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Piecing Together the Genetic Puzzle of Autism

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One of the privileges I have had as director of the National Institute of Mental Health is chairing the Interagency Autism Coordinating Committee (IACC). The IACC, charged with coordinating activities across multiple federal agencies with regards to research, services, and policy around autism spectrum disorder (ASD), comprises federal and private partners. Particularly valuable are the contributions from members of the committee who have lived experience with ASD. We also hear regularly from members of the public, most of whom have ASD or care for someone with ASD. They all speak eloquently about the challenges associated with this developmental disorder of social cognition and behavior. Their experiences inspire our research portfolio aimed at supporting and enhancing the lives of individuals with ASD.

Fundamental to this effort are long-term investments in understanding the origins of ASD in early development, and central to developing such an understanding is deciphering the disorder’s genetic basis. Last month, I wrote about schizophrenia, a mental disorder that has a significant genetic component. I wrote about large-scale, NIMH-supported research efforts that are using techniques such as gene mapping and whole-exome sequencing to better understand the genetic component of schizophrenia. And I wrote about how these studies have demonstrated that it’s likely a combination of many small-effect-size genetic variants and a handful of large-effect-size genetic variants that increase a person’s chances of developing schizophrenia. These genetic findings offer crucial clues that can help unravel the neurobiology of the disorder and lead to novel treatments.

The story of the genetics of ASD is just as compelling and rapidly evolving. For some time, studies have suggested that large-effect-size genetic variants may play an influential role in autism. A new study, published this February and highlighted in the NIH Director’s Blog and popular press articles, extends these early findings. Using whole-exome sequencing, the research team — which included the NIH-funded Autism Sequencing Consortium — examined data from nearly 12,000 individuals with ASD and more than 23,000 individuals without ASD. The findings revealed 102 genes linked to the disorder, the result of rare mutations that aggregate in these genes. As I discussed in my previous message on schizophrenia genetics, identifying these genetic variants means that the pathway to investigating biological mechanisms and potential clinical targets is (relatively) straightforward.

Having made these genetic discoveries, the researchers proceeded to explore some fundamental questions about ASD. One major question in the field has been whether the neurobiological mechanisms underlying ASD differ depending on whether an individual also has an intellectual disability or other developmental delay. In this study, the researchers found that although many of the 102 genes are implicated in both ASD and other neurodevelopmental disorders, approximately half of the genes are altered more frequently in individuals with ASD who do not have a co-occurring developmental delay. These findings suggest that there may be a set of biological mechanisms underlying the characteristic social and behavioral features of ASD that are separate from, and in addition to, a set of mechanisms that underlies more general brain development.

Another fundamental question is why ASD is more frequently diagnosed in boys than in girls. One hypothesis is that unknown biological mechanisms may make girls more resilient to autism risk factors. In this study, the researchers found that the genetic variants they had identified were more than twice as frequent among girls with ASD than among boys with ASD. These data fit with the hypothesis that girls are more likely to have certain biological resilience factors and, as a result, it may take a greater burden of genetic risk for girls to receive an ASD diagnosis.

To learn more about the biology of ASD, the researchers also took a close look at what the ASD-associated genes do in the brain, and when and where in the brain they do it. Prior studies had suggested that genes linked with autism may play a role in the early development of the cortex, the outer layer of the brain that is critical to many important functions, including attention, thought, memory, and language. Having identified a much broader set of ASD-associated genes, the authors of this new study were able to make some interesting new observations. First, they confirmed that the vast majority of the 102 genes are expressed in the cortex, early in development. But they also found differences depending on whether the genes were primarily associated with ASD or with broader neurodevelopmental delay: genes associated with ASD were likely to be expressed in the developing brain soon after birth, while those associated with neurodevelopmental delay tended to be expressed even earlier, before birth.

The researchers also found that most of the 102 ASD-associated genes could be categorized as belonging to one of two broad mechanistic families: genes that play a role in turning other genes on and off and genes that are involved in synapses and other forms of neuronal communication. And finally, they found that these genes tended to be expressed in neurons belonging to both major classes of neuron types: excitatory and inhibitory neurons.

These exciting findings begin to write the story of the complex causal web that leads from genes to autism. The story seems to begin early in brain development. It involves the regulation of development through gene expression and the establishment of connections between neurons. And it culminates in different observable features (which we categorize as ASD or other neurodevelopmental delays) depending upon the genes involved. This is genuine progress, though there is much work left to be done. For starters, the authors point out that the type of rare variation they examined in these 102 genes explains only a small fraction of the variation in outcomes in the population.

We need to continue to work on understanding the myriad factors, genetic and environmental, that play a causal role in autism. And most importantly, we need to take this growing knowledge base and translate it into better treatments to improve the lives of individuals and families living with ASD.


Satterstrom, F. K., Kosmicki, J. A., Wang, J., Breen, M. S., De Rubeis, S., An, J.-Y., Peng, M., Collins, R., Grove, J., Klei, L., Stevens, C., Reichert, J., Mulhern, M. S., Artomov, M., Gerges, S., Sheppard, B., Xu, X., Bhaduri, A., Norman, U.,…Buxbaum, J. D. (2020). Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell, 180(3), 568-584.e23. doi:10.1016/j.cell.2019.12.036