Understanding how the brain develops and functions remains among the most difficult of scientific challenges, as is the effort to understand the causes of conditions that alter its function. Among these is autism spectrum disorder (ASD). ASD is described as a spectrum because of the considerable variation in how individuals manifest both symptoms and severity. The core symptoms of ASD, including difficulty in social communication and restricted, often repetitive behaviors, are present in all those affected, but otherwise, there is wide variability in ASD. At the more severe end of the spectrum are individuals who need services as a result of co-occurring intellectual disability or minimal verbal ability, for example. At the other end are individuals with average or superior intellectual ability who can achieve considerable professional and personal success. And in between are the majority of children and adults living with a combination of social, intellectual, and behavioral challenges they and their families face on a daily basis.
Identifying the causes of ASD has proven to be a significant challenge. And while there are several available behavioral treatments that can benefit many if not all of those diagnosed with ASD, much remains to be done in terms of both making helpful treatments more widely available and discovering novel therapies that have the potential to dramatically enhance quality of life. In honor of Autism Awareness Month, I am writing two Director’s Messages about ASD in April. The first, below, explains what we know so far about what causes ASD, and what NIMH researchers are doing to clarify how these causes lead to symptoms. The second, to follow in a few weeks, will discuss currently available therapies for ASD, and NIMH research aimed at learning how to improve access to these therapies.
For some time, we have known that ASD is a heritable condition—that is, it runs in families. We know this from a variety of studies—including twin studies, which demonstrate that if one identical twin has ASD, the other twin almost always does also. Indeed, studies suggest that up to 90 percent of the variation in developing ASD is due to genetic factors.1 Nonetheless, as with all complex genetic conditions, environment also plays a role.
Gene mutations that raise the risk for ASD come in two basic types—common variants with small effects, and rare variants with large effects. Common variants are, well, common. Many people in the population carry these and most of them do not have ASD. However, each of these genetic variants raises the risk for developing ASD very slightly—often by as little as 5 percent, meaning that if you have any one of these variants, your risk of ASD is 1.05 times that of someone who doesn't carry it. We know from family and population studies that common variation explains a large portion of risk for ASD. Identifying the genes in which common variants play a role in ASD is difficult, however, and we have very few as yet. Ultimately, common variants can (and do, see below) give us clues about the biology underlying ASD. Even then, however, any single common variant can’t really predict with any great certainty whether an individual will develop ASD. Rare variants are bigger deals—they can confer significant risk on their own for ASD. For some of these variants, carriers are 30-50 times more likely to develop ASD than non-carriers.
Understanding how these genetic variants lead to ASD may help us understand particular features of risk. For example, we’ve known for a while that a child of older parents (mothers older than 35 or fathers older than 40) seem to be at higher risk for developing ASD.4 At least part of this increased risk appears to be due to the fact that new mutations—especially mutations that disrupt the function of genes—are found more often in the sperm of older men.5 Scientists have also found that girls with ASD have more frequent and more damaging mutations than boys, suggesting that girls are more resilient and boys more susceptible to ASD-related genetic variation, an insight that may help clarify why ASD is diagnosed much more often in boys. Finally, genetic factors that increase risk for ASD also influence normal differences in cognitive, social, and communication abilities in individuals in the general population, suggesting that these factors are important for normal development as well as for explaining ASD.
Current research is focused on the two-fold goal of identifying additional causal factors, as well as exploiting those we already know about to understand the biology of ASD. Identifying additional causal factors requires that investigators examine large datasets with sophisticated “big data” techniques. To facilitate such efforts, NIMH supports several databases and consortia, including the National Database for Autism Research (NDAR), the Autism Brain Imaging Data Exchange (ABIDE), the Biomarkers Consortium, and the NeuroBioBank/Autism BrainNet partnership.
On the biological mechanism front, NIMH supports research using a range of advanced technologies to understand the impact of risk factors on the brain. For example, scientists are using a technique by which they can use skin cells from patients to create neurons and grow them in a dish. Using these neurons, they can explore how genetic variants associated with ASD alter neuronal function.16, 17, 18 Other researchers are engineering mice to carry ASD risk genes to test the behavioral effects of these mutations, and to search for treatments that reverse these effects.19 While findings from animals need to be interpreted with caution, they can provide clues as to possible treatments.
In terms of research time frames, genetic research is in the category of work that will pay off in the long-term. These insights will help provide the basis for mitigating the factors that cause impairment in ASD early in childhood, when behavioral interventions are more likely to be beneficial. Research is also underway aimed at providing benefits in the short term: new ways of identifying and treating children early, and providing services as they mature. That will be the subject of the next message.
10 Varcin KJ and Jeste SS. The emergence of autism spectrum disorder: insights gained from studies of brain and behaviour in high-risk infants. Curr. Opin. Psychiatry. 2017 Mar;30(2):85-91. PMID: 28009726.