Autism Speaks Official Blog

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.

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.

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

Last week, the Senate Environment and Public Works Committee convened a panel of experts to investigate the role of environmental factors in autism spectrum disorders (ASD; link to web archive for video). Although genetic factors are known to contribute to the risk of autism, we also need to understand environmental factors and their interactions with genetic susceptibility.

The dramatic increase in autism prevalence over the last two decades—over 600% during this period—underscores the need for more research on environmental factors.  Our understanding of typical brain development combined with what we’ve learned from examining the brains of individuals with autism have focused efforts on the prenatal and early postnatal environment.  To investigate environmental factors that may be active during this time, researchers are casting a wide net on potential environmental agents that can alter neurodevelopment, including exposure to metals, pesticides, polybrominated diphenylethers and other chemicals.

Isaac Pessah, Ph.D., Director of the University of California, Davis, Children’s Center for Environmental Health and Disease Prevention, participated in the panel and said in his testimony, “We must identify which environmental exposures and combination of exposures are contributing to increased overall risk in the population and identify the most susceptible groups. Only by bringing together the concerted effort of multidisciplinary teams of scientists can we identify which of the >80,000 commercially important chemicals currently in production promote developmental neurotoxicity consistent with the immunological and neurological impairments identified in individuals with idiopathic autism”.

To help speed an understanding of environmental factors, Autism Speaks is supporting research on several fronts. In 2008, Autism Speaks launched the Environmental Factors Initiative to fund investigators researching aspects of environmental causes and autism.

A collaboration with the National Institute for Environmental Health Sciences (NIEHS) has resulted in a network of 35 international scientists who gathered at this year’s International Meeting for Autism Research (IMFAR) to promote collaboration, identify gaps in our understanding and foster opportunities for innovative research which is discussed in more detail in Dr. Dawson’s 2010 IMFAR recap.  This fall, Autism Speaks and NIEHS will co-sponsor a workshop to help identify the most promising strategies and scientific directions for understanding the role of the environment in ASD.

A large collaborative study which will pull together data from six international registries is being funded by Autism Speaks to explore early environmental risk factors for ASD.

Autism Speaks is also leveraging longstanding investments to make the best use of research resources that currently exist. For example, the Autism Genetic Resource Exchange (AGRE), a premiere genetic resource for scientists studying autism, is now collecting environmental data from families to pair with the genetic and medical data. Autism Speaks has partnered with the National Institutes of Health to fund the the EARLI and IBIS research networks to study environmental factors in infants at risk for autism. The EARLI network is following 1200 mothers of children with autism from the start of another pregnancy through the baby sibling’s third birthday. The IBIS network is charting the course of brain development in infant siblings of children with autism. Together with Autism Speaks, these groups are exploring both genetic and environmental risk factors for ASD.

Taken together, Autism Speaks’ investment in research on environmental factors promises to shed light on an important area of autism research that has until recently remained in the shadows.  We look forwarding to following the new directions illuminated by the discoveries made possible by these various research opportunities.

As the emphasis on a role for environmental factors in autism continued to grow at this year’s International Meeting for Autism Research (IMFAR), so did the list of candidate environmental risk factors under study. Among the many factors discussed at the meeting were hazardous air pollutants, assisted reproductive technologies, medications given during pregnancy and childbirth, maternal infections, smoking, nutritional factors, maternal stress, and chemicals such as flame retardants.

Several studies presented by researchers at the latest International Meeting for Autism Research (IMFAR) suggested that a variety of environmental factors likely contribute to the risk of developing autism.  This year, as the emphasis on the role for environmental factors in autism continued to grow, so did the list of candidate environmental risk factors under study. Among the many factors discussed at the meeting were hazardous air pollutants, assisted reproductive technologies, medications given during pregnancy and childbirth, maternal infections, smoking, nutritional factors, maternal stress, and chemicals such as flame retardants.  Many of the projects were funded by Autism Speaks or Autism Speaks-funded researchers, including those leading the Early Autism Risk Longitudinal Investigation (EARLI) study the International Collaboration for Autism Registry Epidemiology.

Epidemiological data presented at IMFAR 2010 supported a link to autism for some environmental factors while ruling out a link for others.   Two of the exposures found to be associated with autism were gestational diabetes in pregnancy and medical interventions related to assisted reproductive technology, specifically ovulation induction or in vitro fertilization. Other exposures, such as smoking, prenatal stress, and hazardous air pollutants in Southern California were not found to be associated with an increased risk for autism or differences in autism severity.   Many of the findings presented by researchers were considered preliminary and will require replication with larger samples.

Not all risk factors will impact everyone equally, and researchers at the conference found that the effects of some early environmental exposures, such as maternal infection during pregnancy, were dependent on the particular individuals being exposed.  For example, maternal bacterial infection during pregnancy was more likely to increase risk for autism when the infant was born prematurely or have low birth weight infants.  Additional “high risk” groups may include children who spent time in neonatal care units as infants either due to low birth weight or gestational age.  Further research needs to be carried out to validate and extend these findings, helping to better identify particularly susceptible – or perhaps even protected – subgroups.  Moreover, although these epidemiological studies have found a link between these specific factors and autism risk, beyond replication of the data it will be important to address the biological mechanisms through which the candidate environmental factors are operating, including the role of genetic variation in vulnerability to specific environmental factors.  As one example, using samples available through Autism Speaks’ genetic data base, AGRE, researchers found variations in the sequences for genes related to the oxidative stress response.  These gene mutations may impact the ability of a person to metabolize toxins.

