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Autism Spectrum Disorder Studies Uncover Additional Genetic Risk Variants

NEW YORK — A pair of new studies examines genetic variations that confer risk of developing autism spectrum disorder, providing insight into the different phenotypes associated with the disorder.

"Autism is a spectrum and includes individuals with profound autism who often have cognitive differences and/or epilepsy, as well as individuals who are talented and exceptional, often in specific areas," Columbia University Medical Center's Wendy Chung, principal investigator of the Simons Powering Autism Research cohort (SPARK), said in a statement. "We are now appreciating that the genetic contributions to different phenotypes vary in terms of the genes involved; when those genes are activated during brain development; and how common some of the genetic variants are in the population."

In one paper appearing in Nature Genetics, Chung and colleagues identified five new risk genes for developing autism spectrum disorder, four of which they considered moderate risk genes.

The researchers conducted a two-stage analysis of rare de novo and inherited coding variants in sequencing data from more than 42,600 individuals with autism, including about 35,000 cases newly recruited by SPARK. In the first stage, they examined de novo mutations in 16,877 autism spectrum disorder trios and 5,764 unaffected trios as well as rare loss-of-function variants in nearly 20,500 parents who did not have autism or an intellectual disability to select 404 genes for further analysis.

In the second stage, they examined those 404 genes in more than 22,700 people with autism and 236,000 people without autism to home in on 60 genes that contributed to autism risk and that were sensitive to loss-of-function variants. Five of these — NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2 — were novel autism risk genes.

The researchers additionally noted that individuals with autism with loss-of-function variants in the four moderate risk genes they identified — NAV3, ITSN1, SCAF1, and HNRNPUL2 — had lower levels of cognitive impairment than that observed among individuals with autism with loss-of-function variants in highly penetrant genes.

"The majority of parents who passed down these genetic variants in our study do not have cognitive differences or autism, but we know that these genes are associated with autism because we find that these variants are more frequently inherited by children with autism," co-first author Pamela Feliciano from the Simons Foundation said in a statement. "We hypothesized that people with autism who have these inherited genetic variants are not as likely to have seizures and cognitive differences as people with de novo genetic variants. So far our data strongly support[s] this hypothesis."

Meanwhile, in another paper also appearing in Nature Genetics, Michael Talkowski from Massachusetts General Hospital and the Broad Institute and colleagues examined rare coding variation found among individuals with autism spectrum disorder to find overlaps with other neuropsychiatric conditions.

They combined exome sequencing data from 33 different autism spectrum disorder cohorts, including SPARK, to yield data on more than 63,000 individuals, including about 15,000 affected individuals, 28,500 parents, and nearly 5,500 unaffected siblings from family studies as well as nearly 5,600 affected and nearly 8,600 unaffected individuals from case-control analyses. Through this, they tied 72 genes to autism risk. At these genes, copy number variants, as compared to de novo protein-truncating or missense variants, were associated with the highest relative risk, the researchers noted.

In a further meta-analysis that included individuals with developmental delay, the researchers uncovered 373 genes associated with both conditions, though noted that their frequency varied between the conditions. Genes with greater ties to developmental delay were more likely to be expressed by progenitor and immature neuronal cells, whereas genes with greater autism ties were more likely to be involved in neural maturation or to have also been linked to schizophrenia.

"These analyses suggested that most of the genes identified play a role very early in brain development, though the genes with higher mutation rates in autism displayed slightly greater enrichment in more mature excitatory neurons," Talkowski added in a statement.