- Is there something in my genetic or family history that poses a risk for ASD?
- How might genetics and/or the environment influence the occurrence of ASD?
- Could an exposure to something in the environment lead to the development of ASD?
What do we know?
As with many complex disorders, causation is generally thought to involve some forms of genetic risk interacting with some forms of non-genetic environmental exposure. The balance of genetic risk and environmental exposure likely varies across the spectrum of ASD.
The greatly increased concordance of strictly defined autism in monozygotic (identical) twins (70 - 90%) compared to dizygotic (fraternal) twins (0-10%) argues for the importance of genetic factors (Bailey et al., 1995; Steffenburg et al., 1989). Moreover, there are subpopulations of those diagnosed with ASD that have a known genetic mutation, often associated with a genetic disorder, such as Fragile X syndrome, Rett syndrome, or tuberous sclerosis. Using new technology that reveals gaps and extra copies in DNA sequences, researchers have found that some people with ASD have deletions and duplications of genetic material not found in their parents' DNA (Sebat et al., 2007). Recent research has revealed additional mutations of specific genomic regions (15q21 and 16p11) (Marshall et al., 2008; Weiss et al., 2008). These findings have contributed to new hypotheses about the inheritance of ASD. In families with just one affected member, spontaneous deletions and duplications may be causal factors of ASD. However, what causes these spontaneous deletions and duplications is not clear and could be due to environmental exposures.
Taken together, these genetic structural abnormalities account for 10-20% of ASD cases, yet individually each abnormality accounts for only 1-2% of cases (Abrahams & Geschwind, 2008). This suggests that the genetic factors in ASD may involve many rare mutations. Possible models include: (a) additional genetic mutations to be discovered; (b) multiple genetic variations each conferring a small increased risk; and, (c) many forms of ASD with different genetic contributions.
Progress in identifying susceptibility genes has been made possible due to collaborations and resources, both public and private, including: the National Institute of Mental Health (NIMH) Center for Collaborative Genetic Studies; the Collaborative Programs of Excellence in Autism (CPEA) co-sponsored by NICHD and the National Institute on Deafness and Other Communication Disorders (NIDCD); the National Institute of Environmental Health Sciences (NIEHS) Childhood Autism Risks from Genetics and the Environment (CHARGE) study; the Autism Genetic Resource Exchange (AGRE) sponsored by Cure Autism Now (CAN) with a large consortium of researchers assembled by Autism Speaks/National Alliance for Autism Research; CDC's Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE); the Norwegian cohort study supported by the National Institute of Neurological Disorders and Stroke (NINDS); and the Simons Foundation Collection. In addition, existing research resources in toxicology could be tapped to provide important infrastructure for studying some forms of environmental risk.
Research on environmental risk factors is also underway. An Institute of Medicine workshop held in 2007 summarized what is known and what is needed in this field (Institute of Medicine of the National Academies, 2007). Numerous epidemiological studies have found no relationship between ASD and vaccines containing the mercury based preservative, thimerosal (Immunization Safety Review Committee, 2004). These data, as well as subsequent research, indicate that the link between autism and vaccines is unsupported by the research literature. Some do not agree and remain concerned that ASD is linked or caused by vaccination through exposure to Measles Mumps Rubella (MMR), imposing challenges to a weakened immune system, or possibly due to mitochondrial disorder. Public comment to the Committee reflected opposing views on vaccines as a potential environmental cause. Those who are convinced by current data that vaccines do not play a causal role in autism argue against using a large proportion of limited autism research funding toward vaccine studies when many other scientific avenues remain to be explored. At the same time, those who believe that prior studies of the possible role of vaccines in ASD have been insufficient argue that investigation of a possible vaccine/ASD link should be a high priority for research (e.g., a large-scale study comparing vaccinated and unvaccinated groups). A third view urges shifting focus away from vaccines and onto much-needed attention toward the development of effective treatments, services and supports for those with ASD.
In addition, a number of other environmental agents are being explored through research that are known or suspected to influence early development of the brain and nervous system. Recent studies suggest factors such as parental age, exposure to infections, toxins, and other biological agents may confer environmental risk. These findings require further investigation and testing, some of which is ongoing through the CADDRE Program, the Norwegian cohort study, the CHARGE study, and the Children's Centers for Environmental Health and Disease Prevention supported by NIEHS and the Environmental Protection Agency (EPA).
What do we need?
Although most scientists believe that risk factors for ASD are both genetic and environmental, there is considerable debate about whether potential environmental causes, genetic precursors, or interactions between genes and environmental factors should be the highest priority for research aimed at identifying the causes of ASD. To date, few studies have ruled in or ruled out specific environmental factors. While there are reports of associations of ASD with exposure to medications or toxicants prenatally, and to infections after birth, it is still not known whether any specific factor is necessary or sufficient to cause ASD. Similar to other disease areas, advancing research on the potential role of environmental factors requires resources and the attraction of scientific expertise. Bringing this to bear on autism will help focus the environmental factors to study, as well as the best approach for staging studies to examine environmental factors, interaction between factors, and between individual susceptibility and various environmental factors. For example, some researchers believe that it is important to study a large number of exposures, or classes of exposure, that are known to affect brain development. Others support more tightly focused studies of one exposure or a limited number of exposures, with greatest biologic plausibility for interacting with known or suspected biologic or genetic ASD risk factors. In addition, it is also important to design studies that assess environmental exposure during the most relevant exposure windows: pregnancy and early development. In doing this research, it will be important for the field to develop sound standards for identifying and claiming that environmental factors contribute to ASD, as it would be for genetics.
