Archive
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.
|
12:29
|
|
|
12:32
|
|
|
12:32
|
|
|
12:34
|
|
|
12:35
|
|
|
12:36
|
|
|
12:36
|
|
|
12:37
|
|
|
12:38
|
|
|
12:40
|
|
|
12:40
|
|
|
12:40
|
|
|
12:41
|
|
|
12:41
|
|
|
12:42
|
|
|
12:43
|
|
|
12:43
|
|
|
12:44
|
|
|
12:44
|
|
|
12:45
|
|
|
12:46
|
|
|
12:47
|
|
|
12:48
|
|
|
12:49
|
|
|
12:49
|
|
|
12:50
|
|
|
12:52
|
|
|
12:53
|
|
|
12:54
|
|
|
12:54
|
|
|
12:55
|
|
|
12:55
|
|
|
12:56
|
|
|
12:57
|
|
|
12:58
|
|
|
12:59
|
|
|
1:00
|
|
|
1:03
|
|
|
1:04
|
|
|
1:05
|
|
|
1:05
|
|
|
1:06
|
|
|
1:07
|
|
|
1:09
|
|
|
1:10
|
|
|
1:10
|
|
|
1:12
|
|
|
1:14
|
|
|
1:15
|
|
|
1:16
|
|
|
1:17
|
|
|
1:18
|
|
|
1:19
|
|
|
1:19
|
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?
|
|
1:20
|
|
|
1:21
|
|
|
1:22
|
|
|
1:22
|
|
|
1:24
|
|
|
1:25
|
|
|
1:26
|
|
|
1:27
|
|
|
1:29
|
|
|
1:29
|
|
|
1:31
|
|
|
1:32
|
|
|
1:34
|
|
|
1:34
|
|
|
1:37
|
|
|
1:38
|
|
|
1:38
|
|
|
1:39
|
|
|
1:43
|
|
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.
Gene expression in the brain reveals surprising similarities and differences
Autism is a very heterogeneous disorder. As the grand lady of neurology, Dr. Isabelle Rapin liked to emphasize when training new students “If you have seen one child with autism, you have seen one child with autism.” This heterogeneity has made understanding causes and designing effective treatments more challenging than it would be otherwise.
However, a new study published this week in Nature and supported by Autism Speaks’ Autism Tissue Program and Autism Genome Project reveals that the heterogeneity may not be as problematic as it initially seems. Differences in common molecular pathways appear to underlie the pathology in the brains of individuals with ASD.
Daniel Geschwind, M.D., Ph.D. (UCLA) launched an ambitious study to examine not just the variants of genes that may confer risk for autism, but the interaction with those genes and proteins working to support brain function. Looking for patterns of interaction in the brain, Dr. Geschwind and his colleagues sought to characterize the transcriptome – the set of fragments of instructions, called RNA, read from the gene DNA on the path to making functional proteins. Importantly, unlike the gene DNA that is relatively fixed for an individual’s life, the RNA transcriptome is modified through experience and interaction with the environment.
The authors analyzed patterns of expression of RNA for three areas of the post-mortem brain tissue from individuals with ASD or typically-developing individuals. Two areas of the late-developing cerebral cortex (prefrontal cortex and the superior temporal gyrus) and a region of the cerbellum known as the vermis were compared between the autism and typically developed brain tissue. The first big surprise was that although the cortex transcriptome revealed over 400 different genes with different expression between the autism and typical brain tissue samples, the similar comparison in the cerebellar transcriptome revealed exactly two differently expressed genes. Whatever differences exist in the brains of individuals with autism, these differences are greatest in the instructions that guide the structure and function of the cerebral cortex.
This, however, was just the beginning of what the research team found. Imagine the cerebral cortex of brain is like a bustling metropolis – one part of the city develops into a residential area and the other becomes a business district. Both neighborhoods have very distinctive features that make them unique due in part to the time and manner in which they developed and the people who inhabit them. So too for different regions of the typically-developing cerebral cortex. Different regions of the cortex develop at different times and with different inputs from the environment. The prefrontal cortex is one of the late-developing regions in the infant brain. Different regions also serve different functions, like integrating information from sight, sound and touch in the case of the superior temporal gyrus, and higher cognitive functions in the prefrontal cortex.
