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Genetic sequencing yields more than 100 genes linked to autism

In a large genetic sequencing study, researchers identified 102 genes associated with autism spectrum disorder, according to findings presented at the American Society of Human Genetics 2018 annual meeting.

Using this exome sequencing approach, future research may be able to differentiate ASD from intellectual disability/developmental delay genes, according to researchers.

"Being able to look at other disorders in connection to ASD is significant and valuable for being able to explain the genetics behind the variety of possible outcomes within ASD," Jack Kosmicki, PhD candidate in the bioinformatics and integrative genomics program at Harvard University, said in a press release.

Both identifying the genes associated with ASD and understanding their effects in the context of ASD’s heterogeneous phenotypic presentation have been longstanding goals, the researchers noted in the study abstract.

Prior research has focused on de novo variation for gene discovery and has ignored other sources of variation, according to the researchers. Therefore, Kosmicki and colleagues conducted exome sequencing of 37,269 samples from large cohorts worldwide using a Bayesian framework that incorporated de novo and case-control variation and leveraged gene and regional constraint.

The researchers identified 26 genome-wide significant genes and 102 genes connected to autism spectrum disorder.

After performing meta-analyses these results with published de novo variants from 5,264 intellectual disability/developmental delay trios, Kosmicki and colleagues found that 47 of the 102 ASD-associated genes were more strongly linked to intellectual disability/developmental delay than ASD. They explained this was shown by a higher rate of de novo variants identified in individuals with intellectual disability/developmental delay.

Of the other 55 genes discovered, 52 were more strongly related to ASD, while three were equally associated with ASD and intellectual disability/developmental delay. In addition, the genes were identified at a 10% false discovery rate, according to the release.

The study also revealed that comorbid ASD-intellectual disability/developmental delay genes were very different from ASD-preferential genes based on the degree of negative selection, phenotypic presentation and expression from single-cell RNA sequencing in 531 cell-types. On average, patients with ASD who had variants in comorbid ASD-intellectual disability/developmental delay genes walked 2.6 months later and had an IQ 11.7 points lower than patients with a variant in ASD-preferential genes, according to the results.

"With about twice as many samples as any previous studies, we were able to substantially increase the number of genes studied, as well as incorporate recent improvements to the analytical methodology," Mark J. Daly, PhD, chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital, said in the release. "By bringing together data from several existing sources, we hope to create a resource for definitive future analysis of genes associated with ASD." – by Savannah Demko

References:

Kosmicki J, et al. Discovery and characterization of 102 genes associated with autism from exome sequencing of 37,269 individuals. Presented at: The American Society of Human Genetics 2018 Annual Meeting; October 16-20; San Diego.

Disclosure: Healio Psychiatry was unable to confirm any relevant financial disclosures at the time of publication.