Through what they claim is the largest genetic sequencing study of autism spectrum disorder (ASD) carried out to date, an international team of researches has identified 102 genes associated with risk for autism, of which 30 represent completely novel risk genes. Their results from the study, involving almost 50,000 individuals, including about 12,000 with ASD, also start to tease apart which genes are associated with ASD and which are associated with intellectual disability and developmental delay, conditions that often overlap.

“This is a landmark study, both for its size and for the large international collaborative effort it required,” stated Joseph D. Buxbaum, PhD, director of the Seaver Autism Center for Research and Treatment at Mount Sinai, and professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. “With these identified genes we can begin to understand what brain changes underlie ASD and begin to consider novel treatment approaches.”

Buxbaum and colleagues report on their study and findings in Cell, in a paper titled, “Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.”

Rare inherited, and spontaneous (de novo) gene variants are major contributors to the risk for ASD, the authors explained. “When such a rare variation disrupts a gene in individuals with ASD more often than expected by chance, it implicates that gene in risk.” Identifying these risk genes provides some insight into the potential mechanisms that underpin ASD, but, as the investigators acknowledged, “ … fundamental questions about the altered neurodevelopment and altered neurophysiology in ASD—including when it occurs, where, and in what cell types—remain poorly resolved.”

For their reported study, collaborating scientists at more than 50 sites around the world collected and analyzed 35,584 participant samples, including 11,986 from individuals with ASD, which represented the largest autism sequencing cohort to date. Obtaining such a large sample was possible through the Autism Sequencing Consortium (ASC), an international group of scientists who share ASD samples and data. Co-founded by Buxbaum in 2010 and originally funded by the Beatrice and Samuel A. Seaver Foundation and the Seaver Autism Center for Research and Treatment at Mount Sinai, the ASC is now a multiple-principal investigator grant funded by the National Institute of Mental Health.

Using an enhanced analytic framework to integrate both rare, inherited genetic mutations and those occurring spontaneously (de novo mutations)—when egg or sperm are formed— the researchers identified 102 genes associated with ASD risk. “Of the 102 ASD-associated genes, 60 were not discovered by our earlier analyses,” they wrote. “These include 30 considered truly novel because they have not been implicated in autosomal dominant neurodevelopmental disorders (ASD, developmental delay, epilepsy, and intellectual disability) and were not significantly enriched for de novo and/or rare variants in previous studies.”

Of those 102 genes highlighted, 49 were also associated with other developmental delays. “Because ASD is often one of a constellation of symptoms of neurodevelopmental delay (NDD), we identify subsets of the 102 ASD-associated genes that have disruptive de novo variants more often in NDD-ascertained or ASD-ascertained cohorts,” they wrote. “Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay (NDD) whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences.”

In addition to identifying subsets of the 102 ASD-associated genes that have disruptive de novo variants more often in people with developmental delays or those with ASD, the researchers showed that ASD genes impact brain development or function, and that both types of disruption can result in autism. They also found that both excitatory, and inhibitory can be affected in autism. “In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD … Single-cell gene expression data from the developing human cortex implicate mid-to-late fetal development and maturing and mature neurons in both excitatory and inhibitory lineages in ASD risk.”

The team subdivided the 102 ASD genes by phenotypic effect—53 genes linked with ASD, and 49 linked with a risk of both ASD and NDD (ASDNDD)—and by functional role, including 58 genes involved in gene expression analysis (GER) and 24 implicated in neuronal communication (NC), including synaptic function. “Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants,” they noted.

The scientists applied statistical analyses to assess the relative prenatal, and postnatal expression bias for each gene. The results indicated that cortically expressed ASD and ASDNDD genes are enriched prenatally, with ASDNDD genes showing more of a prenatal bias. The GER genes also displayed a prenatal bias, and reached their highest levels during early to late fetal development. In contrast, NC genes showed postnatal bias, and were expressed at their highest between late midfetal development and infancy. “Thus, in keeping with prior analyses, ASD genes are expressed at high levels in the human cortex and early in development, the scientists stated. “The differing expression patterns of GER and NC genes could reflect two distinct periods of ASD susceptibility during development or a single susceptibility period when both functional gene sets are highly expressed in mid- to late fetal development.”

“Through our genetic analyses, we discovered that it’s not just one major class of cells implicated in autism, but rather that many disruptions in brain development and in neuronal function can lead to autism,” Buxbaum commented. “It’s critically important that families of children with and without autism participate in genetic studies because genetic discoveries are the primary means to understanding the molecular, cellular, and systems-level underpinnings of autism …We now have specific, powerful tools that help us understand those underpinnings, and new drugs will be developed based on our newfound understanding of the molecular bases of autism.”


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