To address public concerns regarding a possible vaccine/ASD link, it will be important over the next year for the IACC to engage the National Vaccine Advisory Committee (NVAC) in mutually informative dialogues. The NVAC is a Federal advisory committee chartered to advise and make recommendations regarding the National Vaccine Program. Communication between the IACC and NVAC will permit each group to be informed by the expertise of the other, enhance coordination and foster more effective use of research resources on topics of mutual interest. Examples of such topics include: studies of the possible role of vaccines, vaccine components, and multiple vaccine administration in ASD causation and severity through a variety of approaches; and assessing the feasibility and design of an epidemiological study to determine whether health outcomes, including ASD, differ among populations with vaccinated, unvaccinated, and alternatively vaccinated groups.
Research studies on risk factors can be pursued through several means. Smaller, focused studies are needed for hypothesis testing and to provide insight for replication studies. Similar to other health outcomes research for relatively rare conditions, case-control studies can be an effective first line of inquiry. The CHARGE and CADDRE (SEED) studies are good examples of this approach where environmental exposures and biological pathways, along with genetics, are being examined. Other existing cohorts could also be identified and used.
Another approach for studying risk factors for ASD requires large sample sizes to disentangle the many possible genetic and environmental factors that contribute to and help explain ASD and the frequently co-occurring conditions. For other complex disorders, large DNA collections, i.e. >20,000 samples, have been necessary to detect the full genetic risk architecture. There are no genetic repositories of this size for ASD. Similarly, large birth cohort studies in which biological samples have been collected throughout pregnancy and early postnatal life may be essential for detecting the interplay of environmental exposures and genetic factors that lead to ASD. As a complement to these large-scale studies, research on critical sub-populations that may be at higher risk could provide leverage in identifying genetic and environmental risk factors.
Aspirational Goal: Causes of ASD will be Discovered that Inform Prognosis and Treatments and Lead to Prevention/Preemption of the Challenges and Disabilities Of ASD
- Genomic variations in ASD and the symptom profiles associated with these variations.
- Environmental influences in ASD and the symptom profiles associated with these influences.
- Family studies of the broader autism phenotype that can inform and define the heritability of ASD.
- Studies in simplex families that inform and define de novo gene differences and the role of the environment in inducing these differences.
- Standardized methods for collecting and storing biospecimen resources from well-characterized people with ASD as well as a comparison group for use in biologic, environmental and genetic studies of ASD.
- Case-control studies of unique subpopulations of people with ASD that identify novel risk factors.
- Monitor the scientific literature regarding possible associations of vaccines and other environmental factors (e.g., ultrasound, pesticides, pollutants) with ASD to identify emerging opportunities for research and indicated studies.
- Environmental and biological risk factors during pre- and early post-natal development in "at risk" samples.
- Cross-disciplinary collaborative efforts to identify and analyze biological mechanisms that underlie the interplay of genetic and environmental factors relevant to the risk and development of ASD, including co-occurring conditions.
- Convene ASD researchers on a regular basis to develop strategies and approaches for understanding gene - environment interactions.
- Exposure assessment — efficient and accurate measures of key exposures for use in population and clinic based studies and standards for sample collection, storage, and analysis of biological materials.
- Initiate studies on at least five environmental factors identified in the recommendations from the 2007 IOM report "Autism and the Environment: Challenges and Opportunities for Research" as potential causes of ASD by 2010. IACC Recommended Budget: $23,600,000 over 2 years.
- Coordinate and implement the inclusion of approximately 20,000 subjects for genome-wide association studies, as well as a sample of 1,200 for sequencing studies to examine more than 50 candidate genes by 2011. IACC Recommended Budget: $43,700,000 over 4 years.
- Within the highest priority categories of exposures for ASD, identify and standardize at least three measures for identifying markers of environmental exposure in biospecimens by 2011. IACC Recommended Budget: $3,500,000 over 3 years.
- Initiate efforts to expand existing large case-control and other studies to enhance capabilities for targeted gene - environment research by 2011. IACC Recommended Budget: $27,800,000 over 5 years.
- Enhance existing case-control studies to enroll broad ethnically diverse populations affected by ASD by 2011. IACC Recommended Budget: $3,300,000 over 5 years.
- Determine the effect of at least five environmental factors on the risk for subtypes of ASD in the pre- and early postnatal period of development by 2015. IACC Recommended Budget: $25,100,000 over 7 years.
- Conduct a multi-site study of the subsequent pregnancies of 1,000 women with a child with ASD to assess the impact of environmental factors in a period most relevant to the progression of ASD by 2014. IACC Recommended Budget: $11,100,000 over 5 years.
- Identify genetic risk factors in at least 50% of people with ASD by 2014. IACC Recommended Budget: $33,900,000 over 6 years.
- Support ancillary studies within one or more large-scale, population-based surveillance and epidemiological studies, including U.S. populations, to collect nested, case-control data on environmental factors during preconception, and during prenatal and early postnatal development, as well as genetic data, that could be pooled (as needed), to analyze targets for potential gene/environment interactions by 2015. IACC Recommended Budget: $44,400,000 over 5 years.