Risk of Autism/Autism Spectrum Disorders. O. Zerbo*1, I. Hertz- Picciotto2,3, A. M. Iosif4, R. L. Hansen5,6,7 and C. K. Walker8, (1)Sacramento, CA, (2)University of California, Davis, Davis, CA, (3)Department of Public Health Sciences, University of California Davis, Davis, CA, (4)UC Davis, Davis, CA, (5)University of California, Davis, MIND Institute, Sacramento, CA, (6)MIND Institute, University of California at Davis, Sacramento, CA, (7)MIND Institute and Dept. of Pediatrics, University of California Davis, Davis, CA, (8)Department of Public Health Sciences, University of California at Davis, Davis, CA

5.     Cesarean Birth and Autism Spectrum Disorder. C. K. Walker*1, P. Krakiowiak2, A. S. Baker3, R. L. Hansen4, S. Ozonoff5 and I. Hertz-Picciotto6, (1)Obstetrics & Gynecology, UC Davis, Sacramento, CA, (2)Public Health Sciences, UC Davis, Sacramento, CA, (3)Public Health Sciences, UC Davis, Davis, CA, (4)Pediatrics, M.I.N.D. Institute, UC Davis, Sacramento, CA, (5)Psychiatry and Behavioral Sciences, M.I.N.D. Institute, UC Davis, Sacramento, CA, (6)Public Health Sciences, M.I.N.D. Institute, UC Davis, Davis, CA

6.     Prenatal and Neonatal Peripheral Blood Mercury Levels and Autism Spectrum Disorders. L. A. Croen*1, M. A. Lutsky1, C. Yoshida1, C. P. Alaimo2, M. Kharrazi3, J. K. Grether4 and P. Green2, (1)Kaiser Permanente Division of Research, Oakland, CA, (2)Civil and Environmental Engineering, Univ. of California Davis, Davis, CA, (3)Genetic Disease Screening Program, California Department of Public Health, Richmond, CA, (4)California Department of Public Health, Richmond, CA

7.     Prenatal and Neonatal Thyroid Stimulating Hormone Levels and Autism Spectrum Disorder. M. A. Lutsky*1, C. Yoshida1, B. Lasley2, M. Kharrazi3, J. K. Grether4, G. Windham4 and L. A. Croen1, (1)Kaiser Permanente Division of Research, Oakland, CA, (2)Department of Population Health and Reproduction, UC Davis, Davis, CA, (3)Genetic Disease Screening Program, California Department of Public Health, Richmond, CA, (4)California Department of Public Health, Richmond, CA

8.     Autism Spectrum Disorders In Relation to Parental Occupational Exposures During Pregnancy. G. Windham*1, J. K. Grether2, A. Sumner3, S. Li4, E. Katz5 and L. A. Croen6, (1)California Department of Public Health, Richmond, CA, (2)California Department of Public Health, Richmond, CA, (3)Vermont Department of Health, Burlington, VT, (4)Kaiser Permanente Divison of Research, Oakland, CA, (5)Occupational Health Branch, CA Department of Public Health, Richmond, CA, (6)Kaiser Permanente Division of Research, Oakland, CA

5|25: Celebrating Five Years of Autism Science Day 14: Autism as a Disorder of the Synapse

February 14, 2010 Leave a comment
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