Abstract
Most of the genetic risk for autism spectrum disorder (ASD) is inherited as common genetic variants, although some rare mutations have been identified in individuals with ASD. Common genetic variants are most parsimoniously identified by genome wide association studies. Genome wide association studies have identified several genetic loci with genome wide association with ASD. However, genome wide association studies only identify regions of the genome associated with phenotypic traits. Identification of the functional elements requires additional experimental evidence. Here, we demonstrate that a genome wide association study locus for ASD on chromosome 20p12.1, rs4141463, implicates a noncoding RNA as a functional element. Although rs4141463 lies within an intron of the protein-coding MACROD2 (MACRO domain containing 2) gene, expression of MACROD2 is neither altered in postmortem temporal cortex of individuals with ASD nor correlated with rs4141463 genotype. Our bioinformatics approaches revealed a noncoding RNA transcript near the autism susceptibility signal, RPS10P2-AS1 (ribosomal protein S10 pseudogene 2 anti-sense 1). In a panel of 15 human tissues, RPS10P2-AS1 was expressed at higher levels than the protein-coding MACROD2 in both fetal temporal cortex and adult peripheral blood. In postmortem temporal cortex, expression of RPS10P2-AS1 was increased 7-fold in individuals with ASD (P = 0.02) and increased 8-fold in individuals with the ASD-associated rs4141463 genotype (P = 0.01). Further, RPS10P2-AS1 expression was increased in human neural progenitor cells exposed to model air pollutants, indicating that both genetic and environmental factors that contribute to ASD increased RPS10P2-AS1 expression. Overexpression of RPS10P2-AS1 in human neural progenitor cells indicated substantial changes in neuronal gene expression. These data indicate that genome-wide significant associations with ASD implicate long noncoding RNAs. Because long noncoding RNAs are more abundant in human brain than protein-coding RNAs, this class of molecules is likely to contribute to ASD risk.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in social communication and behavioral flexibility (Levitt and Campbell, 2009)
Our data indicate that the long noncoding RNA RPS10P2-AS1, not the protein-coding RNA MACRO domain containing 2 (MACROD2), is a functional element revealed by the genome wide significant association of rs4141463 with autism spectrum disorder (ASD) risk
RPS10P2-AS1 expression is increased in postmortem temporal cortex of individuals with ASD
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is characterized by deficits in social communication and behavioral flexibility (Levitt and Campbell, 2009). The first published GWAS for ASD reported genomewide significant association (P < 5 × 10-8) of genetic markers on chromosome 5p14.1 (Wang et al, 2009) These markers mapped between two protein-coding genes known to be involved in brain development. We later found that overexpression of MSNP1AS in human neural progenitor cells altered neuronal morphology and expression of genes involved in two biological processes: protein synthesis and chromatin remodeling (DeWitt et al, 2016a). The biological processes implicated by altered MSNP1AS expression in human neural progenitor cells are reminiscent of those implicated by rare de novo loss-offunction mutations, and suggest a convergent biology of ASD implicated by divergent genetic association approaches (DeWitt et al, 2016a; DeWitt et al, 2016b)
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