Importantly for Dr. Geschwind and his colleagues, these two cortical regions also have their own unique pattern of expression in brains from typically developed individuals. However, when looking for these unique signatures, the research team instead found surprisingly similar patterns of gene expression across the two regions in the brains of people with autism. Referring back to the metropolis analogy, in the autism brain samples, the residential and business districts are more alike than they ought to be.
There were also differences in expression of two gene networks between the autism and control brain samples. The first network of genes encodes synaptic function. This is reassuring because most of the autism risk genes identified through previous studies focused on synaptic function. The second network of differential gene expression was related to immune function and inflammation. This too harkens back to previous studies showing inflammation and immune system activation in the brains of individuals with autism. This gene network does not correlate with the results of large gene association studies like the synaptic network, indicating that secondary or environmental effects are involved in stimulating the observed inflammatory markers.
“This is the first study to show differences in the patterns of gene expression between brain regions, said Rob Ring, Ph.D., Autism Speaks vice president for translational research. “It’s those patterns of gene expression that enable the brain to function normally and to communicate properly with other regions of the brain.”
Taken together, these results have quite an impact on how we understand autism. The similarity of gene expression across different regions of cerebral cortex in the brains of individuals with autism tells us that we should look closely at very early brain development as these patterns in cerebral cortex emerge. The same goes for the network of synaptic genes that are differentially regulated in individuals with autism. However, the differences observed in immune and inflammation gene networks are more likely to be related to secondary or environmental effects. We must follow all the leads this research has provided if we are to make the next steps in developing supportive treatments and therapies for those living with autism spectrum disorders today.
The Emerging Neuroscience of Autism: an Opportunity to Learn and to Share
Autism is a complex disorder. Answers will be found by taking multi-disciplinary approaches. A broad vision of autism spectrum disorder (ASD) considers how the brain develops and affects cognition, what treatments work for core symptoms, and how ASD changes over the lifespan. However, opportunities for scientists to appreciate the broad vision and diversity of approaches are unfortunately few.
This year a special 2-day conference on autism was held prior to the annual Society for Neuroscience meeting in San Diego, giving scientists an opportunity to focus on ASD and share ideas. The conference, called The Emerging Neuroscience of Autism Spectrum Disorders: Etiologic Insights; Treatment Opportunities, offered an overview of current autism research from many of the world’s leading autism researchers.
There were two strong themes in the meeting. The first was that autism research has historically studied different groups of children at specific time points. This kind of study is known as cross-sectional research. There has been comparatively little research on how children change over time, known as longitudinal research. Given that ASD is a developmental disorder which changes over the lifespan, more longitudinal research is needed. The second theme highlighted what we can learn from the incredible diversity of symptom and subtypes of ASD. Future ASD research demands a greater focus on individual differences instead of the common comparisons between averages derived from groups of individuals with ASD and typically-developed individuals.
Biological mechanisms
The first session of the meeting included a review of what is known about autism risk genes. Steve Scherer, M.D. (University of Toronto) described how small variations in the number of copies of a piece of genetic code (copy number variations, CNVs) can be risk factors for ASD. These CNVs may be inherited or occur for the first time in the individual with ASD (de novo). Similar CNVs have also been identified in ADHD, schizophrenia and bipolar disorder, suggesting that there may be some common pathways underlying related developmental and psychiatric disorders. The incredible advances in genetic research, in no small part from Dr. Scherer and the Autism Genome Project, enable scientists to explore how these genetic variations affect brain development in animal models and provide clues into the underlying biology of ASD.
Declan Murphy, M.D. (Institute of Psychiatry, UK) impressed the audience with his proposal that brain imaging could be used to assist future clinicians in the diagnosis of ASD. The high costs of diagnosing individuals with ASD in Dr. Murphy’s South London community clinic motivated him to explore new methods. He used statistical methods combined with functional brain imaging to identify brain networks that may be different in adults with ASD. The use of brain scans may one day make the diagnosing ASD cheaper, quicker and potentially more accurate.