To hasten discovery of environmental risk factors through epidemiological studies, Autism Speaks partnered with the National Institute of Environmental Health Sciences to facilitate the creation of a network of over 35 researchers involved in a dozen studies that collect biosamples and other data related to gene / environment interactions in ASD. It is hoped that the establishment of a network of researchers with common goals, challenges and needs, will facilitate advances in this field through collaborative efforts that could provide larger data sets.  Researchers in the new network met together for the first time at this year’s IMFAR.  “We are thrilled to be partnering with the National Institute of Environmental Health Science to promote collaboration among epidemiologists studying environmental risk factors for autism,” commented Autism Speaks’ Chief Science Officer, Geri Dawson, Ph.D.   “We hope this new collaborative effort will help us identify strategies for accelerating research on environmental factors, what are the needed tools and gaps, and what are the most important questions we should be addressing.”  For more on this network, read Dr. Geri Dawson’s summary of IMFAR.

One specific environmental factor that was particularly highlighted among the IMFAR presentations this year was BDE-47, a chemical in the class of poly-brominated diphenyl ethers, or PBDEs, which are flame retardants used in plastics and consumer electronics.  Scientists reported that peripheral blood cells treated with BDE-47 show an increased production of a cytokine called IL-6, which has previously been linked to autism-like behaviors in mice.   Following up on this study, researchers from the same institution found behavioral deficits were induced by pre- and post- natal exposure to BDE-47, including spatial learning and perseverative behaviors.  Another study at the conference focused on the interaction between exposure to BDE-47 and certain genetic risk factors, finding that deficits caused by BDE-47 were more severe in the presence of a mutation that effected expression of MeCP2, the gene that causes Rett Syndrome, a neurodevelopmental disorder related to autism.  Finally, although an epidemiological study did not find increased levels of BDE-47 in children that had already been diagnosed with autism, a follow-up study using a prospective design to study “at-risk” infants is underway to determine possible critical windows of exposure during development.  Therefore, in the case of BDE-47, the neurobiological mechanisms of action are in the process of being identified.  However, further epidemiological research is needed to determine if this exposure is specifically associated with an outcome of autism.

While these findings are interesting, how do scientists convey important research findings related to risk for autism when there is still uncertainty regarding their meaning for individual families affected by autism?  This was the topic of a special IMFAR symposium this year titled “Ethics of Communicating Scientific Risk,” led by Craig Newschaffer, Ph.D. and Michael Yudell, Ph.D. from Drexel University.  Families rely on scientific research to establish the credibility and reliability of findings, and on advice from professionals regarding whether and how they should change their behavior to modify risk.   Discussions at the symposium centered around making sure to keep in mind the prevalence of the risk factor in the general population – how common it is – and whether the benefits of exposure outweigh the risks.   Because families primarily seek information from autism care providers, such experts should be receiving training on how to evaluate findings and communicate them effectively.  Overall, this symposium and the discussions to follow will provide a framework for scientists, clinicians, autism providers and the media to more effectively convey information in an ethical and responsible way.

Find more  information about the broad range of environmental exposures being studied through Autism Speaks support.

This post is from a Guest Blogger, Amy Kelly. Amy is a Community Outreach Liaison for the The EARLI Study in Philadelphia, PA., www.EARLIStudy.org

As a mother of three children, two boys, ages 6 and 9, and a daughter with severe autism who is 8 years old, I often wonder, how did it happen?  How did Annie get autism, and how did I beat the odds of 4:1 boys to girls that have autism and have two typical sons and a daughter who is nonverbal on the autism spectrum?  Interestingly enough my journey through autism (and ask ANY parent… it’s a journey all right) has led me to help the cause at a greater level than just my own daughter’s prognosis. I work as the Community Liaison/Outreach Coordinator for the Early Autism Risk Longitudinal Investigation (EARLI) Study.

The EARLI Study is a nationwide study that was launched last year in June 2009 across four sites in the U.S.:

1. Southeast Pennsylvania (with Drexel University and Children’s Hospital of Philadelphia)

2. Northeast Maryland (with Johns Hopkins University and Kennedy Krieger Institute)

3. Northern California (with Kaiser Permanente Northern California Division of Research)

4. Northern California (with University of California, Davis and the M.I.N.D. Institute)

Researchers are actively enrolling participants who live near the study sites. They are currently seeking 1200 women who already have a child with an autism spectrum diagnosis, and who are thinking of becoming pregnant, or who are less than 20 weeks into their pregnancy.

Both biological samples (such as blood and urine, samples from the umbilical cord, the placenta, and meconium of the new baby), and environmental samples and information (such as dust, medications, diet, medical history) will be collected. These samples and information will be analyzed to investigate:

(1) How environmental exposures during pregnancy and early life might play a role in the development of an Autism Spectrum Disorder

(2) How genetics may influence risk of Autism Spectrum Disorders – especially how genetic make-up might make certain children more vulnerable to environmental exposures

(3) Whether there are biological markers (for example, things we can easily measure in blood or urine) that will predict whether a baby eventually develops an Autism Spectrum Disorder

(4) How the behavior of newborn siblings of children with an Autism Spectrum Disorder changes over time and what behaviors might be early signs of an Autism Spectrum Disorder

Dr. Craig Newschaffer, a department chair at the Drexel University School of Public Health in Philadelphia, is the principal investigator for the study across all sites nationwide.  It is my hope that with the brilliant team of researchers and staff working on The EARLI Study, the incredible families that participate in the study, and a little bit of hope, we will one day find the causes for autism… and maybe answer my own personal question about Annie and her brothers.

For more on the EARLI study, see Early Autism Risk Longitudinal Investigation to Expand Epigenetic Studies at autismpeaks.org.

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.