Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism

Abstract

Gene expression analysis in brain tissue from individuals with and without autism spectrum disorder (ASD) suggests that the transcription factor SOX5 contributes to an ASD-associated reduction in transcriptional differences between brain areas and indicates that common transcriptomic changes occur in different forms of ASD. This paper presents transcriptome-wide RNA sequencing analysis of post-mortem brains of 48 patients with idiopathic autism spectrum disorders (ASD) and 49 control individuals. The authors identify alterations in the noncoding transcriptome, including in primate-specific long noncoding RNAs, and in splicing of activity-dependent neuronal genes in samples of cortex from individuals with ASD cortex. They confirm that the normal transcriptional differences between frontal and temporal cortex are reduced in ASD samples, and provide evidence for a role for the transcription factor SOX5 in this attenuation. Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood1,2,3. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge4,5,6,7, we interrogate the noncoding transcriptome, alternative splicing, and upstream molecular regulators to broaden our understanding of molecular convergence in ASD. Our analysis reveals ASD-associated dysregulation of primate-specific long noncoding RNAs (lncRNAs), downregulation of the alternative splicing of activity-dependent neuron-specific exons, and attenuation of normal differences in gene expression between the frontal and temporal lobes. Our data suggest that SOX5, a transcription factor involved in neuron fate specification, contributes to this reduction in regional differences. We further demonstrate that a genetically defined subtype of ASD, chromosome 15q11.2-13.1 duplication syndrome (dup15q), shares the core transcriptomic signature observed in idiopathic ASD. Co-expression network analysis reveals that individuals with ASD show age-related changes in the trajectory of microglial and synaptic function over the first two decades, and suggests that genetic risk for ASD may influence changes in regional cortical gene expression. Our findings illustrate how diverse genetic perturbations can lead to phenotypic convergence at multiple biological levels in a complex neuropsychiatric disorder.

Cite this article

Parikshak, N., Swarup, V., Belgard, T. et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540, 423–427 (2016). https://doi.org/10.1038/nature20612

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