The largest genetic study of autism spectrum disorder (ASD) to date has identified 65 genes that contribute to autism, including 28 for which there is "very high confidence" that they play a role in the risk of developing ASD, a multicenter US research team reports.
Twenty-seven of these genes are new discoveries, first author Stephan Sanders, PhD, of the University of California, San Francisco, told Medscape Medical News.
The study also confirms that there are six larger regions of the genome that are prone to de novo copy number variants (dnCNVs) that contribute to autism risk. The study also hints that small deletion dnCNVs "often have a single critical gene," Dr Sanders added.
"Autism is largely a genetic disorder, so it follows that finding the genes involved in autism is a logical first step to understanding the biology of autism," Dr Sanders said. "The discovery of 65 autism risk genes and six risk regions serves as a foundation for understanding the neurobiology of autism. By considering when, where, and how these genes interact, we can focus on the developmental time period, brain region, and cell type that is disrupted in autism," he said.
The findings were published online September 23 in Neuron.
Clues to Sex Disparity
The ASD-associated genes fall into two main functional categories, one related to the development and function of synapses, and the other involving chromatin. The relationship between these two broad categories is a "key question in autism research," Dr Sanders notes in a news release.
"They may be two separate biological paths to the disorder or two sides of the same coin, with the chromatin-related genes identified in this study regulating the expression of those that drive synapse formation and function, or vice versa," he said.
The study also provides clues to the well-documented sex disparity in ASD, with diagnoses three to four times more common in boys than girls. "One mechanism for this sex bias is that females are protected against autism risk, and we find strong evidence to support this hypothesis," Dr Sanders said.
Specifically, the analysis finds that the same genetic risk factors lead to ASD in both boys and girls, although girls with ASD have a much greater number of dnCNV. This suggests that girls are protected from ASD, unless their mutation burden reaches a tipping point.
"We see a higher burden of autism risk factors in affected females compared to affected males, suggesting that more risk is required for an autism diagnosis in females than males, as would be expected if females were protected," Dr Sanders further explained. "Second, we find that the mutations are distributed randomly across the genes between males and females, suggesting that autism risk factors are the same in both sexes, rather than there being a set of male-only risk genes," he added.
Hopefully, these findings will lead to a greater understanding of autism, which "will allow us to develop therapeutics," Dr Sanders said. "The mutations we find are present in about 10% of individuals with autism. In these individuals, discovering the mutation may give some insight into the child's future development. However, further work is required to clarify the long-term outcomes in the presence of most of these genes."
Loss of Function
In an interview with Medscape Medical News, Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at Children's Hospital of Philadelphia, Pennsylvania, said this study involves a "big dataset and confirms that de novo variants are important. They classify them into two sorts of networks ― genes involved in synaptic transmission, and genes involved with DNA chromatin modeling ― and those genes often can confer damaging functions if they are mutated."
Some of the genes with loss of function variants are "clearly of interest. For these loss of function variants, and sort of these high-impact variants, you could envision intervening, reconstituting function, and fixing the consequences of those variants, but you would only hit on a very trivial number of patients," Dr Hakonarson said.
The study was primarily funded by the Simons Foundation Autism Research Initiative, with additional funding from the National Institute of Mental Health. The authors report no relevant financial relationships.