The expanding genomic landscape of autism: discovering the 'forest' beyond the 'trees'

Autism spectrum disorders are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. As autism spectrum disorders are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the 'trees'). However, no single gene can account for more than 1% of the cases of autism spectrum disorders. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively transcribed and may participate in the regulation of genes, including genes on different chromosomes. This article summarizes evidence that suggests that the research spotlight needs to be expanded to encompass far-reaching gene-regulatory mechanisms that include a variety of epigenetic modifications, as well as noncoding RNA (i.e., the 'forest'). Given that noncoding RNA represents over 90% of the transcripts in most cells, we may be observing just the 'tip of the iceberg' or the 'edge of the forest' in the genomic landscape of autism.