Cognition and new treatments
Day 2 of the meeting shifted focus away from biology to cognitive development and the evaluation of behavioral interventions. Tony Charman, Ph.D., (Institute of Education, London) described his study of cognitive strengths and weaknesses in a large sample of children with ASD. He argued for the importance of understanding the unique pattern of cognitive skills found in ASD to guide neuroimaging research and developing assessments of skills for early intervention programs. Dr. Charman also identified challenges in this area of research, noting that the field must address issues, such as small sample sizes and reliance on group comparisons if we are to progress.
Cathy Lord, Ph.D., (University of Michigan) showed longitudinal data collected using the Autism Diagnostic Observation Schedule (ADOS)—a tool to identify and quantify features of ASD. Her data revealed individual differences in the development of particular skills, such as eye contact, and joint attention skills, even though overall ADOS scores remain mostly constant. Language IQ remains an important predictor of children’s expected progress. Perhaps in the future, the ADOS diagnostic tool can also be used to monitor the long-term benefits of interventions.
The final two sessions focused on interventions. Fred Frankel, Ph.D. (UCLA) presented data from new interventions in friendship training. Judith Reaven, Ph.D., (University of Colorado School of Medicine) showed her data on cognitive behavioral therapy for anxiety in ASD. Aubyn Stahmer, Ph.D., (Rady Children’s Hospital, San Diego) evaluated the use of an integrated intervention model in community settings. Sally Rogers, Ph.D. (MIND Institute) concluded this session with a summary of the challenges in developing good outcome measures for intervention studies.
The last session summarized the evidence behind pharmacological treatments for ASD. One of the real challenges for behavioral pharmacologists is how to identify drug treatments for core social and communication skills. Currently only two drugs are approved for treating irritability in ASD. Several other drug treatments have been tested in clinical trials with minimal or no evidence for their effectiveness. Individual differences and variation in symptoms over time make finding treatments for the core symptoms of ASD like trying to hit a moving target.
Putting it all together
David Amaral, Ph.D. of the MIND Institute and current president of the International Society for Autism Research, summarized the meeting by focusing on autism research ‘Promises and Pitfalls’. On the positive side, he noted a dramatic rise in research, supported by increases in public and private funding, such as the major contribution by Autism Speaks. As for pitfalls, Dr. Amaral underscored the significant variability among individuals with autism that must be recognized if research results are to be meaningful. He also encouraged the continuation of brain research across the lifespan acknowledging age-related changes in brain development and behavior over time.
Progress in the field of brain research will require an on-going partnership among people with autism, families and researchers. We are both optimistic about progress and impatient to find answers. We all look forward to IMFAR 2011 in May when autism researchers return to San Diego with a broader perspective and new insights.
What is mitochondrial disease? How often does it occur in individuals with ASD? Are their effective treatments?
“Got Questions?” is a new weekly feature on our blog to address the desire for scientific understanding in our community. We received over 3000 responses when we asked what science questions were on your mind. We answered a few here and the Autism Speaks Science staff will address the other themes we received in this weekly post.
Mitochondrial disease is caused by an error in the functioning of mitochondria, which are essential energy-producing compartments of nearly every cell in the body. Certain mutations can cause the mitochondria to function inefficiently. These mutations can be within the mitochondria itself, with its own small circle of DNA, or within the nucleus where the rest of the cell’s DNA resides. Over 1500 genes carry some part of the recipe for the optimal functioning of mitochondria. This means that there are many ways for mitochondria to function imperfectly but there are also complex means available to mask a deficit by altering some of the other protein interactions.
Mitochondria are responsible for the process of oxidative phosphorylation that turns nutrients into energy through a series of stages involving complexes of enzymes. A break at any particular stage results in an atypical balance of metabolites in affected body tissues and fluids.
Most people consider mitochondrial disease to be one of a growing number of disorders caused by a defined set of mutations and presenting with a set of characteristics that typically involve three or more organ systems. However, mitochondrial disorders are often diagnosed when no mutation is found despite observations of metabolic signatures of mitochondrial dysfunction. The symptoms may also be more mild.
We do not have a firm estimate of mitochondrial disease in ASD. However, if we use the broader definition of mitochondrial disorder then according to a population-based study in Portugal, there may be as many as 4% of the ASD population affected. Autism Speaks’ research is addressing this and related questions through a grant to Cecilia Giulivi, Ph.D. at UC Davis and also through a collaborative research project at UC Irvine and UC San Diego.
