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

Nature. 2016 Dec 15;540(7633):423-427. doi: 10.1038/nature20612. Epub 2016 Dec 5.


Autism spectrum disorder (ASD) involves substantial genetic contributions. These contributions are profoundly heterogeneous but may converge on common pathways that are not yet well understood. Here, through post-mortem genome-wide transcriptome analysis of the largest cohort of samples analysed so far, to our knowledge, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Autism Spectrum Disorder / genetics*
  • Autopsy
  • Case-Control Studies
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 15 / genetics
  • Exons / genetics
  • Frontal Lobe / metabolism
  • Gene Expression Profiling*
  • Gene Expression Regulation*
  • Genome, Human / genetics*
  • Humans
  • Intellectual Disability / genetics
  • Neurons / metabolism
  • Primates / genetics
  • RNA, Long Noncoding / genetics*
  • SOXD Transcription Factors / metabolism
  • Species Specificity
  • Temporal Lobe / metabolism
  • Transcriptome / genetics


  • RNA, Long Noncoding
  • SOX5 protein, human
  • SOXD Transcription Factors

Supplementary concepts

  • Duplication 15q11-q13 Syndrome