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Autism-Linked Variants at Chromosome 16p Influence Nearby Gene Expression

NEW YORK — Both common and rare genetic variants that influence autism spectrum disorder risk can be traced to a region of chromosome 16, where they affect gene expression, a new study has found.

Researchers from the Broad Institute and elsewhere used a new statistical approach to examine polygenic signals associated with the risk of autism spectrum disorder, finding that there was an excess of such signals in the chromosome 16p region — where a CNV also linked to autism is located. Further, as they reported in Nature Genetics on Monday, they found that both these common and rare genetic variants have similar effects on gene expression throughout the chromosomal region, likely due to patterns of chromatin contact.

"Our results motivate a model of convergent common and rare genetic influences on autism at 16p and more broadly suggest that chromatin contact may facilitate coordinated genetic and transcriptional effects within very large regions of the genome," senior author Elise Robinson from the Broad and her colleagues wrote in their paper.

Previous studies have found that individuals with autism tend to inherit more common polygenic loci associated with the condition than would be expected by chance. Using an approach dubbed stratified polygenic transmission disequilibrium test (S-pTDT), which is based on the trio-based polygenic transmission disequilibrium test, the researchers examined such over-transmission of common autism-linked loci within three different autism trio cohorts. Through this, they uncovered a large cluster of loci on the p-arm of chromosome 16, which harbors 62 genes that are expressed in the brain.

The correlation between autism and loci in this region held after the researchers accounted for the gene-dense nature of chromosome 16p, and they further noted that no one locus drove the association.

This chromosomal region is also home to the 16p11.2 CNV locus, which is associated with autism spectrum disorder. In a series of induced pluripotent stem cell experiments in which CRISPR-Cas9 was used to delete the 16p11.2 locus, the iPSCs differentiated into neurons, but the other genes on chromosome 16p were expressed at lower levels than expected. By contrast, deletions at 15q13.3, which is also recurrently deleted in individuals with autism spectrum disorder, did not lead to transcriptional changes in its nearby genes.

Similarly, the researchers found that individuals with higher regional polygenic scores at chromosome 16p also exhibited decreased expression of genes along that chromosomal arm.

"These transcriptional effects of the 16p11.2 deletion and 16p autism [polygenic scores] were correlated at the level of individual genes on 16p, suggesting mechanistic convergence of common and rare variant influences on autism in the region," the researchers added.

In particular, through Hi-C contact data, they further found that chromosome 16p had higher-than-expected levels of within-region chromatin contacts. This suggested to the researchers that these patterns of contacts could explain why a rare deletion and widespread common variants could lead to similar transcriptional results.

Robinson and colleagues added that their findings raise a number of questions, including why genetic and transcription changes at chromosome 16p are associated with autism spectrum disorder. They noted that while this genomic region has a number of genes that are expressed in the brain, exome studies have not found a higher-than-usual number of genes implicated in autism. "Future studies will probe the biological consequence of modest expression changes spread across many genes," they wrote.