There is currently no cure for mitochondrial disease or disorder. There are, however, treatments and practices that can improve the quality of life and slow the progression of the disease. The most effective treatments are for specific symptoms that tend to accompany mitochondrial dysfunction such as seizures treated with anti-convulsants. Regular exercise, a healthy diet, stress and extreme temperature avoidance are among the common recommendations. Some dietary and supplement regimes have anecdotal support but there is a need for empirical studies to test the efficacy of these therapies.
For more information, please visit the United Mitochondrial Disease Foundation (UMDF) website. Also, read our report on a joint Autism Speaks’ supported symposium at the annual UMDF meeting.
The Next Big Thing?
This post is from Guest Blogger, Stanley Nelson, M.D. Dr. Nelson is the Director for the UCLA Site of the NIH Neuroscience Microarray Consortium, and Professor of Human Genetics and Psychiatry at the David Geffen School of Medicine at UCLA. Dr. Nelson was also a co-author on last week’s collaborative Nature paper.
Investments in the genetics of autism have been substantial and the results are beginning to come forth, with last week’s announcement of the latest findings from our collaborative Autism Genome Project adding to previously identified genes and copy number variations that made last year’s Top 10 Autism Research Achievements of 2009. The latest results, funded in large part by the tremendous efforts of Autism Speaks, are interesting alone, and I hope that all have learned that there are indeed novel genes being identified that lead to autism. However, there is a perhaps more important message from the paper which relates directly to the couple hundred thousand families directly affected by an autism spectrum disorder in the US alone.
Within the recent Nature paper are compelling new findings demonstrating that autism can be caused by genetic mutations in a wide range of different genes, but the findings highlight how complex the genetic causes will be, likely in the hundreds. With this level of complexity, it is also clear that this sized sample that took 15-20 years to collect at the cost of tens of millions of dollars including molecular testing and analytical effort, we were only able to find genetic causes for a small minority of the children with autism (a few percent). So detecting the meaningful gene variants is largely a game of statistics. With the relatively small size of the autism samples available to us today, many gene mutations that may be causative in an individual with autism will go ‘undetected’ because our sample size lacks the statistical power to identify them as definitively associated with autism. This is because these causative variants are each “rare” in the whole autism population. Even though rare, each gene variant that confers risk is important. Why? When considered together, these gene variants will collectively explain the majority of cases of the disorder, as well as inform us greatly about the still largely unresolved biological causes, both genetic and environmental. To get us to the next phase of understanding the genetic risk of autism, we need a way to cost-effectively recruit tens of thousands of affected individuals and their families to enable the appropriate large scale genetic studies needed to address this pressing scientific need. My attitude is well described in an interview written by Nancy Shute at US News and World Report.
Until recently, we have not had a nationwide infrastructure that could allow anyone in the US to participate with a child with a diagnosis of autism. That has changed with the initiation of the IAN Genetics Project, funded by Autism Speaks through the High Risk, High Impact Initiative. Using the web portal of the IAN Genetics Project, families provide information about their child through simple web-based questionnaires that require only a few hours effort from home, anytime. Families also give consent for the DNA collection portion of study online. Interested families may participate in this study by taking their child to one of 1,600 blood draw sites nationwide with our corporate partner, Labcorp. This is all made possible through the Interactive Autism Network, and more information can be found at IANPROJECT.ORG, where I encourage all families with an affected child to register and complete the requested questionnaires. For those interested in learning more about the DNA Study, specific information can be found by following this link. Any questions about the project can be answered by IAN staff, who can be reached through the link.
Please register at IANPROJECT.ORG, even if not interested in the DNA Study. Simply filling out the online forms provides powerful new data to researchers that can only come from many thousands of individual families taking the time to help solve the complex issues of autism beyond genetics alone. Together we can take this next step to help reveal the causes of autism and help alleviate the struggles of those living with autism today.
5|25: Celebrating Five Years of Autism Science Day 13: AGP Releases First Results
In honor of the anniversary of Autism Speaks’ founding on Feb 25, for the next 25 days we will be sharing stories about the many significant scientific advances that have occurred during our first five years together. Our 13th item, AGP Releases First Results, is from Autism Speaks’ Top 10 Autism Research Events of 2007.
